TERT mediates the U-shape of glucocorticoids effects in modulation of hippocampal neural stem cells and associated brain function.

BACKGROUND: Glucocorticoids (GCs) are steroidal hormones produced by the adrenal cortex. A physiological-level GCs have a crucial function in maintaining many cognitive processes, like cognition, memory, and mood, however, both insufficient and excessive GCs impair these functions. Although this phenomenon could be explained by the U-shape of GC effects, the underlying mechanisms are still not clear. Therefore, understanding the underlying mechanisms of GCs may provide insight into the treatments for cognitive and mood-related disorders. METHODS: Consecutive administration of corticosterone (CORT, 10 mg/kg, i.g.) proceeded for 28 days to mimic excessive GCs condition. Adrenalectomy (ADX) surgery was performed to ablate endogenous GCs in mice. Microinjection of 1 µL of Ad-mTERT-GFP virus into mouse hippocampus dentate gyrus (DG) and behavioral alterations in mice were observed 4 weeks later. RESULTS: Different concentrations of GCs were shown to affect the cell growth and development of neural stem cells (NSCs) in a U-shaped manner. The physiological level of GCs (0.01 µM) promoted NSC proliferation in vitro, while the stress level of GCs (10 µM) inhibited it. The glucocorticoid synthesis blocker metyrapone (100 mg/kg, i.p.) and ADX surgery both decreased the quantity and morphological development of doublecortin (DCX)-positive immature cells in the DG. The physiological level of GCs activated mineralocorticoid receptor and then promoted the production of telomerase reverse transcriptase (TERT); in contrast, the stress level of GCs activated glucocorticoid receptor and then reduced the expression of TERT. Overexpression of TERT by AD-mTERT-GFP reversed both chronic stresses- and ADX-induced deficiency of TERT and the proliferation and development of NSCs, chronic stresses-associated depressive symptoms, and ADX-associated learning and memory impairment. CONCLUSION: The bidirectional regulation of TERT by different GCs concentrations is a key mechanism mediating the U-shape of GC effects in modulation of hippocampal NSCs and associated brain function. Replenishment of TERT could be a common treatment strategy for GC dysfunction-associated diseases.

Prenatal stress modulates HPA axis homeostasis of offspring through dentate TERT independently of glucocorticoids receptor.

In response to stressful events, the hypothalamic-pituitary-adrenal (HPA) axis is activated, and consequently glucocorticoids are released by the adrenal gland into the blood circulation. A large body of research has illustrated that excessive glucocorticoids in the hippocampus exerts negative feedback regulation of the HPA axis through glucocorticoid receptor (GR), which is critical for the homeostasis of the HPA axis. Maternal prenatal stress causes dysfunction of the HPA axis feedback mechanism in their offspring in adulthood. Here we report that telomerase reverse transcriptase (TERT) gene knockout causes hyperactivity of the HPA axis without hippocampal GR deficiency. We found that the level of TERT in the dentate gyrus (DG) of the hippocampus during the developmental stage determines the responses of the HPA axis to stressful events in adulthood through modulating the excitability of the dentate granular cells (DGCs) rather than the expression of GR. Our study also suggests that the prenatal high level of glucocorticoids exposure-induced hypomethylation at Chr13:73764526 in the first exon of mouse Tert gene accounted for TERT deficiency in the DG and HPA axis abnormality in the adult offspring. This study reveals a novel GR-independent mechanism underlying prenatal stress-associated HPA axis impairment, providing a new angle for understanding the mechanisms for maintaining HPA axis homeostasis.

Design of fast-onset antidepressant by dissociating SERT from nNOS in the DRN.

Major depressive disorder (MDD) is one of the most common mental disorders. We designed a fast-onset antidepressant that works by disrupting the interaction between the serotonin transporter (SERT) and neuronal nitric oxide synthase (nNOS) in the dorsal raphe nucleus (DRN). Chronic unpredictable mild stress (CMS) selectively increased the SERT-nNOS complex in the DRN in mice. Augmentation of SERT-nNOS interactions in the DRN caused a depression-like phenotype and accounted for the CMS-induced depressive behaviors. Disrupting the SERT-nNOS interaction produced a fast-onset antidepressant effect by enhancing serotonin signaling in forebrain circuits. We discovered a small-molecule compound, ZZL-7, that elicited an antidepressant effect 2 hours after treatment without undesirable side effects. This compound, or analogous reagents, may serve as a new, rapidly acting treatment for MDD.

