The Medial Prefrontal Cortex, Nucleus Accumbens, Basolateral Amygdala, and Hippocampus Regulate the Amelioration of Environmental Enrichment and Cue in Fear Behavior in the Animal Model of PTSD

Abstract

A growing body of evidence showed that environmental enrichment (EE) ameliorated footshock-induced fear behavior of posttraumatic stress disorder (PTSD). However, no research comprehensively tested the effect of EE, cue, and the combination of EE and cue in footshock-induced fear behavior of PTSD symptoms. The present study addressed this issue and examined whether the medial prefrontal cortex (mPFC, including the cingulate cortex 1 (Cg1), prelimbic cortex (PrL), and infralimbic cortex (IL)), the nucleus accumbens (NAc), the basolateral amygdala (BLA), and the hippocampus (e.g., CA1, CA3, and dentate gyrus (DG)) regulated the amelioration of the EE, cue, or the combination of EE and cue. The results showed that EE or cue could reduce fear behavior. The combination of EE and cue revealed a stronger decrease in fear behavior. The cue stimulus may play an occasion setting or a conditioned stimulus to modulate the reduction in fear behavior induced by footshock. Regarding the reduction of the EE in fear behavior, the Cg1 and IL of the mPFC and the NAc upregulated the c-Fos expression; however, the BLA downregulated the c-Fos expression. The mPFC (i.e., the Cg1, PrL, and IL) and the hippocampus (i.e., the CA1, CA3, and DG) downregulated the c-Fos expression in the suppression of the cue in fear behavior. The interaction of EE and cue in reduction of fear behavior occurred in the Cg1 and NAc for the c-Fos expression. The data of c-Fos mRNA were similar to the findings of the c-Fos protein expression. These findings related to the EE and cue modulations in fear behavior may develop a novel nonpharmacological treatment in PTSD.

The systemic effects of the enriched environment on the conditioned fear reaction

“…Facilitation of CFR due to increased activity of CS under the EE conditions has not been manifested in many experiments ( Rampon et al, 2000 ; Duffy et al, 2001 ; Tang et al, 2001 ; Barbelivien et al, 2006 ; Pavlova et al, 2023 ). At the same time, a lot of data demonstrating a link between the effects of EE and contextual fear memory were obtained, although these data had contradictory results ( Rampon et al, 2000 ; Benaroya-Milshtein et al, 2004 ; Hendriksen et al, 2010 ; Lee and Noh, 2016 ; Sun et al, 2016 ; Sukegawa et al, 2022 ; Yu et al, 2022 ). For example, the percentage of freezing time of rats housed in the EE was much less in a neutral context than in the context where animals were experienced with the paired CS-US stimulations ( Barbelivien et al, 2006 ).…”

“…The lowest percentage of freezing time was seen in the EE-EE group (1%), then in the STAND-EE group (2%), while in the STAND-STAND group the freezing time was much higher (12%). In the study of Yu et al (2022) , mice exposed to the EE (from birth to PND 17) showed a significant decrease of CFR in the context where they received a single CS-US pairing with a strong US (2 mA, 10 s). In three successive extinction trials (PNDs 18–20), all mice showed a progressive decrease in CFR, but the mice housed in the EE extinguished the CFR much quicker than animals of the STAND group.…”

“…In the females of the EE group, the freezing time in the context, but not for CS, was shorter than in the rats of the STAND group. The interesting results on mice were obtained by Yu et al (2022). The EE groups were subjected to the enrichment procedure on days 0-17.…”

“…Animal experiments have shown a protective and preventive effect of EE on the development of anxiety-depressive and cognitive disorders ( Laviola et al, 2008 ; Hannan, 2014 ; Guan et al, 2021 ; Ji et al, 2022 ; Xu et al, 2022 ; Zhang et al, 2022 ) caused by prenatal and neonatal stressors (e.g., bacterial intoxication, maternal separation, etc.). EE also counteracts the development of negative consequences of severe stress like post-traumatic stress disorder ( Imanaka et al, 2006 ; Smail et al, 2020 ; Yu et al, 2022 ). It slows down the development and alleviates the course of Alzheimer’s disease ( Sommerlad et al, 2019 ; Li et al, 2021 ; Liew et al, 2022 ; Colavitta et al, 2023 ), Parkinson’s disease ( Jungling et al, 2017 ; Alarcón et al, 2023 ), Huntington’s disease ( Spires et al, 2004 ; Novati et al, 2022 ), autism spectrum disorders ( Aronoff et al, 2016 ) and other pathologies.…”

Panicolytic‐like effects of environment enrichment on male mice threatened by Bothrops jararaca lancehead pit vipers

“…The power of a positive environment cannot be underestimated when it comes to treating fear‐related psychiatric disorders (Imanaka et al., 2006). Indeed, it was demonstrated that several limbic structures involved with defensive behaviors and related emotions in mammals (de Mello et al., 2022; Graeff, 1994; Ullah et al., 2015) are recruited to regulate the amelioration of environmental enrichment and cue in fear behavior in an animal model of post‐traumatic stress disorder (Yu et al., 2022), and there is evidence for enhancement of hippocampal neurons in adult rodents submitted to an environment enrichment (Kempermann et al., 1997). Controversely, a decrease in hippocampal volume was also reported in a mouse experimental model of post‐traumatic stress disorder (Golub et al., 2011).…”