Long Non-coding RNAs and Circular RNAs: Insights Into Microglia and Astrocyte Mediated Neurological Diseases

Microglia and astrocytes maintain tissue homeostasis in the nervous system. Both microglia and astrocytes have pro-inflammatory phenotype and anti-inflammatory phenotype. Activated microglia and activated astrocytes can contribute to several neurological diseases. Long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), two groups of non-coding RNAs (ncRNAs), can function as competing endogenous RNAs (ceRNAs) to impair the microRNA (miRNA) inhibition on targeted messenger RNAs (mRNAs). LncRNAs and circRNAs are involved in various neurological disorders. In this review, we summarized that lncRNAs and circRNAs participate in microglia dysfunction, astrocyte dysfunction, neuron damage, and inflammation. Thereby, lncRNAs and circRNAs can positively or negatively regulate neurological diseases, including spinal cord injury (SCI), traumatic brain injury (TBI), ischemia-reperfusion injury (IRI), stroke, neuropathic pain, epilepsy, Parkinson’s disease (PD), multiple sclerosis (MS), and Alzheimer’s disease (AD). Besides, we also found a lncRNA/circRNA-miRNA-mRNA regulatory network in microglia and astrocyte mediated neurological diseases. Through this review, we hope to cast light on the regulatory mechanisms of lncRNAs and circRNAs in microglia and astrocyte mediated neurological diseases and provide new insights for neurological disease treatment.


INTRODUCTION
Both microglia and astrocytes are glial cells in the central nervous system (Kwon and Koh, 2020). Microglia are resident immune cells and the first responders to nervous system changes. Astrocytes can modulate cerebral blood flow (Greenhalgh et al., 2020). And both of them can also promote neurotransmission, synapse formation, and synapse pruning (Vainchtein and Molofsky, 2020). In response to pathological conditions, microglia and astrocytes are activated. Activated microglia and activated astrocytes lose their homeostatic functions and involve in neuroinflammation in the central nervous system (Leng and Edison, 2021). Increasing evidence investigates that the dysfunctions of microglia and astrocytes are beneficial for various neurological diseases, like central nervous system injury and neurodegenerative disorders (Gao et al., 2013;Jha et al., 2019;Pietrowski et al., 2021). Targeting microglia and astrocytes could be a promising approach for the treatment of neurological diseases (Peterson and Binder, 2020;Huang X. et al., 2017).
Long non-coding RNA (lncRNA) and circular RNA (circRNA) are two types of non-coding RNAs (ncRNAs) without the potential to encode proteins (Han T. S. et al., 2020). LncRNAs are transcripts with more than 200 nucleotides in length. LncRNAs include five different subtypes: sense lncRNA, antisense lncRNA, bidirectional lncRNA, intergenic lncRNA, and intronic lncRNA (Braga et al., 2020). LncRNAs regulate gene transcription and translation via interacting with the 3 untranslated region (3 UTR) of messenger RNA (mRNA) (Dykes and Emanueli, 2017). MicroRNAs (miRNAs) are small single-stranded RNAs. MiRNAs recognize miRNA response elements (MREs) on 3 UTR of mRNA and silence target genes through repressing mRNA translation or degrading the mRNA (Cheng et al., 2015;Salim et al., 2021). LncRNAs contain MREs and can use MREs to bind miRNAs. LncRNAs function as competing endogenous RNAs (ceRNAs) to sponge miRNAs and reduce miRNA activity, finally, impair the interaction between miRNAs and their targeted genes (Kalpachidou et al., 2020;Moreno-García et al., 2020). LncRNAs have been demonstrated to involve in epigenetic mediation and the modulation of transcription, translation, RNA metabolism, cell autophagy, cell apoptosis, etc. (Qian et al., 2019). In particular, it is suggested that lncRNAs can influence neural cell behaviors, including neurons, microglia, astrocytes, and oligodendrocytes (Shi et al., 2018). For example, lncRNA AK148321 can abrogate microglial neuroinflammation (Gao et al., 2021). LncRNAs are also related to the development of spinal cord injury (SCI), brain injury, and neurodegenerative diseases (Cuevas-Diaz Duran et al., 2019). CircRNAs have covalently closed loop structures without 5 caps or 3 Poly A tails. CircRNAs are stable in eukaryotic cells. CircRNAs can interact with RNAbinding proteins and modulate mRNA stability, and gene transcription. It is proved that endogenous circRNAs can be translated into proteins (Chen and Yang, 2015;Meng et al., 2017). Moreover, like lncRNAs, circRNAs also have MREs. CircRNAs also act as ceRNAs and inhibit miRNA repression on its targeted mRNA (Moreno-García et al., 2020). Many studies report that circRNAs can influence cell proliferation, autophagy, differentiation, and pyroptosis (Fu and Sun, 2021). For instance, one research indicated that circHIPK2 knockout can suppress astrocyte autophagy and astrocyte activation (Huang R. et al., 2017). CircRNAs also play pivotal roles in neurological diseases, including ischemic stroke and cerebral ischemia-reperfusion injury (IRI) .
In this review, we discussed the effects of both lncRNAs and circRNAs on microglia and astrocyte mediated neurological diseases. We also found a network of lncRNA/circRNA-miRNA-mRNA in neurological diseases. In addition, there are also targeted therapies for the treatment of neurological diseases.