A novel LGI1 mutation causing autosomal dominant lateral temporal lobe epilepsy confirmed by a precise knock-in mouse model.

AIMS: This study aimed to explore the pathomechanism of a mutation on the leucine-rich glioma inactivated 1 gene (LGI1) identified in a family having autosomal dominant lateral temporal lobe epilepsy (ADLTE), using a precise knock-in mouse model. METHODS AND RESULTS: A novel LGI1 mutation, c.152A>G; p. Asp51Gly, was identified by whole exome sequencing in a Chinese family with ADLTE. The pathomechanism of the mutation was explored by generating Lgi1D51G knock-in mice that precisely phenocopied the epileptic symptoms of human patients. The Lgi1D51G/D51G mice showed spontaneous recurrent generalized seizures and premature death. The Lgi1D51G/+ mice had partial epilepsy, with half of them displaying epileptiform discharges on electroencephalography. They also showed enhanced sensitivity to the convulsant agent pentylenetetrazole. Mechanistically, the secretion of Lgi1 was impaired in the brain of the D51G knock-in mice and the protein level was drastically reduced. Moreover, the antiepileptic drugs, carbamazepine, oxcarbazepine, and sodium valproate, could prolong the survival time of Lgi1D51G/D51G mice, and oxcarbazepine appeared to be the most effective. CONCLUSIONS: We identified a novel epilepsy-causing mutation of LGI1 in humans. The Lgi1D51G/+ mouse model, precisely phenocopying epileptic symptoms of human patients, could be a useful tool in future studies on the pathogenesis and potential therapies for epilepsy.

Agomelatine: An Astounding Sui-generis Antidepressant?

Major depressive disorder (MDD) is one of the foremost causes of disability and premature death worldwide. Although the available antidepressants are effective and well tolerated, they also have many limitations. Therapeutic advances in developing a new drug's ultimate relation between MDD and chronobiology, which targets the circadian rhythm, led to a renewed focus on psychiatric disorders. In order to provide a critical analysis about antidepressant properties of agomelatine, a detailed PubMed (Medline), Scopus (Embase), Web of Science (Web of Knowledge), Cochrane Library, Google Scholar, and PsycInfo search was performed using the following keywords: melatonin analog, agomelatine, safety, efficacy, adverse effects, pharmacokinetics, pharmacodynamics, circadian rhythm, sleep disorders, neuroplasticity, MDD, bipolar disorder, anhedonia, anxiety, generalized anxiety disorder (GAD), and mood disorders. Agomelatine is a unique melatonin analog with antidepressant properties and a large therapeutic index that improves clinical safety. Published articles revealed that agomelatine is a melatonin receptors (MT1 and MT2) agonist and 5HT2C receptor antagonist. The effects receptors' on melatonin receptors enable the resynchronization of irregular circadian rhythms with beneficial effects on sleep architectures. In this way, agomelatine is accredited for its unique mode of action, which helps to exert antidepressant effects and resynchronize the sleep-wake cycle. To sum up, an agomelatine has not only antidepressant properties but also has anxiolytic effects.

Neuronal nitric oxide synthase in dorsal raphe nucleus mediates PTSD-like behaviors induced by single-prolonged stress through inhibiting serotonergic neurons activity.

The pathogenesis of post-traumatic stress disorder (PTSD) remains largely unclear. A large body of evidence suggests that the abnormal level of serotonin (5-HT) is closely related to the onset of PTSD. Several reports reveal that nitric oxide (NO) affects extracellular 5-HT levels in various brain regions, but no consistent direction of change was found and the underlying mechanisms remain unknown. The most of serotonergic neurons in dorsal raphe nucleus (DRN), a major source of serotonergic input to the forebrain, co-expresses neuronal nitric oxide synthase (nNOS), a synthase derived nitric oxide (NO) in the central nervous system. Here, we found that the excessive expression of nNOS and thereby the high concentration of NO followed by single-prolonged stress (SPS) caused suppression of the activity of DRN 5-HT neurons, inducing PTSD-like phenotype including increased anxiety-like behaviors, enhanced contextual fear memory, and fear generalization. Our study uncovered an important role of DRN nNOS-NO pathway in the pathology of PTSD, which may contribute to new understanding of the molecular mechanism of PTSD.

