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

Abstract

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. relieves symptoms in some patients: estrogen administered along with antidepressants [8] could give rise to detrimental effects [9,10]. Due to the lack of clarity in the current forms of treatment, there is an urgent need to determine the underlying pathogenesis of menopausal depression and to identify new therapeutic drugs.There is a strong association between depression and metabolic syndrome. The nervous and endocrine systems orchestrate adaptive responses to stressful stimuli involving behavioral, emotional, and metabolic alterations [11]. Metabolic disorders, such as obesity and diabetes, are associated with elevated rates of depression [12]. Depression is often associated with increased hypothalamic-pituitary-adrenal (HPA) axis activity and increased levels of glucocorticoids. In particular, increased levels of circulating proinflammatory cytokines and concomitant inflammation activation such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) in the brain and blood can lead to depressive symptoms. Several studies have revealed that repeated environmental or psychosocial stress gives rise to synaptic plasticity deficits and neurotransmitter dysregulation, resulting in depressive-like behavior [13].Synaptic plasticity, one of the most fundamental brain functions, has recently been found to be an indispensable target in treating depression [14]. Mounting evidence has suggested that stress has profound effects on synaptic forms and functions [15]. Synaptic plasticity includes both structure and transmission plasticity. Studies have indicated that postsynaptic density (PSD) molecules, such as PSD-95, ar...

Sex and age influence gonadal steroid hormone receptor distributions relative to estrogen receptor β‐containing neurons in the mouse hypothalamic paraventricular nucleus

“…However, expression of PR mRNA measured by in situ hybridization in magnocellular divisions of the female rat PVN (Thomas et al, 1999) indicates that PR is expressed in specific PVN subregions in both rat and mouse. Functionally, PRs are coupled to stress responses in male (Romeo et al, 2005) and female (Yang et al, 2019) rodents,…”

Applications of Acupuncture Therapy in Modulating the Plasticity of Neurodegenerative Disease and Depression: Do MicroRNA and Neurotrophin BDNF Shed Light on the Underlying Mechanism?

“…The literature also suggests that late-life depressive symptoms are associated with downregulation of prefrontal cortex miR-484, which is related to synaptic transmission [ 117 ]. In addition, miR-99a may be involved in the regulation of hypothalamic synaptic plasticity and might be a potential therapeutic target for peri/postmenopausal depression [ 118 ].…”

<p>MicroRNA-Based Biomarkers in the Diagnosis and Monitoring of Therapeutic Response in Patients with Depression</p>

“…However, to the best of our knowledge, only one study has focused on the altered status of hypothalamic miRNAs in an animal depression model. 53 The results showed that, compared with the sham group, the miR-99a level decreased significantly in the hypothalamus during "postmenopausal depression" by using a novel "perito postmenopausal depression" model induced by a two-step ovariectomy plus chronic mild stress (CMS). 53 Structural and functional imaging studies have shown that the prefrontal cortex (PFC) plays an important role in the regulation of emotion and is related to some neurobiological abnormalities involved in the pathophysiology of depression and suicide.…”

“…53 The results showed that, compared with the sham group, the miR-99a level decreased significantly in the hypothalamus during "postmenopausal depression" by using a novel "perito postmenopausal depression" model induced by a two-step ovariectomy plus chronic mild stress (CMS). 53 Structural and functional imaging studies have shown that the prefrontal cortex (PFC) plays an important role in the regulation of emotion and is related to some neurobiological abnormalities involved in the pathophysiology of depression and suicide. 54,55 Several human studies have examined whether the miRNA network is altered in the PFC of depressed suicide subjects.…”