Spinal Cord Injury
Spinal cord injury is one neurological disease with impairment of sensory and motor function. The SCI pathological process includes primary and secondary injury (Anjum et al., 2020). Primary SCI occurs owing to mechanical damage, for instance, compression or contusion in the spinal cord. Secondary SCI is caused by pathological changes after primary injury, which can result in inflammation, oxidative stress, glial scar formation, neuronal apoptosis, and neuronal necrosis (Anjum et al., 2020;Wang et al., 2020d). Recently, SCI models induced by lipopolysaccharide (LPS) are widely used to explore SCI pathogenesis and find new therapeutic medicine to treat SCI (Xiao et al., 2021).
MiR-382-5p expression is significantly induced by LPS in BV2 cells (mouse microglial cell lines). MiR-382-5p targets 3 UTR of Neuregulin-1 (Nrg1). MiR-382-5p deletion stimulated by its inhibitor can remarkably increase Nrg1 expression in BV2 cells (Xiang et al., 2021). LncRNA Ftx expression is markedly decreased in tissues collected from SCI mice and in LPSstimulated BV2 cells. Ftx targets miR-382-5p and represses its expression. Besides, Ftx also competes with Nrg1 for miR-382-5p binding, resulting in suppressing miR-382-5p repression on Nrg1 expression (Xiang et al., 2021). Ftx over-expression increases Nrg1 expression levels through miR-382-5p. Increased Nrg1 attenuates the expressions of inflammation factors (e.g., iNOS, IL-6, TNF-α, and IL-1β) in LPS-treated BV2 cells. As a result, increased Ftx relieves microglia inflammation response through the miR-382-5p-Nrg1 axis (Xiang et al., 2021). In addition, this study also indicated that over-expressed Ftx can suppress inflammation response and improve functional recovery in the SCI mouse model (Xiang et al., 2021). Exosomes, which belong to extracellular vesicles (EVs), can be secreted by all cells and carry various materials, including proteins, lipids, mRNA, ncRNAs, etc. And exosomes derived from mesenchymal stem cells possess the potential for SCI treatment (Ren et al., 2020). It is reported that peroxisome proliferator-activated receptor γ (PPARγ) can suppress inflammatory phenotype in macrophages (Nelson et al., 2018). MiR-130b-3p can interact with 3 UTR of PPARγ and reduce its expression. LncGm37494 is reported to be abundant in exosomes originated from hypoxia-treated adipose-derived stem cells (ADSCs). Exosomal lncGm37494 from ADSCs can shift microglia polarization from M1 to M2 via decreasing miR-130b-3p and increasing PPARγ. Finally, exosomal lncGm37494 contributes to improving functional recovery following SCI in mice (Shao et al., 2020). In the SCI rat model, receptor-activity modifying proteins 3 (RAMP3) is up-regulated and miR-222-5p is decreased. MiR-222-5p can target RAMP3 3 UTR and inhibit RAMP3 expression. Enhanced RAMP3 expression or miR-222-5p inhibitor can promote cell apoptosis and increase TNF-α and IL-6 expressions in LPS-treated microglia . LncRNA lymphoid enhancer-binding factor 1 (LEF1) antisense RNA 1 (LEF1-AS1) is up-regulated in LPStreated microglia cells that are collected from the central nervous system of normal rats. LEF1-AS1 acts as a ceRNA via sponging miR-222-5p. LEF1-AS1 small interfering RNA (siRNA) can augment miR-222-5p expression. Knocking down LEF1-AS1 dampens microglia apoptosis and promotes microglial cell viability through the miR-222-5p-RAMP3 axis. LEF1-AS1 silence can impede SCI progression in rats . Pyroptosis is a type of programmed cell death involved in neuroinflammation (Dai et al., 2019). And it is proved that inhibiting microglial pyroptosis can promote motor function recovery following SCI . F630028O10Rik levels are higher in the peripheral blood from SCI patients compared with normal people. F630028O10Rik can sponge miR-1231-5p to up-regulate Col1a1. Subsequently, increased Colla1 can enhance microglial pyroptosis through the activation of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway. Increased F630028O10Rik expression can indicate worse functional recovery after SCI . Smad ubiquitination regulatory factor 1 (Smurf1) is a downstream target of miR-27a and its expression can be attenuated by miR-27a. Smurf1 over-expression or miR-27a down-regulation can promote TNF-α and IL-6 secretion in LPS-treated microglia . LncRNA X-inactive specific transcript (XIST) expression is elevated in LPS-treated microglial cells and in injured rat spinal cord tissues. XIST sponges miR-27a and negatively mediates miR-27a expression. XIST deletion abrogates SCI-evoked microglia apoptosis and inflammatory injury through the miR-27a up-regulation and Smurf1 downregulation. Moreover, the deficiency of XIST can relieve SCI . The expression of lncRNA metastasisassociated lung adenocarcinoma transcript 1 (MALAT1) is higher in SCI rats compared to normal rats. Over-expressed MALAT1 activates the IkappaB kinase β (IKKβ)/nuclear factor kappa B (NF-κB) signaling pathway by down-regulating miR-199b. Eventually, MALAT1 over-expression promotes proinflammatory cytokine production in LPS-treated microglial cells . Zhou et al. (2018) also revealed that MALAT1 silence can alleviate SCI through inhibiting microglial inflammatory responses.

