MiR-153 downregulation alleviates PTSD-like behaviors and reduces cell apoptosis by upregulating the Sigma-1 receptor in the hippocampus of rats exposed to single-prolonged stress.

Posttraumatic stress disorder (PTSD) is a psychiatric disorder that may lead to a series of changes in the central nervous system, including impaired synaptic plasticity, neuronal dendritic spine loss, enhanced apoptosis and increased inflammation. However, the specific mechanism of PTSD has not been studied clearly. In the present study, we found that the level of miR-153-3p in the hippocampus of rats exposed tosingle-prolonged stresss (SPS) was upregulated, but its downstream target σ-1R showed a significant decrease. The downregulation of miR-153 could alleviate the PTSD-like behaviors in the rats exposed to SPS, and this effect might be related to the upregulation of σ-1R and PSD95. Furthermore, anti-miR-153 could also increase the dendritic spine density and reduce cell apoptosis in the hippocampus of SPS rats. In addition, we showed that the mTOR signaling pathway might be involved in the regulation of σ-1R in the hippocampus of rats exposed to SPS. The results of this study indicated that miR-153 might alleviate PTSD-like behaviors by regulating cell morphology and reducing cell apoptosis in the hippocampus of rats exposed to SPS by targeting σ-1R, which might be related to the mTOR signaling pathway.

miR-142 downregulation alleviates the impairment of spatial learning and memory, reduces the level of apoptosis, and upregulates the expression of pCaMKII and BAI3 in the hippocampus of APP/PS1 transgenic mice.

MicroRNA-142-5p (miR-142-5p) has been found to be dysregulated in several neurodegenerative disorders. However, little is known about the involvement of miR-142-5p in Alzheimer's disease (AD). Brain angiogenesis inhibitor 3 (BAI3), which belongs to the adhesion-G protein-coupled receptor subgroup, contributes to a variety of neuropsychiatric disorders. Despite its very high expression in neurons, the role of BAI3 in AD remains elusive, and its mechanism at the cellular and molecular levels needs to be further elucidated. The current study sought to investigate whether miR-142-5p influenced BAI3 expression and neuronal synaptotoxicity induced by Aß, both in APP/PS1 transgenic mice and a cellular model of Alzheimer's disease. Altered expression of miR-142-5p was found in the hippocampus of AD mice. Inhibition of miR-142 could upregulate BAI3 expression, enhance neuronal viability and prevent neurons from undergoing apoptosis. In addition, the reduction of phosphorylation of Synapsin I and calcium/calmodulin-dependent protein kinase II (CaMKII), as well as the expression of PSD-95 in the hippocampus of APP/PS1 transgenic mice, were significantly restored by inhibiting miR-142. Meanwhile, the levels of Aß1-42, ß-APP, BACE-1 and PS-1 in cultured neurons were detected, and the effects of inhibiting miR-142 on spatial learning and memory were also observed. Interestingly, we found that BAI3, an important regulator of excitatory synapses, was a potential target gene of miR-142-5p. Collectively, our findings suggest that miR-142 inhibition can alleviate the impairment of spatial learning and memory, reduce the level of apoptosis, and upregulate the expression of pCaMKII and BAI3 in the hippocampus of APP/PS1 transgenic mice; thus, appropriate interference of miR-142 may provide a potential therapeutic approach to rescue cognitive dysfunction in AD patients.

miR-142 downregulation alleviates rat PTSD-like behaviors, reduces the level of inflammatory cytokine expression and apoptosis in hippocampus, and upregulates the expression of fragile X mental retardation protein.

