G9a-Mediated Regulation of OXT and AVP Expression in the Basolateral Amygdala Mediates Stress-Induced Lasting Behavioral Depression and Its Reversal by Exercise

Abstract

Chronic stress produces behavioral depression. Conversely, physical exercise is held to be beneficial in the treatment of depression. Although genomic mechanisms are likely involved in these behavioral changes, underlying mechanisms are not clearly understood. In the present study, we investigated whether stress effects and their reversal by exercise occur via genomic mechanisms in the amygdala, a core part of the limbic system important for regulating mood states. Mice treated with chronic restraint showed lasting depression-like behaviors, which were counteracted by treatment with scheduled forceful exercise. Microarray analysis identified a number of genes whose expression in the amygdala was either upregulated or downregulated after repeated stress, and these changes were reversed by exercise. Of these genes, the neuropeptides oxytocin (OXT) and arginine vasopressin (AVP) were selected as representative stress-induced and exercise-responded genes in the BLA. Stereotaxic injection of OXT or AVP receptor agonists within the BLA in normal mice produced depression-like behaviors, whereas small interfering RNA (siRNA)-mediated suppression of the OXT or AVP transcripts in the BLA was sufficient to block stress-induced depressive behaviors. Stress-induced depression-like behaviors were accompanied by a global reduction of G9a histone methyltransferase and H3K9me2 at the OXT and AVP promoters. Conversely, repeated exercise increased the levels of G9a and H3K9me2 at the OXT and AVP promoters in the BLA, which was associated with the suppression of OXT and AVP expressions. These results identify G9a-induced histone methylation at the OXT and AVP promoters in the BLA as a mechanism for mediating stress-induced lasting behavioral depression and its reversal by exercise.

Physical Exercise Counteracts Stress-induced Upregulation of Melanin-concentrating Hormone in the Brain and Stress-induced Persisting Anxiety-like Behaviors

“…Scheduled repeated restraints were performed as described previously [3132]. In brief, mice were individually placed in a 50-ml conical tube with many holes for good ventilation and were restrained within this tube for 2 h daily beginning at 10 a.m. After each session of restraint, the mice were returned to their home cages and allowed to have free access to food and water.…”

“…Passive wheel-running exercise was performed as described previously [3132]. In brief, the running wheel consisted of a rotating drum with two circular ventilated plastic walls (20 cm, in inner diameter) with a rim (7 cm, in width) composed of evenly spaced aluminum bars (each 2 mm in width, spaced by 0.65 cm).…”

“…Real-time PCR for the quantification of mRNA levels was carried out as described previously [3132]. Total RNA from tissue samples or cell cultures was purified with TRI reagent (15596-018, Invitrogen, CA, USA).…”

“…Behavioral tests were performed as described previously [313235]. Mice were brought to the testing room 30 min prior to the start of each behavioral test.…”

“…The social interaction test was performed as described previously [3234]. In brief, a U-shaped field was prepared by partitioning an open field (45×45×40 cm) to the central point with a wall (20×40 cm, width by height), so that each field had one enclosed and one open square.…”