Ischemia-Reperfusion Injury
More and more evidence revealed that recovery of blood flow in a short time after cerebral ischemia can lead to cerebral IRI (Pan et al., 2007). IRI gives rise to reactive oxygen species (ROS), calcium overload, neuron death, platelet activation, and inflammation, which can ultimately cause irreversible damage to the brain (Wu et al., 2010;Bai and Lyden, 2015). In research studies, middle cerebral artery occlusion (MCAO)/reperfusion (MCAO/R) treatment in vivo and oxygen-glucose deprivation (OGD)/reoxygenation (OGD/R) treatment in vitro are used to mimic cerebral IRI . It is reported that upregulated Krüppel-like factor 4 (KLF4) decreases M1 marker (CD86 and iNOS), TNF-α, and IL-1β levels, while increases M2 marker (CD206 and Arg1), IL-10, and IL-4 expressions in OGD/R-induced BV2 cells (Li T. et al., 2020). MEG3 is elevated in the brain tissues from MCAO/R mice and in OGD/Rinduced BV2 cells. MEG3 binds to KLF4 and represses its protein progression. MEG3 absence enhances M2 polarization and reduces M1 polarization in microglial cells by targeting KLF4. Eventually, MEG3 knockdown decreases neuroinflammation to lessen cerebral IRI (Li T. et al., 2020).
Long non-coding RNA small nucleolar RNA host gene 4 (SNHG4) is remarkably down-regulated in blood and cerebrospinal fluid samples obtained from patients with acute cerebral infarction. Enhanced SNHG4 expression can facilitate microglia M2 polarization and promote anti-inflammatory factor release . MiR-449c-5p can bind with the 3 UTR of signal transducers and activators of transcription 6 (STAT6). MiR-449c-5p inhibitor increases STAT6 expression. SNHG4 targets miR-449c-5p and inhibits its expression. Upregulated SNHG4 activates the STAT6 signaling pathway by suppressing miR-449c-5p. Therefore, SNHG4 up-regulation attenuates microglial inflammatory responses and microgliamediated neuronal damage during cerebral IRI . LncRNA SNHG3 is elevated in OGD/R-stimulated BV2 cells. Interference with SNHG3 impedes microglial activation and dampens the release of pro-inflammatory factors (TNF-α and IL-6) through abrogating histone deacetylase 3 (HDAC3) expression (Huang D. et al., 2021). In transient MCAO mice, SNHG3 deletion weakens cerebral IRI (Huang D. et al., 2021). Diabetes mellitus (DM) is characterized by high sugar in the blood and can worsen cerebral IRI . MALAT1 is highly expressed in cortical tissues of diabetic rats suffering the IRI and in HAPI cells (rat immortalized microglia cell line) undergoing high glucose and hypoxia-reoxygenation. Overexpressed MALAT1 enhances microglia inflammatory response through activating the MyD88/IRAK1 (IL-1 receptor-associated kinase 1)/TRAF6 signaling pathway. Finally, increased MALAT1 aggravates cerebral IRI in diabetic rats . LncRNA nuclear enriched abundant transcript 1 (NEAT1) expresses highly in the blood of ischemic stroke patients and in OGD/R-induced BV2 cells (Ni et al., 2020). One research reported that NEAT1 can serve as a ceRNA for miR-224 and thus enhance IL-33 production and promote M2a polarization in macrophages. NEAT1 can also hinder A1 astrocyte activation . Ni et al. (2020) found that suppressing NEAT1 abrogates microglial M1 polarization to reduce neuronal apoptosis after cerebral IRI.