BACKGROUND: FMRP is a selective mRNA-binding protein that regulates protein synthesis at synapses, and its loss may lead to the impairment of trace fear memory. Previously, we found that FMRP levels in the hippocampus of rats with post-traumatic stress disorder (PTSD) were decreased. However, the mechanism underlying these changes remains unclear. METHODS: Forty-eight male Sprague-Dawley rats were randomly divided into four groups. The experimental groups were treated with the single-prolonged stress (SPS) procedure and injected with a lentivirus-mediated inhibitor of miR-142-5p. Behavior test as well as morphology and molecular biology experiments were performed to detect the effect of miR-142 downregulation on PTSD, which was further verified by in vitro experiments. RESULTS: We found that silence of miRNA-142 (miR-142), an upstream regulator of FMRP, could alleviate PTSD-like behaviors of rats exposed to the SPS paradigm. MiR-142 silence not only decreased the levels of proinflammatory mediators, such as interleukin-1ß, interleukin-6, and tumor necrosis factor-α, but also increased the expressive levels of synaptic proteins including PSD95 and synapsin I in the hippocampus, which was one of the key brain regions associated with PTSD. We further detected that miR-142 silence also downregulated the transportation of nuclear factor kappa-B (NF-κB) into the nuclei of neurons and might further affect the morphology of neurons. CONCLUSIONS: The results revealed miR-142 downregulation could alleviate PTSD-like behaviors through attenuating neuroinflammation in the hippocampus of SPS rats by binding to FMRP.

miR-132 Regulates PTSD-like Behaviors in Rats Following Single-Prolonged Stress Through Fragile X-Related Protein 1.

Fragile X-related protein 1 (FXR1) is a member of the fragile X family of RNA-binding proteins, which regulates a number of neurological and neuropsychiatric disorders such as fragile X syndrome, and is expected as a novel therapeutic target for some psychiatric diseases. However, it is unknown how FXR1 changes and functions in post-traumatic stress disorder (PTSD), a common mental disorder related to trauma and stressor. In this study, we characterized the expression pattern of FXR1 in the pathophysiological process of PTSD and further investigated the possible mechanism underlying these changes by finding an upstream regulator, namely miRNA-132 (miR-132). Furthermore, we verified whether miR-132 silence had an effect on the PTSD-like behaviors of single prolonged stress (SPS) rats through open field test, forced swimming test, and water maze test. At last, we examined the expression levels of PSD95 and synapsin I in the hippocampus, which was one of the key brain regions associated with PTSD. We showed that the levels of FXR1 and fragile X mental retardation protein (FMRP), an autosomal homolog of FXR1, were decreased in the hippocampus of PTSD rats, but the levels of PSD95 and synapsin I were increased, which could be reversed by downregulation of miR-132. The results revealed that miR-132 could modulate PTSD-like behaviors in rats following SPS through regulating FXR1 and FMRP.

Dysregulation of miR-142 results in anxiety-like behaviors following single prolonged stress.

Posttraumatic stress disorder (PTSD) is a prevalent mental disorder that is classified as a trauma- and stressor-related disorder. While numerous epigenetic factors are related to the risk for PTSD, the precise mechanisms underlying this disorder remain unclear. However, accumulating evidence has demonstrated that dysregulation of microRNAs is involved in stress-related psychiatric disorders, resulting in anxiety-like behavior, memory-related deficits and aberrant neuronal plasticity. Here, rats exposed to single prolonged stress showed increased microRNA-142-5p levels in the amygdala and a concurrent reduction in the levels of its predicted target Npas4, an activity-regulated transcription factor, which was implicated in stress-related psychopathologies. In addition, the inhibition of microRNA-142 following exposure to single prolonged stress exhibited decreased anxiety-like behaviors and memory deficits, as well as increased expression of Npas4 and BDNF. Furthermore, a dual-luciferase reporter assay indicated that Npas4 was a direct downstream target of miR-142. Taken together, these data suggest that miR-142 may play a key role in the pathogenesis of stress-related psychiatric disorders.

Sigma-1 receptor activation ameliorates anxiety-like behavior through NR2A-CREB-BDNF signaling pathway in a rat model submitted to single-prolonged stress.

