Enhancing neurogenesis within the hippocampal dentate gyrus (DG) is critical for maintaining brain development and function in many neurological diseases. However, the neural mechanisms underlying neurogenesis in depression remain unclear. Here, we show that microglia transfer a microglia-enriched microRNA, miR-146a-5p, via secreting exosomes to inhibit neurogenesis in depression. Overexpression of miR-146a-5p in hippocampal DG suppresses neurogenesis and spontaneous discharge of excitatory neurons by directly targeting Krüppel-like factor 4 (KLF4). Downregulation of miR-146a-5p expression ameliorates adult neurogenesis deficits in DG regions and depression-like behaviors in rats. Intriguingly, circular RNA ANKS1B acts as a miRNA sequester for miR-146a-5p to mediate post-transcriptional regulation of KLF4 expression. Collectively, these results indicate that miR-146a-5p can function as a critical factor regulating neurogenesis under conditions of pathological processes resulting from depression and suggest that microglial exosomes generate new crosstalk channels between glial cells and neurons.

Neuroinflammation has recently emerged as a critical risk factor in the pathophysiology of depression. However, the underlying molecular mechanisms and the development of novel therapeutic strategies as means to target these inflammatory pathways for use in the treatment of depression remain unresolved. In the present study, we aimed to investigate the molecular events of neuroinflammation as related to its induction of depression-like behaviors. Chronic unpredictable mild stress (CUMS) or lipopolysaccharide (LPS) was used to induce depression-like behaviors in rats. The inflammatory factors and related proteins were verified by RT-PCR, immunoblotting, and immunofluorescence assay. In vivo intracerebral injection of adenovirus-associated virus (AAV) in rats was used to overexpress or block the function of the β form of the calcium/calmodulin-dependent protein kinase type II (βCaMKII). In vivo intracerebroventricular injection of SB203580 was used to block p38 mitogen-activated protein kinase (MAPK). Finally, the prostaglandin E2 (PGE2) concentration was verified by using enzyme-linked assay kit. The expression of cyclo-oxygenase (COX)-2, which is responsible for production of the pro-inflammatory factor PGE2 and thus glial activation, was increased in the CA1 hippocampus in a rat model of depression. Further, the βCaMKII in CA1 was significantly upregulated in depressed rats, while antidepressant treatment downregulated this kinase. Overexpression of βCaMKII via infusion of a constructed AAV-βCaMKII into the CA1 region resulted in phosphorylation of the p38 MAPK and the activating transcription factor 2 (ATF2). These effects were accompanied by an enhanced activity of the COX-2/PGE2 pathway and effectively induced core symptoms of depression. Conversely, knockdown of βCaMKII within the CA1 region reversed these inflammation-related biochemical parameters and significantly rescued depression symptoms. These results demonstrate that βCaMKII can act as a critical regulator in depression via activating neuroinflammatory pathways within the CA1 region. Moreover, this study provides new perspectives on molecular targets and drug therapies for future investigation in the treatment of depression.

Depression is considered a neuropsychiatric disease associated with various neuronal changes within specific brain regions. We previously reported that ginsenoside-Rg1, a potential neuroprotective agent extracted from ginseng, significantly alleviated depressive-like disorders induced by chronic stress in rats. However, the mechanisms by which ginsenoside-Rg1 exerts its neuroprotective effects in depression remain largely uncharacterized. In the present study we confirm that ginsenoside-Rg1 significantly prevented the antidepressant-like effects in a rat model of chronic unpredictable mild stress (CUMS) and report on some of the underlying mechanisms associated with this effect. Specifically, we found that chronic pretreatment with ginsenoside-Rg1 prior to stress exposure significantly suppressed inflammatory pathway activity via alleviating the overexpression of proinflammatory cytokines and the activation of microglia and astrocytes. These effects were accompanied with an attenuation of dendritic spine and synaptic deficits as associated with an upregulation of synaptic-related proteins in the ventral medial prefrontal cortex (vmPFC). In addition, ginsenoside-Rg1 inhibited neuronal apoptosis induced by CUMS exposure, increased Bcl-2 expression and decreased cleaved Caspase-3 and Caspase-9 expression within the vmPFC region. Furthermore, ginsenoside-Rg1 could increase the nuclear factor erythroid 2-related factor (Nrf2) expression and inhibit p38 mitogen-activated protein kinase (p-p38 MAPK) and nuclear factor κB (NF-κB) p65 subunit activation within the vmPFC. Taken together, these results suggest that the neuroprotective effects of ginsenoside-Rg1, which may assume the antidepressant-like effect in this animal model of depression, appears to result from amelioration of a CUMS-dependent neuronal deterioration within the vmPFC. Moreover, they also provide support for the therapeutic potential of ginsenoside-Rg1 in the treatment of stress-related mental disorders.

Depression is suggested to be a neuropsychiatric disease resulting from neuroinflammation within specific brain regions. Curcumin, a potential neuroprotective agent extracted from curcuma loga, exerts antidepressant-like effects in various animal models of depression. However, the underlying mechanisms, in particular whether curcumin may exert neuroprotection through suppression of inflammatory pathway activity in depression remains largely unknown. In the present study, we examined the molecular events of curcumin as related to its capacity for neuroprotection against inflammation-induced neuronal apoptosis and depression-like behaviors in a rat model of depression. Our results show that chronic administration of curcumin (40 mg/kg, i.p., 5 weeks) prior to stress exposure significantly alleviated depression-like behaviors, expression of the proinflammatory cytokine interleukin-1β (IL-1β) and inhibited neuronal apoptosis within neurons of the ventromedial prefrontal cortex (vmPFC). Within the vmPFC of stressed rats, an intracerebral infusion of an RNAi form of IL-1β in adenovirus associated virus (AAV-IL-1β RNAi) significantly ameliorated depression-like behaviors, neuronal apoptosis and reduced phosphorylated-p38 mitogen-activated protein kinase (p-p38 MAPK) expression levels. More important, within the vmPFC of wild type rats, overexpression of IL-1β via intracerebral infusion of AAV-IL-1β induced p38 MAPK phosphorylation and neuronal apoptosis, which could be significantly prevented by chronic treatment of curcumin. Collectively, these findings reveal that curcumin protects against IL-1β-induced neuronal apoptosis, which may be related to the display of depression-like behaviors in stressed rats. Moreover, they provide new insights into the mechanisms and therapeutic potential for curcumin in the treatment of inflammation-related neuronal deterioration in this disorder.