Contextual Fear Memory Maintenance Changes Expression of pMAPK, BDNF and IBA-1 in the Pre-limbic Cortex in a Layer-Specific Manner.

Nicholas Chaaya,Andrew Raymond Battle,Joshua Wang,Michael Chaaya,Selena E Bartlett,Luke R Johnson,Arnauld Belmer,Kate Beecher,Angela Jacques,Fatemeh Chehrehasa

doi:10.3389/fncir.2021.660199

Abstract

Post-traumatic stress disorder (PTSD) is a debilitating and chronic fear-based disorder. Pavlovian fear conditioning protocols have long been utilised to manipulate and study these fear-based disorders. Contextual fear conditioning (CFC) is a particular Pavlovian conditioning procedure that pairs fear with a particular context. Studies on the neural mechanisms underlying the development of contextual fear memories have identified the medial prefrontal cortex (mPFC), or more specifically, the pre-limbic cortex (PL) of the mPFC as essential for the expression of contextual fear. Despite this, little research has explored the role of the PL in contextual fear memory maintenance or examined the role of neuronal mitogen-activated protein kinase (pMAPK; ERK 1/2), brain-derived neurotrophic factor (BDNF), and IBA-1 in microglia in the PL as a function of Pavlovian fear conditioning. The current study was designed to evaluate how the maintenance of two different long-term contextual fear memories leads to changes in the number of immune-positive cells for two well-known markers of neural activity (phosphorylation of MAPK and BDNF) and microglia (IBA-1). Therefore, the current experiment is designed to assess the number of immune-positive pMAPK and BDNF cells, microglial number, and morphology in the PL following CFC. Specifically, 2 weeks following conditioning, pMAPK, BDNF, and microglia number and morphology were evaluated using well-validated antibodies and immunohistochemistry (n = 12 rats per group). A standard CFC protocol applied to rats led to increases in pMAPK, BDNF expression and microglia number as compared to control conditions. Rats in the unpaired fear conditioning (UFC) procedure, despite having equivalent levels of fear to context, did not have any change in pMAPK, BDNF expression and microglia number in the PL compared to the control conditions. These data suggest that alterations in the expression of pMAPK, BDNF, and microglia in the PL can occur for up to 2 weeks following CFC. Together the data suggest that MAPK, BDNF, and microglia within the PL of the mPFC may play a role in contextual fear memory maintenance.

Highlights

Post-traumatic stress disorder (PTSD) is a debilitating and enduring fear-based disorder, typically associated with many cycles of relapse (Boschen et al, 2009; Maren, 2011)
To confirm that the fear conditioning procedures produced long-term behavioural alterations, the number of time rats displayed freezing behaviour during training and testing was quantified as a function of condition
This study investigated the relative contribution of the pre-limbic cortex (PL) in the medial prefrontal cortex (mPFC) in the long-term maintenance of contextual fear memories by examining changes in expression of Brain derived neurotrophic factor (BDNF), neuronal pMAPK, and microglial IBA-1

Summary

Introduction

Post-traumatic stress disorder (PTSD) is a debilitating and enduring fear-based disorder, typically associated with many cycles of relapse (Boschen et al, 2009; Maren, 2011). The contextual component of fear allows for the long-term storage of fear memories and can prevent the extinction of such memories (Maren, 2011). In animals, such as rodents, this contextual component can be manipulated and studied via the use of Pavlovian fear conditioning protocols (Foa et al, 1992; Rothbaum and Davis, 2003; Fanselow, 2010; LeDoux, 2014; Chaaya et al, 2018). Additional research has identified numerous other brain regions to be involved in CFC, one being the medial prefrontal cortex (mPFC; Gilmartin et al, 2014; Rozeske et al, 2015)

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