Abnormal expression profile of plasma-derived exosomal microRNAs in patients with treatment-resistant depression.

Whether microRNAs (miRNAs) from plasma exosomes might be dysregulated in patients with depression, especially treatment-resistant depression (TRD), remains unclear, based on study of which novel biomarkers and therapeutic targets could be discovered. To this end, a small sample study was performed by isolation of plasma exosomes from patients with TRD diagnosed by Hamilton scale. In this study, 4 peripheral plasma samples from patients with TRD and 4 healthy controls were collected for extraction of plasma exosomes. Exosomal miRNAs were analyzed by miRNA sequencing, followed by image collection, expression difference analysis, target gene GO enrichment analysis, and KEGG pathway enrichment analysis. Compared with the healthy controls, 2 miRNAs in the plasma exosomes of patients with TRD showed significant differences in expression, among which has-miR-335-5p were significantly upregulated and has-miR-1292-3p were significantly downregulated. Go and KEGG analysis showed that dysregulated miRNAs affect postsynaptic density and axonogenesis as well as the signaling pathway of axon formation and cell growths. The identification of these miRNAs and their target genes may provide novel biomarkers for improving diagnosis accuracy and treatment effectiveness of TRD.

New application of an old drug proparacaine in treating epilepsy via liposomal hydrogel formulation.

Proparacaine (PPC) is a previously discovered topical anesthetic for ophthalmic optometry and surgery by blocking the central Nav1.3. In this study, we found that proparacaine hydrochloride (PPC-HCl) exerted an acute robust antiepileptic effect in pilocarpine-induced epilepsy mice. More importantly, chronic treatment with PPC-HCl totally terminated spontaneous recurrent seizure occurrence without significant toxicity. Chronic treatment with PPC-HCl did not cause obvious cytotoxicity, neuropsychiatric adverse effects, hepatotoxicity, cardiotoxicity, and even genotoxicity that evaluated by whole genome-scale transcriptomic analyses. Only when in a high dose (50 mg/kg), the QRS interval measured by electrocardiography was slightly prolonged, which was similar to the impact of levetiracetam. Nevertheless, to overcome this potential issue, we adopt a liposome encapsulation strategy that could alleviate cardiotoxicity and prepared a type of hydrogel containing PPC-HCl for sustained release. Implantation of thermosensitive chitosan-based hydrogel containing liposomal PPC-HCl into the subcutaneous tissue exerted immediate and long-lasting remission from spontaneous recurrent seizure in epileptic mice without affecting QRS interval. Therefore, this new liposomal hydrogel formulation of proparacaine could be developed as a transdermal patch for treating epilepsy, avoiding the severe toxicity after chronic treatment with current antiepileptic drugs in clinic.

A novel method for automatic pharmacological evaluation of sucrose preference change in depression mice.

Sucrose preference test (SPT) is a most frequently applied method for measuring anhedonia, a core symptom of depression, in rodents. However, the method of SPT still remains problematic mainly due to the primitive, irregular, and inaccurate various types of home-made equipment in laboratories, causing imprecise, inconsistent, and variable results. To overcome this issue, we devised a novel method for automatic detection of anhedonia in mice using an electronic apparatus with its program for automated detecting the behavior of drinking of mice instead of manual weighing the water bottles. In this system, the liquid surface of the bottles was monitored electronically by infrared monitoring elements which were assembled beside the plane of the water surface and the information of times and duration of each drinking was collected to the principal machine. A corresponding computer program was written and installed in a computer connected to the principal machine for outputting and analyzing the data. This new method, based on the automated system, was sensitive, reliable, and adaptable for evaluation of stress- or drug-induced anhedonia, as well as taste preference and effects of addictive drugs. Extensive application of this automated apparatus for SPT would greatly improve and standardize the behavioral assessment method of anhedonia, being instrumental in novel antidepressant screening and depression researching.