Stroke
Stroke is a severe disorder with high rates of mortality and disability around the world. Stroke can be divided into ischemic stroke (major type) and hemorrhagic stroke . Ischemic stroke is mainly due to atherosclerosis in large vessels and atherosclerotic plaque ruptures. MCAO models in rodents and OGD in vitro models are usually used for experimental ischemic stroke researches (Sommer, 2017).
Malate dehydrogenase 2 (MDH2) binds to the mRNA of neutrophil chemoattractant C-X-C motif ligand 2 (CXCL2) and reduces CXCL2 mRNA levels . LncRNA U90926 is highly increased in microglia isolated from the ischemic hemispheres in C57BL/6J mice. U90926 interacts with MDH2 to impair the interaction between MDH2 and CXCL2 mRNA. Increased microglial U90926 enhances CXCL2 protein levels. Increased CXCL2 release from microglia can ultimately stimulate neutrophil infiltration, which can exacerbate brain injury during ischemic stroke. Once microglial U90926 is silenced, the neurological function is improved and infarct volume is diminished in ischemic stroke mice . LncRNA opa-interacting protein 5 antisense RNA 1 (OIP5-AS1) lowly expresses in the blood of stroke patients.
Frontiers in Molecular Neuroscience | www.frontiersin.org It is shown that OIP5-AS1 down-regulation increases miR-186-5p levels . Over-expressed miR-186-5p leads to microglia inflammation and oxidative stress via blocking the expression of C1q/tumor necrosis factor-related protein 3 (CTRP3), resulting in neuron damage during ischemic stroke. Further, OIP5-AS1 up-regulation lessens infarct volume and weakens neuron apoptosis and loss in rats with ischemic stroke . One research demonstrated that lincRNA-EPS can be loaded in leukosomes (biomimetic vesicles). And these leukosomes carrying lincRNA-EPS can target the ischemic area and co-localize with microglia in ischemic stroke mice . LincRNA-EPS from leukosomes impedes microglia activation and microglia infiltration in vivo. In addition, leukosomes-loaded lincRNA-EPS can also accelerate neuron regeneration via hindering microglia inflammation in cerebral infarction . It is said that sirtuin1 activation can abolish NF-κB signaling (Kauppinen et al., 2013). MiR-425-5p can target sirtuin1. In brain tissues of MCAO mice, SNHG8 expression is downregulated. MiR-425-5p can share binding sites with SNHG8 and sirtuin1. SNHG8 functions as a ceRNA for miR-425-5p and inhibits miR-425-5p effects on sirtuin1 (Tian et al., 2021). SNHG8 over-expression can attenuate miR-425-5p to increase sirtuin1 expression and suppress NF-κB phosphorylation. SNHG8 amplification suppresses microglial activation and inflammation through the miR-425-5p/sirtuin1/NF-κB pathway, resulting in diminishing brain microvascular endothelial cell (BMEC) damage. Furthermore, after ischemic stroke, overexpressed SNHG8 dampens neuron damage, cerebral edema, and neurological function loss in mice (Tian et al., 2021). H19 levels are significantly raised in the plasma isolated from stroke patients compared to normal people. Repressing H19 reduces HDAC1 to facilitate microglial polarization from M1 to M2. H19 inhibition promotes cerebral IL-10 production and decreases cerebral TNFα and IL-1β levels in ischemic mice. Therefore, H19 reduction can inhibit neuroinflammation in ischemic stroke (Wang et al., 2017). In ischemic stroke mice, H19 siRNA decreases cerebral ischemic injury and attenuates neurological deficits. Moreover, H19 would be a promising biomarker to diagnose ischemic stroke (Wang et al., 2017). LncRNA Nespas is greatly expressed in ischemic cerebral tissues of MCAO mice and in BV2 cells subjected to OGD. High Nespas expression hinders transforming growth factor-beta-activated kinase 1 (TAK1) activation via abolishing the interaction between tripartite motif 8 (TRIM8) and TAK1 (Deng et al., 2019). Over-expressed Nespas limits NF-κB activation through TAK1, which can restrain microglia death and neuroinflammation in the ischemic microenvironment. Moreover, Nespas silence in MCAO mice deteriorates ischemic brain injury (Deng et al., 2019). LncRNA 1810034E14Rik declines markedly in microglial cells after the OGD exposure. Elevated 1810034E14Rik expression impedes microglia activation and microglia inflammation in vitro and in vivo (Zhang et al., 2019b). In addition, up-regulated 1810034E14Rik can abrogate neuronal damage caused by OGD-treated microglia. Further, enhanced 1810034E14Rik expression promotes motor function recovery and decreases infarct volumes in MCAO mice (Zhang et al., 2019b). SNHG14 and cytosolic phospholipase A2 (cPLA2) group IVA (PLA2G4A) are notably up-regulated in ischemic cerebral tissues and in OGD-treated BV2 cells. MiR-145-5p is downregulated in MACO mice. PLA2G4A is a downstream target of miR-145-5p. The miR-145-5p inhibitor can increase TNF-α, and nitrate levels in OGD-treated BV2 cells (Qi et al., 2017). SNHG14 elevates PLA2G4A expression and abrogates miR-145-5p expression. Functionally, SNHG14 can facilitate microglia activation and microglia-mediated neuron apoptosis through the miR-145-5p-PLA2G4A axis in response to ischemic stroke conditions. Further, highly expressed SNHG14 can act as an induction effector of cerebral infarction severity (Qi et al., 2017). MiR-96-5p abrogates NF-κB signaling and TNF-α production via suppressing IKKβ expression in OGD-stimulated BV2 cells . LncRNA XIST is highly expressed in BV2 cells exposed to OGD treatment. XIST serves as a sponge for miR-96-5p to antagonize inhibitory effects of miR-96-5p on the TNF-α expression. XIST up-regulation increases TNF-α expression through the miR-96-5p-IKKβ-NF-κB axis . Moreover, TNF-α stimulation can increase XIST mRNA levels in BV2 cells. The XIST-TNF-α feedback enhances the pro-inflammatory polarization of microglial cells, leading to exacerbating cerebral neuron apoptosis in cerebral infarction .

Neuropathic Pain
Accumulating evidence reveals that neuropathic pain develops owing to the diseases or damaging stimuli in the nervous system. Neuropathic pain includes postherpetic neuralgia, trigeminal neuralgia, and nerve injury pain. Patients with neuropathic pain usually suffer from allodynia and hyperalgesia (Jensen and Finnerup, 2014). It is investigated that enhancer of zeste homolog 2 (EZH2), one RNA-binding protein of Lncenc1, can promote histone methylation in the promoter of brainspecific angiogenesis inhibitor 1 (BAI1) and decrease BAI1 expression . After nerve injury, lncRNA embryonic stem cells expressed 1 (Lncenc1) is notably increased in dorsal root ganglion in mice. Increased Lncenc1 enhances EZH2 expression to down-regulate BAI1, which can accelerate microglia activation and microglial inflammatory response. Decreasing Lncenc1 can impede neuropathic pain development in rats .

