Abstract
Stress during postnatal development is associated with an increased risk for depression, anxiety disorders, and substance abuse later in life, almost as if mental illness is able to be programed by early life stressors. Recent studies suggest that such “programmed” effects can be caused by epigenetic regulation. With respect to conditioned fear, previous studies have indicated that early life stress influences its development in adulthood, whereas no potential role of epigenetic regulation has been reported. Neurotensin (NTS) is an endogenous neuropeptide that has receptors densely located in the amygdala and hippocampus. Recently, NTS systems have constituted an emerging target for the treatment of anxiety. The aim of the present work is to clarify whether the NTS system is involved in the disturbance of conditioned fear in rats stressed by maternal separation (MS). The results showed that MS enhanced freezing behaviors in fear-conditioned stress and reduced the gene expression of NTS receptor (NTSR) 1 but not of NTS or NTSR2 in the amygdalas of adult rats. The microinjection of a NTSR1 antagonist into the amygdala increased the percentage of freezing in conditioned fear, whereas the microinjection of NTSR1 agonist decreased freezing. These results suggest that NTSR1 in the amygdala may play a role in the effects of MS on conditioned fear stress in adult rats. Moreover, MS increased DNA methylation in the promoter region of NTSR1 in the amygdala. Taken together, MS may leave epigenetic marks in the NTSR1 gene in the amygdala, which may enhance conditioned fear in adulthood. The MS-induced alternations of DNA methylation in the promoter region of NTSR1 in the amygdala may be associated with vulnerability to the development of anxiety disorders and depression in adulthood.
Highlights
Past clinical studies have shown that exposure to stress during the postnatal development periods is associated with an increased risk for depression, anxiety disorders, and substance abuse later in life [1,2]
We have shown that maternal separation (MS) enhances conditioned fear in adulthood and increases the DNA methylation in the promoter region on the NTSR1 gene in AMY
The pharmacological blockade of NTSR1 in AMY activated conditioned fear, whereas the activation of NTSR1 disrupted it. These findings suggest that MS may enhance conditioned fear via DNA methylation of the promoter region of NTSR1 in AMY, underlying its decreased mRNA expression
Summary
Past clinical studies have shown that exposure to stress during the postnatal development periods is associated with an increased risk for depression, anxiety disorders, and substance abuse later in life [1,2]. Other mammals suffering from early life stress (ELS) in the postnatal period have a vulnerability towards anxiety states and depression-like syndromes [3,4,5,6,7]. These findings suggest that variations in one’s early environment may be associated with changes in gene expression and biological function that persist into adulthood. Such ‘‘programmed’’ effects may derive from epigenetic regulation, which causes structural alterations in genomic DNA [4,8]. With respect to conditioned fear, previous studies have indicated that ELS continues its influence into adulthood [13,14]; no potential role of epigenetic regulation in fear learning and memory caused by ELS has been reported
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