Accumulating evidence has demonstrated that the σ-1 receptor (σ­1R) possesses neuroprotective effects and is a potential novel therapeutic target for certain psychiatric diseases, including post­traumatic stress disorder (PTSD) accompanied with anxiety disorder. It has been reported that σ­1R agonist treatment could be modulated by the brain­derived neurotrophic factor (BDNF) signaling pathway. However, it remains unclear whether BDNF and its upstream regulator are mechanistically involved in the therapeutic effect of σ­1R in PTSD. To address this question, rats were subjected to a single­prolonged stress (SPS) paradigm and σ­1R agonist administration. Open­field and elevated plus maze tests were implemented to evaluate the effect of σ­1R activation on the improvement of anxiety­like behaviors. Furthermore, the expression levels of BDNF, phosphorylated cAMP responsive element­binding protein (CREB) and glutamate receptor ionotropic N­methyl D­aspartate 2A (NMDAR2A) were investigated in the hippocampi of rats. It was revealed that the downregulation of BDNF, phosphorylated CREB and NMDAR2A induced by SPS were reversed by σ­1R activation. Collectively, the results of the present study suggest that the NMDAR2A/CREB/BDNF signaling pathway is involved in the activation of σ­1R resulting in therapeutic effects for PTSD.

Activation of Sigma-1 receptor ameliorates anxiety-like behavior and cognitive impairments in a rat model of post-traumatic stress disorder.

Among learning and memory processes, fear memories are crucial in some psychiatric disorders like post-traumatic stress disorder (PTSD). Accumulating evidence shows that the sigma-1 receptor (Sig-1R) has comprehensive involvement in cognitive impairment and neuroprotective effects. It has also been reported that BDNF appears to enhance extinction of fear in anxiety disorders via the MAPK signaling cascade. However, it remains unclear whether BDNF-TrkB-MAPK pathway may be mechanistically involved in the therapeutic effect of sigma-1 receptor in the development of PTSD. To address this question, rats were subjected to a classical single-prolonged stress procedure (SPS) and kept undisturbed for 7 days. After that, rats were re-stressed by re-exposure to the forced swim component of SPS (RSPS). Behavior tests were subsequently performed to assess anxiety and cognitive impairments. Furthermore, we analyzed the expression of BDNF and the phosphorylation of TrkB and three MAPK pathways, namely, the ERK, JNK and p38. We found that the levels of BDNF and p-TrkB were increased following the RSPS procedure, which were reversed by the administration of PRE-084. Meanwhile, among the three MAPK signaling pathways, only the p-ERK expression was increased following the RSPS procedure. Collectively, our results indicate that BDNF-TrkB-ERK signaling pathway may be involved in the activation of sigma-1 receptor to yield therapeutic benefits for PTSD.

Intra-hippocampal administration of ZIP alleviates depressive and anxiety-like responses in an animal model of posttraumatic stress disorder.

BACKGROUND: Given that impairment of fear extinction has been implicated in the pathogenesis of posttraumatic stress disorder (PTSD), effective pharmacological interventions that facilitate fear extinction may provide alternative strategies to conventional treatment. It is generally accepted that the zeta inhibitory peptide (ZIP), a controversial inhibitor of protein kinase M zeta (PKMζ), could erase certain types of previously established long-term memories. However, it is unclear whether ZIP administration may alleviate PTSD-associated depressive and anxiety-like abnormalities. METHODS: Here we developed a re-stressed single-prolonged stress (SPS) paradigm, a modified prevalent animal model of PTSD, and assayed the expressions of PKMζ in the hippocampus after SPS procedure. Next, Seven days prior to re-stress, ZIP was injected into the hippocampus, and the depressive and anxiety-like behavior was examined by the subsequent forced swim (FS), open-field and elevated plus maze (EPM) test. RESULTS: Rats given ZIP prior to FS exhibited a reduction of immobility time in FS test, and more open arms (OA) entries and longer OA duration in EPM. They also spent longer time in the center of the open field. CONCLUSIONS: Our results suggested that re-stressed SPS could reproduce behavioral alteration similar to that observed in patients with PTSD, and these behavioral symptoms co-morbid with PTSD could be effectively alleviated by the intro-hippocampal administration of ZIP.