Epilepsy
Epilepsy is a neurological disorder characterized by a persistent predisposition to produce epileptic seizures (Fisher et al., 2014). Epilepsy includes focal epilepsy, generalized epilepsy, combined generalized and focal epilepsy, and unknown epilepsy (the patient has epilepsy but the clinician cannot determine if the epilepsy is focal epilepsy or generalized epilepsy) (Scheffer et al., 2017). Temporal lobe epilepsy is the most common form of focal epilepsy. And patients with temporal lobe epilepsy usually experience hippocampal sclerosis (Lévesque and Avoli, 2013). Epilepsy can be caused by genetic mutations, stroke, TBI, infection, cancers, etc. Although there are many antiseizure drugs, approximately one-third of patients can't achieve seizure control (Devinsky et al., 2018). Recently, rodents with spontaneous seizures that mimic human epilepsy can be used to study epilepsy. For example, the kainic acid (KA)induced epilepsy model is widely used to explore pathogenetic mechanisms of temporal lobe epilepsy (Lévesque and Avoli, 2013). H19 expression is notably higher in the hippocampus in epileptic rats compared to normal rats . Han C. L. et al. (2018) showed that H19 can stimulate hippocampal microglia and astrocyte activation through the Janus kinase (JAK)/STAT3 signaling pathway in a KA-induced rat model of temporal lobe epilepsy. Another research investigated that H19 can bind to miRNA let-7b and restrain its expression. Increased H19 promotes STAT3 mRNA expression levels via sponging let-7b. Subsequently, up-regulated STAT3 results in microglia and astrocyte activation during epileptogenesis. Eventually, the activation of both microglia and astrocytes can aggravate epileptic seizures in rats undergoing temporal lobe epilepsy induced by KA . Feng et al. (2020) revealed that up-regulated 26S proteasome non-ATPase regulatory subunit 11 (Psmd11) can not only inactivate microglia and astrocytes but also abrogate neuron injury and inflammation in the epileptic hippocampus in mice. In addition, Psmd11 is a downstream target of miR-490-3p . LncRNA Peg13 is lowly expressed in epileptic hippocampal tissues from mice. Peg13 acts as a ceRNA for miR-490-3p. Peg13 competitively binds with miR-490-3p to elevate Psmd11 expression. Ultimately, in epileptic mice, high Peg13 expression suppresses epilepsy progression .

Depression
Depression is a mood disorder affecting human beings at any age. Depressed people usually experience persistent sadness, decreased interest, loss of pleasure, diminished or increased sleep, etc. Childhood maltreatment (e.g., abuse, loss, and neglect) and stressful life can increase the risk of depression (Malhi and Mann, 2018). It is indicated that 2007 lncRNAs were differentially expressed in peripheral blood of major depressive disorder (MDD) patients compared to that in normal people, including 1,556 up-regulated lncRNAs and 441 down-regulated lncRNAs (Liu et al., 2014). LncRNAs related to cognitive function, synaptic plasticity, and psychiatry diseases (e.g., schizophrenia) potentially contribute to MDD (Huang X. et al., 2017). LncRNA uc.80-is down-regulated in the hippocampus obtained from depressed rats induced by chronic unpredictable mild stress (CUMS) regiment. Over-expressed uc.80-inhibits microglia M1 polarization and facilitates microglia M2 polarization. In addition, uc.80-up-regulation can attenuate neuron apoptosis mediated by microglia under inflammation exposure. Functionally, uc.80-over-expression ameliorates depression via enhancing M2 polarization of microglial cells in CUMS-treated rats (Gu et al., 2020).

Multiple Sclerosis
Multiple sclerosis is a chronic inflammatory disease in the central nervous system. The MS pathological process consists of multifocal inflammation, demyelination, reactive gliosis, and axonal degeneration (Baecher-Allan et al., 2018). GAS5 is significantly increased in microglia from experimental autoimmune encephalomyelitis (EAE) mice (an animal MS model). Up-regulated GAS5 attenuates the expression of interferon-regulatory factor 4 (IRF4) via binding with EZH2, which can impede microglia M2 polarization. Besides, enhanced microglial GAS5 can exacerbate myelin loss in EAE mice .

Spinal Cord Injury
Long non-coding RNA SNHG5 expression is increased in the astrocytes and microglia isolated from SCI rats. High SNHG5 expression elevates KLF4 expression. Enhanced SNHG5 expression improves cell viability and hampers apoptosis through KLF4 in astrocytes and microglia. In SCI rats, SNHG5 upregulation promotes SCI progression (Jiang and Zhang, 2018).

Traumatic Brain Injury
Extracellular vesicles are cargo-carrying vesicles that can affect cell communication (Teng and Fussenegger, 2020).  can target nucleotide-binding leucine-rich repeat containing family member X1 (NLRX1). LncRNA nuclear transcription factor NF-κB interacting lncRNA (NKILA) can be transferred from astrocytes into neurons through EVs. NKILA functions as a ceRNA for miR-195. NKILA competitively binds to miR-195 and counteracts miR-195 inhibitory effect on NLRX1 . NKILA from astrocyte-derived EVs diminishes miR-195 to augment NLRX1 expression. Subsequently, increased NLRX1 enhances proliferation and declines apoptosis in injured neurons. Moreover, in TBI mice, NKILA-enriched EVs from astrocytes accelerate brain recovery . It is reported that astrocyte swelling is one of the early consequences of TBI-induced brain edema. When astrocyte swelling occurs, the astrocyte volume is increased (Zhang et al., 2019d). MALAT1 expression is decreased in the edematous brain after TBI. Over-expressed MALAT1 abrogates astrocyte swelling through attenuating aquaporin 4 (AQP4), NF-κB, and IL-6 expressions in response to trauma. This study suggests the negative relationship between MALAT1 and TBI-related brain edema (Zhang et al., 2019d).

