Abstract
Early-life stress in adolescence has a long-lasting influence on brain function in adulthood, and it is mostly recognized as a predisposing factor for mental illnesses, such as anxiety and posttraumatic stress disorder. Previous studies also indicated that adolescent predictable chronic mild stress (PCMS) in early life promotes resilience to depression- and anxiety-like behaviors in adulthood. However, the role of PCMS in associated memory process is still unclear. In the present study, we found that adolescent PCMS facilitated extinction and inhibited fear response in reinstatement and spontaneous recovery tests in adult rats, and this effect was still present 1 week later. PCMS in adolescence increased the activity of brain-derived neurotrophic factor (BDNF)-extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in infralimbic cortex (IL) but not prelimbic cortex in adulthood. Intra-IL infusion of BDNF antibody and the ERK1/2 inhibitor U0126 reversed PCMS-induced enhancement of fear extinction. Moreover, we found that PCMS decreased DNA methylation of the Bdnf gene at exons IV and VI and elevated the mRNA levels of Bdnf in the IL. Our findings indicate that adolescent PCMS exposure promotes fear memory extinction in adulthood, which reevaluates the traditional notion of adolescent stress.
Highlights
Excessive fear and anxiety are hallmarks of anxiety disorders, such as posttraumatic stress disorder (PTSD)
The Tukey’s post hoc test revealed that predictable chronic mild stress (PCMS), Chronic restrain stress (CRS), and chronic unpredictable stress (CUS) had no effects on locomotor activities
We investigated whether PCMS, CRS and CUS during adolescence impacted the acquisition, short-term memory (STM) and long-term memory (LTM) of contextual fear conditioning
Summary
Excessive fear and anxiety are hallmarks of anxiety disorders, such as posttraumatic stress disorder (PTSD). Promoting extinction memory and preventing return of fear response is a prominent strategy to relieve fear-induced anxieties[6]. Life stress and chronic exposure to corticosterone impair fear conditioning and extinction[13, 14]. Chronic restrain stress (CRS) slows fear extinction and enhances anxiety-like behavior[16]. Our previous study suggested that adolescent PCMS had positive effects on brain functions and enhanced resistance to stress-induced depressive-like behavior www.nature.com/scientificreports/. Unknown is the effect of adolescent PCMS experience on fear conditioning and extinction in adulthood. BDNF ameliorates CRS-induced impairments in spatial memory[28] and its expression is inhibited by adolescent CUS exposure[15]. We investigated whether PCMS exposure during adolescence promotes fear conditioning and extinction in adulthood. The underlying mechanisms concerning BDNF signaling and DNA methylation of Bdnf were explored
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