Network Neuromodulation of Opioid and GABAergic Receptors Following a Combination of "Juvenile" and "Adult Stress" in Rats.

Omer Horovitz,Gilad Ritov,Gal Richter-Levin,Rachel Anunu,Shiri Karni Ashkenazi,Ziv Ardi

doi:10.3390/ijms21155422

Omer Horovitz, Gilad Ritov + Show 4 more

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https://doi.org/10.3390/ijms21155422

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Abstract

Early life stress is suggested to alter behavioral responses during stressful challenges in adulthood and to exacerbate pathological symptoms that reminisce posttraumatic stress disorder (PTSD). These effects are often associated with changes in γ-Aminobutyric acid type A (GABAA) and κ opioid receptor expression and neuromodulation of the limbic system. Anxiety-like and stress coping behaviors were assessed in rats exposed to stress in adulthood on the background of previous exposure to stress in juvenility. Two weeks following behavioral assessment in adulthood, GABAAR α1 and α2 subunits and κ opioid receptor expression levels were measured in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), amygdala, and periaqueductal gray (PAG). To illustrate changes at the network level, an integrated expression profile was constructed. We found that exposure to juvenile stress affected rats’ behavior during adult stress. The combination of juvenile and adult stress significantly affected rats’ long term anxious-like behavior. Probabilities predicting model integrating the expression of GABAA α1-α2 and κ opioid receptors in different brain regions yielded highly successful classification rates. This study emphasizes the ability of exposure to stress in juvenility to exacerbate the impact of coping with stress in adulthood. Moreover, the use of integrated receptor expression network profiling was found to effectively characterize the discussed affective styles and their behavioral manifestations.

Highlights

Posttraumatic stress disorder (PTSD) is a common and disabling disorder that occurs after an exposure to a potentially life-threatening traumatic event
No significant effects were found for juvenile stress alone on anxiety-like behaviors in the Elevated Plus Maze (EPM) (Figure 1) (time spent in open arms, distance traveled open arms, and total distance covered (t(54) = 1.145, n.s; t(54) = 1.271, n.s; and t(54) = 1.578, n.s. respectively))
We used the juvenile stress paradigm in order to examine the combined effect of stress in juvenility and in adulthood on pathologic behaviors and the expression of GABAAR and KOR in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), amygdala, and periaqueductal gray (PAG)

Summary

Introduction

Posttraumatic stress disorder (PTSD) is a common and disabling disorder that occurs after an exposure to a potentially life-threatening traumatic event. Recent years have witnessed a growing interest in the development of effective and valid animal models for the long-term consequences of exposure to stress early in life (ELS). It was previously shown by others and us that an exposure to acute stress in juvenility—a period that is suggested to be of relevance to human childhood [8]—can increase vulnerability to stressful events in adulthood [9,10]. This exposure was associated with an impaired ability of animals to cope with stressful challenges in adulthood, lasting alterations in GABA-ergic functioning and with alterations in levels of circulating corticosterone (for a review, see [11])

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