Neuropathic Pain
It is investigated that SNHG5 levels are remarkably increased in mouse spinal cord after spinal nerve ligation (SNL). In SNL mice, miR-154-5p elevation restrains CXCL13 protein levels, and inhibiting SNHG5 augments miR-154-5p levels . Knocking down SNHG5 dampens astrocyte activation and microglia activation via the miR-154-5p-CXCL13 axis. Repressing astrocyte activation and microglia activation can lessen neuropathic pain in SNL mice. This study revealed that SNHG5 deficiency alleviates neuropathic pain through the miR-154-5p-CXCL13 axis .

Epilepsy
It is said that adenosine deficiency is a hallmark of epilepsy. And therapeutic adenosine augmentation can be a promising approach for epileptic seizures (Boison, 2012). LncRNA cancer susceptibility candidate 2 (CASC2) is lowly expressed in the hippocampus in epileptic rats. Elevated CASC2 hinders astrocyte activation and restrains astrocyte adenosine metabolism via triggering phosphatase and tensin homolog (PTEN) expression during epilepsy. Increased CASC2 can also repress epilepsy seizures in epileptic rats . LncRNA urothelial cancer-associated 1 (UCA1) expression is down-regulated in the hippocampus of temporal lobe epilepsy rats. UCA1 overexpression abrogates astrocyte activation and suppresses the expression of astrocyte glutamate aspartate transporter (GLAST) (one factor related to epilepsy) in vivo. And UCA1 upregulation reduces the frequency of epilepsy seizures and promotes learning and memory in temporal lobe epilepsy rats (Wang et al., 2020b). Yu et al. (2020) revealed that upregulated UCA1 can enhance myocyte enhancer factor 2C (MEF2C) expression in IL-1β-treated CTX-TNA2 (the epilepsy cell models). MEF2C declines inflammatory effector [e.g., IL-6, TNF-α, and cyclooxygenase 2 (COX-2)] expression via blocking NF-κB signal in IL-1β-treated astrocytes. Increased UCA1 ultimately attenuates astrocyte inflammation through MEF2C/NF-κB pathway, which can hinder epilepsy progression . It is indicated that miR-129-5p can diminish Notch1 mRNA levels. LncRNA NEAT1 expression levels are elevated in the temporal lobe tissues in epilepsy patients compared to normal people. NEAT1 can target miR-129-5p and inhibit its expression (Wan and Yang, 2020). Increased NEAT1 activates the Notch1 signaling pathway by suppressing miR-129-5p. Finally, NEAT1 up-regulation can enhance astrocyte inflammatory responses in IL-1β-induced epilepsy cell models (Wan and Yang, 2020). In the brain, the brain-derived neurotrophic factor (BDNF) is essential for plasticity, neuronal survival, dendritic branching, etc. (Lima Giacobbo et al., 2019). LncRNA plasmacytoma variant translocation 1 (PVT1) is elevated in hippocampus tissues collected from epileptic rats. PVT1 down-regulation attenuates the Wnt signaling pathway, which can boost BDNF expression, impede neuronal loss, repress astrocyte activation, and decrease pro-inflammatory cytokine (e.g., TNF-α, IL-1β, and IL-6) expressions. PVT1 silence in epileptic rats also promotes spatial memory and learning .

Depression
Postpartum depression (PPD) remains one of the most common complications caused by childbirth. Stress and adverse life events can increase the risk of PPD (Payne and Maguire, 2019). The hormone-simulated pregnancyinduced PPD mouse model is used to explore the cellular mechanisms of PPD. It is indicated that oxytocin receptors play protective roles in PPD (Zhu and Tang, 2020). LncRNA Gm14205 is noticed to be up-regulated in the hippocampus in PPD mice. Up-regulated Gm14205 decreases oxytocin receptors, resulting in activating the NLRP3 inflammasome in hippocampal astrocytes. This study suggests a positive relationship between Gm14205 and PPD progression (Zhu and Tang, 2020).

Multiple Sclerosis
Long non-coding RNA Gm13568 expression is stimulated in astrocytes after IL-9 treatment. Gm13568 interacts with CREB-binding protein (CBP)/P300 to facilitate the expression and activation of Notch1 . The activated Notch1/STAT3 pathway contributes to the secretion of inflammatory cytokines (e.g., IL-6, TNF-α, and interferoninducible protein-10) in activated astrocytes. As a result, Gm13568 promotes astrocyte inflammation to worsen the EAE process ).

