MicroRNA Profiling and Bioinformatics Target Analysis in Dorsal Hippocampus of Chronically Stressed Rats: Relevance to Depression Pathophysiology

Abstract

Studies conducted in rodents subjected to chronic stress and some observations in humans after psychosocial stress, have allowed to establish a link between stress and the susceptibility to many complex diseases, including mood disorders. The studies in rodents have revealed that chronic exposure to stress negatively affects synaptic plasticity by triggering changes in the production of trophic factors, subunit levels of glutamate ionotropic receptors, neuron morphology, and neurogenesis in the adult hippocampus. These modifications may account for the impairment in learning and memory processes observed in chronically stressed animals. It is plausible then, that stress modifies the interplay between signal transduction cascades and gene expression regulation in the hippocampus, therefore leading to altered neuroplasticity and functioning of neural circuits. Considering that miRNAs play an important role in post-transcriptional-regulation of gene expression and participate in several hippocampus-dependent functions; we evaluated the consequences of chronic stress on the expression of miRNAs in dorsal (anterior) portion of the hippocampus, which participates in memory formation in rodents. Here, we show that male rats exposed to daily restraint stress (2.5 h/day) during 7 and 14 days display a differential profile of miRNA levels in dorsal hippocampus and remarkably, we found that some of these miRNAs belong to the miR-379-410 cluster. We confirmed a rise in miR-92a and miR-485 levels after 14 days of stress by qPCR, an effect that was not mimicked by chronic administration of corticosterone (14 days). Our in silico study identified the top-10 biological functions influenced by miR-92a, nine of which were shared with miR-485: Nervous system development and function, Tissue development, Behavior, Embryonic development, Organ development, Organismal development, Organismal survival, Tissue morphology, and Organ morphology. Furthermore, our in silico study provided a landscape of potential miRNA-92a and miR-485 targets, along with relevant canonical pathways related to axonal guidance signaling and cAMP signaling, which may influence the functioning of several neuroplastic substrates in dorsal hippocampus. Additionally, the combined effect of miR-92a and miR-485 on transcription factors, along with histone-modifying enzymes, may have a functional relevance by producing changes in gene regulatory networks that modify the neuroplastic capacity of the adult dorsal hippocampus under stress.

Integrated phosphoproteomic and metabolomic profiling reveals perturbed pathways in the hippocampus of gut microbiota dysbiosis mice

“…In the present results, the phosphorylation of various subtypes of voltage-dependent Ca 2+ channels, glutamate ionotropic receptors, K+ channels, Na+ channel, and K+/Na+ channel was dysregulated. Several prior studies have implicated the dysfunction of these channels in the pathophysiology of depression 46 – 48 and other psychiatric disorders 49 , 50 . Moreover, PTMs help to regulate function and stability of cytoskeletons, abnormal phosphorylation of numerous cytoskeletal proteins were observed in the present study, and these abnormalities may induce changes in dendritic morphology in depression 51 .…”

Negative Memory Engrams in the Hippocampus Enhance the Susceptibility to Chronic Social Defeat Stress

“…Mean Ϯ SEM. has been associated with alterations in microRNA expression (Muñoz-Llanos et al, 2018) and microstructural alterations in the dorsal hippocampus (Liu et al, 2018). We have recently shown that the dorsal hippocampus expresses fewer NMDA receptors in the extrasynaptic location (Tse et al, 2019).…”

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

“…Further research has revealed that miR-124-3p-mediated stress is also related to synaptic plasticity [ 113 ]. Similarly, the combined effect of miR-92a and miR-485 on transcription factors, along with histone-modifying enzymes, may have functional relevance by producing changes in gene regulatory networks that modify the neuroplastic capacity of the adult dorsal hippocampus under stress [ 114 ]. In the depression model, miR-137 loss-of-function results in altered synaptic transmission and plasticity and anxiety and depression-like behaviour in mice [ 115 ].…”