Emerging mechanisms of valproic acid-induced neurotoxic events in autism and its implications for pharmacological treatment.

Autism spectrum disorder (ASD) is a sort of mental disorder marked by deficits in cognitive and communication abilities. To date no effective cure for this pernicious disease has been available. Valproic acid (VPA) is a broad-spectrum, antiepileptic drug, and it is also a potent teratogen. Epidemiological studies have shown that children exposed to VPA are at higher risk for ASD during the first trimester of their gestational development. Several animal and human studies have demonstrated important behavioral impairments and morphological changes in the brain following VPA treatment. However, the mechanism of VPA exposure-induced ASD remains unclear. Several factors are involved in the pathological phase of ASD, including aberrant excitation/inhibition of synaptic transmission, neuroinflammation, diminished neurogenesis, oxidative stress, etc. In this review, we aim to outline the current knowledge of the critical pathophysiological mechanisms underlying VPA exposure-induced ASD. This review will give insight toward understanding the complex nature of VPA-induced neuronal toxicity and exploring a new path toward the development of novel pharmacological treatment against ASD.

Gut-brain axis: A matter of concern in neuropsychiatric disorders !

The gut microbiota is composed of a large number of microbes, usually regarded as commensal bacteria. It has become gradually clear that gastrointestinal microbiota affects gut pathophysiology and the central nervous system (CNS) function by modulating the signaling pathways of the microbiota-gut-brain (MGB) axis. This bidirectional MGB axis communication primarily acts through neuroendocrine, neuroimmune, and autonomic nervous systems (ANS) mechanisms. Accumulating evidence reveals that gut microbiota interacts with the host brain, and its modulation may play a critical role in the pathology of neuropsychiatric disorders. Recently, neuroscience research has established the significance of gut microbiota in the development of brain systems that are essential to stress-related behaviors, including depression and anxiety. Application of modulators of the MGB, such as psychobiotics (e.g., probiotics), prebiotics, and specific diets, may be a promising therapeutic approach for neuropsychiatric disorders. The present review article primarily focuses on the relevant features of the disturbances of the MGB axis in the pathophysiology of neuropsychiatric disorders and its potential mechanisms.

Response of resources and environment carrying capacity under the evolution of land use structure in Chongqing Section of the Three Gorges Reservoir Area.

In this study, a comprehensive model for suitable carrying capacity of resources and environment was proposed based on ecological footprint method. Using the spatiotemporal distribution data of land use in Chongqing Section of Three Gorges Reservoir Area from 2001 to 2016, the response changes of carrying capacity of resources and environment under the evolution of land use structure were investigated. The analytical results showed that the suitable carrying capacity of resources and environment in Chongqing decreased first and then increased. In the early stage of the Three Gorges Project, some districts and counties exhibited the phenomenon of suitable carrying capacity deficit, especially in the northeast of Chongqing. In the main urban area of Chongqing, the suitable carrying capacity was also mainly restricted by the ecological resources conditions, the deficit was getting worse with the increase of population density. In the later stage, by restoring ecology and improving the living and economic conditions, the phenomenon of deficit was gradually alleviated. These findings will provide some references for the protection of ecological environment and the development of social economy in Chongqing Section of the Three Gorges Reservoir Area.

Dentate nNOS accounts for stress-induced 5-HT1A receptor deficiency: Implication in anxiety behaviors.

BACKGROUND: Anxiety is a common disorder with high social burden worldwide. Dysfunction of serotonin-1A receptor (5-HT1A receptor) in the dentate gyrus (DG) of the hippocampus has been predominantly implicated in the anxiety behavior. However, the molecular mechanism underlying the deficiency of postsynaptic 5-HT1A receptor in regulating anxiety behavior remains unclear. METHODS: Using pharmacological and genetic methods, we investigated the role of detate nNOS in 5-HT1A receptor decline and anxiety behavior induced by chronic mild stress (CMS) in mice. RESULTS: Here we showed that local elevation of glucocorticoids in the DG accounted for chronic stress-induced anxiety behavior. Neuronal nitric oxide synthase (nNOS) mediated chronic stress-induced downregulation of 5-HT1A receptor in the DG through peroxynitrite anion (ONOO•) pathway but not cyclic guanosine monophosphate (cGMP) pathway. By using pharmacological tool drugs and nNOS knockout mice, we found that nNOS in the DG played a key role in chronic stress-induced anxiety behavior. CONCLUSIONS: These findings uncovered an important role of nNOS-5-HT1A receptor pathway in the DG of the hippocampus in chronic stress-induced anxiety. Accordingly, we developed a "dentate nNOS-5-HT1A receptor closed-loop" theory (stress-glucocorticoids-nNOS-Nitric oxide-ONOO•-5-HT1A receptor -nNOS) of stress-related anxiety.

