Maternal separation enhances conditioned fear and decreases the mRNA levels of the neurotensin receptor 1 gene with hypermethylation of this gene in the rat amygdala.
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.
Department of Psychiatry, National Defense Medical College, Tokorozawa, Japan; Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Hiroyuki
H
Toda
Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, New York, United States of America.
Shuken
S
Boku
Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Shin
S
Nakagawa
Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Takeshi
T
Inoue
Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Akiko
A
Kato
Pharmaceutical Laboratories, Dainippon Sumitomo Pharma Co. Ltd., Osaka, Japan.
Naoki
N
Takamura
Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan; Department of Psychiatry, The first hospital of China Medical University, Shenyang, China.
Ning
N
Song
Department of Psychiatry, National Defense Medical College, Tokorozawa, Japan.
Masashi
M
Nibuya
Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Tsukasa
T
Koyama
Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Ichiro
I
Kusumi
D000679:Amygdala / Q000378:metabolism*; D000818:Animals; D001007:Anxiety; D001483:Base Sequence; D003214:Conditioning, Classical / Q000502:physiology*; D003346:Corticotropin-Releasing Hormone / Q000737:chemistry; D019175:DNA Methylation; D003907:Dexamethasone / Q000737:chemistry; D044127:Epigenesis, Genetic; D005239:Fear / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System; D008297:Male; D018782:Maze Learning; D008568:Memory; D008969:Molecular Sequence Data; D009035:Mothers; D009496:Neurotensin / Q000378:metabolism; D010913:Pituitary-Adrenal System; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018028:Receptors, Neurotensin / Q000235:genetics / Q000502:physiology*
D012333:RNA, Messenger; D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor; D009496:Neurotensin; D003907:Dexamethasone; D003346:Corticotropin-Releasing Hormone