N-3 PUFA ameliorated bone loss induced by postmenopausal depression following exposure to chronic mild stress and maternal separation by regulating neuronal processes

Abstract Objectives The purpose of the present study was to investigate the hypothesis that lifetime n-3 polyunsaturated fatty acids (PUFA) intake improved depression through serotonergic pathway in post-menopausal rats with chronic mild stress (CMS) and maternal separation (MS). Methods Female rats were fed diets with 0% or 1 energy % n-3 PUFA during lifetime from embryonic day (ED) 0 to postnatal day (PND) 112, or 1% n-3 PUFA before weaning (ED 0-PND 20), or after weaning (PND 20–112). The rats in four diet group were allocated to brief separation from dam (non-MS group) or long-term separation (MS group) on PND 2–14, and then underwent CMS on PND 91–105 after ovariectomy. Thus, there were eight groups in total (n = 8/group). Results MS + CMS increased depressive behaviors, and modified hypothalamic-pituitary-adrenal (HPA) axis activity, inflammation, serotonergic and glutamatergic neurotransmission, and related miRNAs as compared to CMS alone. N-3 PUFA decreased depressive behaviors by decreasing immobility while increasing swimming during forced swim test, and increasing sucrose preference in rats with MS + CMS and with CMS. N-3 PUFA decreased HPA axis activity by modifying expressions of corticotrophin releasing factor and glucocorticoid receptor, and levels of adrenocorticotropic hormone and corticosterone. N-3 PUFA also reduced levels of TNF-α, IL-1β, IL-6, PGE2, and miRNA-218, and increased serotonergic neurotransmission, including expressions of cAMP response element binding protein, brain-derived neurotrophic factor and serotonin 1A receptor, and serotonin level, and expression of miRNA-155. In addition, lifetime supplementation of n-3 PUFA had greater effect than pre- or post-supplementation. N-3 PUFA had no effect on glutamatergic pathway including α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor and N-methyl-D-aspartate receptor. Conclusions The present study suggested that lifetime n-3 PUFA improved depression in post-menopausal rats with MS + CMS through modulation of serotonergic pathway by decreasing HPA axis activity but not glutamatergic pathway. Funding Sources This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF-2018R1A2B6002486).

Download Full-text

Chewing ameliorates chronic mild stress-induced bone loss in senescence-accelerated mouse (SAMP8), a murine model of senile osteoporosis

Experimental Gerontology ◽

10.1016/j.exger.2014.03.003 ◽

2014 ◽

Vol 55 ◽

pp. 12-18 ◽

Cited By ~ 16

Author(s):

Manabu Furuzawa ◽

Huayue Chen ◽

Shu Fujiwara ◽

Kumiko Yamada ◽

Kin-ya Kubo

Keyword(s):

Bone Loss ◽

Murine Model ◽

Chronic Mild Stress ◽

Mild Stress ◽

Senile Osteoporosis ◽

Senescence Accelerated Mouse

Download Full-text

Chronic Mild Stress Causes Bone Loss via an Osteoblast-Specific Glucocorticoid-Dependent Mechanism

Endocrinology ◽

10.1210/en.2016-1658 ◽

2017 ◽

Vol 158 (6) ◽

pp. 1939-1950 ◽

Cited By ~ 5

Author(s):

Holger Henneicke ◽

Jingbao Li ◽

Sarah Kim ◽

Sylvia J. Gasparini ◽

Markus J. Seibel ◽

...

Keyword(s):

Bone Loss ◽

Chronic Stress ◽

Structural Parameters ◽

Chronic Mild Stress ◽

Bone Resorption Marker ◽

Mild Stress ◽

Male Mice ◽

Female Mice ◽

Glucocorticoid Signaling ◽

The Impact

Abstract Chronic stress and depression are associated with alterations in the hypothalamic–pituitary–adrenal signaling cascade and considered a risk factor for bone loss and fractures. However, the mechanisms underlying the association between stress and poor bone health are unclear. Using a transgenic (tg) mouse model in which glucocorticoid signaling is selectively disrupted in mature osteoblasts and osteocytes [11β-hydroxysteroid-dehydrogenase type 2 (HSD2)OB-tg mice], the present study examines the impact of chronic stress on skeletal metabolism and structure. Eight-week-old male and female HSD2OB-tg mice and their wild-type (WT) littermates were exposed to chronic mild stress (CMS) for the duration of 4 weeks. At the endpoint, L3 vertebrae and tibiae were analyzed by micro–computed tomography and histomorphometry, and bone turnover was measured biochemically. Compared with nonstressed controls, exposure to CMS caused an approximately threefold increase in serum corticosterone concentrations in WT and HSD2OB-tg mice of both genders. Compared with controls, CMS resulted in loss of vertebral trabecular bone mass in male WT mice but not in male HSD2OB-tg littermates. Furthermore, both tibial cortical area and area fraction were reduced in stressed WT but not in stressed HSD2OB-tg male mice. Osteoclast activity and bone resorption marker were increased in WT males following CMS, features absent in HSD2OB-tg males. Interestingly, CMS had little effect on vertebral and long-bone structural parameters in female mice. We conclude that in male mice, bone loss during CMS is mediated via enhanced glucocorticoid signaling in osteoblasts (and osteocytes) and subsequent activation of osteoclasts. Female mice appear resistant to the skeletal effects of CMS.