Alzheimer's Disease
Alzheimer's disease, a frequent neurodegenerative disorder, is the leading cause of dementia among elderly individuals. AD patients usually suffer from memory impairment, executive dysfunction, language problems, etc. (Scheltens et al., 2016). MEG3 expression is declined in the hippocampus tissues in AD rats. Up-regulated MEG3 suppresses astrocyte activation and neuronal damage via abrogating PI3K/AKT signaling pathway. Moreover, increased MEG3 can relieve cognitive impairment in AD rats (Yi et al., 2019).

CIRCULAR RNAs IN MICROGLIA AND ASTROCYTE MEDIATED NEUROLOGICAL DISEASES Spinal Cord Injury
It is reported that treating astrocytes with TNF-α in vitro can induce the inflammatory response after SCI. Elevated miR-488 attenuates inflammatory cytokine secretion in TNF-αtreated astrocytes. Chemokine CC motif ligand 2 (CCL2) is a downstream target of miR-488 (Chen et al., 2022). CircPrkcsh is up-regulated in mouse injured spinal cords and in TNF-α-treated astrocytes. CircPrkcsh serves as a miRNA sponge for miR-488. Silencing circPrkcsh decreases CCL2 expression via miR-488 upregulation (Chen et al., 2022). Chen et al. (2022) revealed that circPrkcsh knockout represses inflammatory response after SCI through the miR-488-CCL2 axis.

Ischemia-Reperfusion Injury
Neural stem cells (NSCs) can differentiate into neurons and astrocytes. The NSCs are important for brain tissue regeneration and tissue repair after injury (Gage and Temple, 2013). The expression of circRNA TTC3 (circTTC3) is up-regulated in MCAO/R mice. CircTTC3 can sponge miR-372-3p that targets Toll-like receptor 4 (TLR4). Depleting circTTC3 suppresses OGD-induced astrocyte injury and promotes NSC proliferation and differentiation via the miR-372-3p-TLR4 axis. The circTTC3 knockdown in MCAO/R mice can alleviate cerebral IRI .

Epilepsy
CircHivep2 is shown to be notably diminished in KA-treated BV2 cells and in hippocampus tissues of epilepsy mice. Suppressor of cytokine signaling-2 (SOCS2) is a target of miR-181a-5p. CircHivep2 binds to and sponges miR-181a-5p. CircHivep2 can decline miR-181a-5p to increase SOCS2 in KA-treated BV2 cells (Xiaoying et al., 2020). CircHivep2 elevation can attenuate microglia activation and microglia inflammation via the miR-181a-5p-SOCS2 axis. Over-expressed circHivep2 can ameliorate epileptic seizures in epilepsy mice (Xiaoying et al., 2020). CircIgf1r is up-regulated in the brain tissues in mice with status epilepticus. Inhibiting circIgf1r drives astrocyte A2 polarization via promoting autophagy. Therefore, circIgf1r inhibition reduces astrocyte-associated neuronal toxicity in the epilepsy cell model. Moreover, circIgf1r deficiency in epilepsy mice can impede neuronal damage and dampen epileptic discharge (Shao et al., 2021).

Depression
CircSTAG1 is significantly declined in the plasma and whole blood in depressed patients. In astrocytes, over-expressed circSTAG1 increases the demethylase alkB homolog 5 (ALKBH5) levels in the cell cytoplasm and reduces ALKBH5 translocation into the cell nucleus . Thus, circSTAG1 over-expression facilitates the methylation of fatty acid amide hydrolase (FAAH) mRNA and inhibits FAAH expression. Increased circSTAG1 ultimately hampers astrocyte dysfunction and thereby hinders depressive-like behaviors in mice with MDD . In the plasma and hippocampi of depressed mice, circHIPK2 expression levels are increased (Zhang et al., 2019c). One study indicated that circHIPK2 deficiency can inhibit astrocyte activation via reducing autophagy (Huang R. et al., 2017). Zhang et al. revealed that circHIPK2 expression can be attenuated by the transplantation of the NLRP3-deficient gut microbiota in depressed mice. Suppressing circHIPK2 can block astrocyte dysfunction and therefore reduce depression in mice (Zhang et al., 2019c). It is shown that increased HECT domain E3 ubiquitin protein ligase 1 (HECTD1) can reduce 90-kDa heat shock protein (HSP90) expression via ubiquitination. MiR-9 can bind with the 3 UTR of HECTD1 and repress HECTD1 expression . CircRNA DYM (circDYM) expression is down-regulated in the peripheral blood in patients with MDD CircDYM functions as a molecular sponge to interfere with miR-9 activity, leading to increased HECTD1. CircDYM over-expression inhibits HSP90 expression through the miR-9-HECTD1 axis, which can reduce microglial activation. Therefore, increased circDYM restrains depression in depressed mice .

Targeted Therapy
Long non-coding RNAs and circular RNAs participate in various neurological diseases, suggesting their potential to act as therapeutic targets. Bexarotene, which is a selective agonist of retinoid X receptor, can suppress TBI progression in mice (Zhong et al., 2017a). Bexarotene can stimulate NEAT1 expression to inhibit neuron apoptosis and microglial inflammation, resulting in promoting motor and cognitive function recovery in TBI mice (Zhong et al., 2017b). Curcumin, an anti-inflammatory agent, can be delivered into microglial cells via exosomes. Exosomal curcumin can repress LPS-induced brain inflammation and myelin oligodendrocyte glycoprotein (MOG)-induced EAE development in mice (Zhuang et al., 2011). Moreover, one research suggested that curcumin can increase GAS5 expression to alleviate post-stroke depression in rats (Cai et al., 2020a). Berberine belongs to traditional Chinese medicine. Berberine can elevate circHDAC9 expression in human neurons. Elevated circHDAC9 protects human neuron cells from 42-residue βamyloid (Aβ42)-triggered neuronal damage via sponging miR-142-5p . As mentioned above, targeting lncRNAs and circRNAs will be a promising strategy for the treatment of neurological diseases.

Dexmedetomidine
Dexmedetomidine (DEX), an anesthetic adjuvant, has various advantages in clinical applications, including hemodynamic stability, the ability to promote postoperative recognition, sedative and analgesic effects (Zhao Y. et al., 2020). DEX reduces high-mobility group box 1 (HMGB1) via eliminating SNHG14, resulting in attenuating microglial activation. Subsequently, DEX restrains neurological deficits induced by IRI in vivo (Ta Na et al., 2020). Deng et al. indicated that DEX can increase lncRNA LOC102546895 levels in hippocampus tissues in rats undergoing postoperative cognitive dysfunction (POCD). LOC102546895 promotes the expression of Neuronal Per-Arnt-Sim domain protein 4 (Npas4) (one protective neuronal transcription factor), impedes proliferation, and enhances apoptosis in microglial cells . DEX treatment hampers inflammatory response and neuron injury in the hippocampus. DEX can also ameliorate cognitive deficits in POCD rats .

Valproate
Valproate is an eight-carbon branched-chain fatty acid and possesses anticonvulsant properties. Valproate is approved for the management of epilepsy, bipolar disorders, and migraine (Löscher, 1999). Li et al. reported that valproate can decline lncRNA RMRP levels to activate PI3K/AKT pathway, which can promote proliferation and repress apoptosis in microglial cells in the ischemic stroke cell model (Li and Sui, 2020). In MACO rats, valproate treatment represses ischemic stroke-induced disorders, including cell apoptosis and cerebral infarction (Li and Sui, 2020).

DISCUSSION AND CONCLUSION
Microglia and astrocytes are glial cells that maintain tissue homeostasis in the nervous system. Accumulating evidence reports that both microglia and astrocytes have pro-inflammatory phenotype (M1/A1) and anti-inflammatory phenotype (M2/A2). Activated microglia and activated astrocytes can lead to inflammation, and the inflammation can contribute to microglial injuries, astrocyte injuries, and neuron damages. Inflammatory conditions also accelerate disease progression. LncRNAs and circRNAs are two ncRNAs involved in neural cell behaviors and nerve system development. For instance, up-regulated H19 increases CCL2 expression via sponging miR-1-3p, which can enhance astrocyte proliferation . Knockdown of circHIPK2 can enhance NSC differentiation into neurons and promote neuronal plasticity (Wang et al., 2020a). LncRNA BDNF-antisense (BDNF-AS) is increased in the human amygdala of alcohol use disorder patients who started to drink before 21 years old. Up-regulated BDNF-AS reduces BDNF signaling, resulting in inhibiting synaptic plasticity in the amygdala (Bohnsack et al., 2019). Xu K. et al. (2020) proved that circGRIA1 deficiency contributes to the improvement of synaptogenesis and synaptic plasticity. LncRNA AtLAS is down-regulated in the dorsal medial prefrontal cortex in dominant mice. AtLAS can increase synapsin 2b (syn2b) expression. Syn2b binds with a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) to restrain AMPAR membrane expression. Therefore, syn2b reduces AMPAR-correlated synaptic transmission. Decreased AtLAS contributes to enhanced synaptic strength in dominant mice .
Recently, increasing evidence reveals that lncRNAs and circRNAs can be transferred into recipient cells via EVs and control disease development. For example, astrocytes can transfer lncRNAs and circRNAs to neurons through EVs and repress neuron injuries, leading to alleviating nervous system damage (Figure 2; He et al., 2021). Shao et al. (2020) found that exosomal lncGm37494 from ADSCs stimulates microglia M2 polarization to enhance functional recovery after SCI. One study reported that intranasally delivered lincRNA-Cox2-siRNA loaded EVs can suppress microglia proliferation upon LPS treatment in mice (Liao et al., 2020). And Zhang et al. investigated that lincRNA-EPS can be loaded in biomimetic vesicles targeting microglia. And lincRNA-EPSloaded biomimetic vesicles abolish microglial inflammation to promote neuron regeneration in vivo . These suggest that EV-loaded ncRNAs targeted glial cells could be promising therapeutic therapies for the treatment of neurological disorders.
Presently, despite the great progress that has been made in neurodegeneration, the researches based on the ncRNAglial cell axis are still lacking. It is widely suggested that LPSinduced neuroinflammation can mimic the microenvironment in neurodegenerative diseases (Hu et al., 2018). LPS-treated FIGURE 2 | Astrocytes protect neurons against injuries via EVs. Astrocytes transfer lncRNAs and circRNAs to neurons through EVs. Both lncRNAs and circRNAs can act as miRNA sponges to inhibit miRNA repression on target proteins, which can restrain neuron damage. LncRNAs and circRNAs from astrocyte-derived EVs are beneficial for tissue repair in the nervous system. Frontiers in Molecular Neuroscience | www.frontiersin.org models may be useful to explore the pathological mechanism in neurodegeneration.