Download Full-text

Maternal Separation Followed by Chronic Mild Stress in Adulthood Is Associated with Concerted Epigenetic Regulation of AP-1 Complex Genes

Journal of Personalized Medicine ◽

10.3390/jpm11030209 ◽

2021 ◽

Vol 11 (3) ◽

pp. 209

Author(s):

Lene Lundgaard Donovan ◽

Kim Henningsen ◽

Anne Flou Kristensen ◽

Ove Wiborg ◽

John Dirk Nieland ◽

...

Keyword(s):

Gene Expression ◽

Maternal Separation ◽

Chronic Mild Stress ◽

Mild Stress ◽

Psychiatric Diseases ◽

Gene Promoters ◽

Early Deprivation ◽

Regulation Of Expression ◽

History Of ◽

Deprivation Model

Depression is one of the most prevalent mental diseases worldwide. Patients with psychiatric diseases often have a history of childhood neglect, indicating that early-life experiences predispose to psychiatric diseases in adulthood. Two strong models were used in the present study: the maternal separation/early deprivation model (MS) and the chronic mild stress model (CMS). In both models, we found changes in the expression of a number of genes such as Creb and Npy. Strikingly, there was a clear regulation of expression of four genes involved in the AP-1 complex: c-Fos, c-Jun, FosB, and Jun-B. Interestingly, different expression levels were observed depending on the model, whereas the combination of the models resulted in a normal level of gene expression. The effects of MS and CMS on gene expression were associated with distinct histone methylation/acetylation patterns of all four genes. The epigenetic changes, like gene expression, were also dependent on the specific stressor or their combination. The obtained results suggest that single life events leave a mark on gene expression and the epigenetic signature of gene promoters, but a combination of different stressors at different life stages can further change gene expression through epigenetic factors, possibly causing the long-lasting adverse effects of stress.

Download Full-text

MicroRNA-99a is a Potential Target for Regulating Hypothalamic Synaptic Plasticity in the Peri/Postmenopausal Depression Model

Cells ◽

10.3390/cells8091081 ◽

2019 ◽

Vol 8 (9) ◽

pp. 1081 ◽

Cited By ~ 3

Author(s):

Jin Yang ◽

Ling Zhang ◽

Lu-Lu Cao ◽

Jun Qi ◽

Ping Li ◽

...

Keyword(s):

Synaptic Plasticity ◽

Nuclear Translocation ◽

Chronic Mild Stress ◽

Synaptic Proteins ◽

Mild Stress ◽

Fk506 Binding Protein ◽

Electrophysiological Recordings ◽

Menopausal Women ◽

Serum Hormone ◽

Postmenopausal Depression

Accumulating evidence has demonstrated that there is a growing trend of menopausal women suffering from depression. However, the pathogenesis of menopausal depression still remains unclear. Hence, this paper aims to reveal the pathological mechanisms involved in postmenopausal depression by using a novel peri- to postmenopausal depression model induced by a two-step ovariectomy plus chronic mild stress (CMS). The results of metabolic chambers and serum hormone/cytokine determination revealed that peri/postmenopausal depressive mice exhibited endocrine and metabolic disorders. Electrophysiological recordings indicated that the hippocampal synaptic transmission was compromised. Compared to the sham group, the microRNA-99a (miR-99a) level decreased significantly in the hypothalamus, and its target FK506-binding protein 51 (FKBP51) enormously increased; in contrast, the nuclear translocation of the progesterone receptor (PR) decreased in hypothalamic paraventricular nucleus (PVN) in the peri/postmenopausal depression mouse model. Additionally, synaptic proteins, including postsynaptic density protein 95 (PSD-95) and synaptophysin (SYN), showed a similar decrease in the hypothalamus. Accordingly, the present work suggests that miR-99a may be involved in the regulation of hypothalamic synaptic plasticity and that it might be a potential therapeutic target for peri/postmenopausal depression.

Download Full-text