Screening for Potential Active Components of Fangji Huangqi Tang on the Treatment of Nephrotic Syndrome by Using Integrated Metabolomics Based on "Correlations Between Chemical and Metabolic Profiles".

As for traditional Chinese medicine (TCM) prescription, what puzzled researchers most was how to select proper chemical markers to represent the whole pharmacological action system. In this paper, an integrated metabolomic method was presented for a systematic discovery of potential active components in Fangji Huangqi Tang (FHT), a well-known TCM prescription for nephrotic syndrome treatment, based on "correlations between chemical and metabolic profiles." Firstly, a metabolomics study was carried out to select representative biomarkers of nephrotic syndrome. Then, after drug administration, the dynamic process of serum composition was investigated by the ultra-high performance liquid chromatography coupled with electrospray ionization-quadrupole-time of flight-mass spectrometry (UHPLC-ESI-Q-TOF-MS) technique to detect the prototypes and related metabolites of relative components from FHT. Pearson correlation analysis was finally used to find out the correlations between the endogenous metabolic spectrums and the chemical serum spectrums. As a result, 17 biomarkers for nephrotic syndrome indication were identified, and the main metabolic pathways of their concern included linoleic acid metabolism; cyanoamino acid metabolism; alpha-linolenic acid metabolism; glycine, serine, and threonine metabolism; arachidonic acid metabolism; and glycerophospholipid metabolism. Meanwhile, active components in FHT for nephrotic syndrome treatment were screened out, including (+)-tetrandrine demethylation, fenfangjine G hydrogenation, tetrandrine, N-methylfangchinoline, tetrandrine demethylation, fangchinoline, glycyrrhetic acid, astragaloside II alcohol dehydration, atractylenolide III demethylation + hydrogenation, atractylenolide III demethylation + hydrogenation, and licoricone-N-acetylcysteine conjugation. This study demonstrated a promising way to elucidate the active chemical material basis of TCM prescription.

Cerebrovascular inflammation: A critical trigger for neurovascular injury?

The cerebrovascular system is not only inert bystandard that support the metabolic demands of the brain but also elicit the barrier functions against risk factors mediated neurovascular injury. The onsets of cerebrovascular inflammation are considered as stimuli that can provoke the host defense system and trigger the development of neurological disorders. Homeostasis of the brain function is regulated by the movement of endothelial, glial, and neuronal cells within the neurovascular unit (NVU), which acts as a "platform" for the coordinated action of anti- and pro-inflammatory mechanisms. The cerebrovascular system plays an integral role in the inflammatory response by either producing or expressing a variety of cytokines, adhesion molecules, metalloproteinases, and serine proteases. Excessive inflammatory cytokine production can further be affecting the blood-brain barrier (BBB) integrity and lead to brain tissue damage. In this review, we summarize the more recent evidence highlighting the importance of cerebrovascular injury in terms of risk prediction, and the mechanisms mediating the upregulation of inflammatory mediators in cerebrovascular dysfunction and neurodegeneration.

Chitosan oligosaccharide (COS): An overview.

The frequently studied polysaccharide, chitosan oligosaccharide/chitooligosaccharide (COS) is the major degradation product of chitosan/chitin via chemical hydrolysis or enzymatic degradation involving deacetylation and depolymerization processes. Innumerable studies have revealed in the recent decade that COS has various promising biomedical implications in the past analysis, current developments and potential applications in a biomedical, pharmaceutical and agricultural sector. Innovations into COS derivatization has broadened its application in cosmeceutical and nutraceutical productions as well as in water treatment and environmental safety. In relation to its parent biomaterials and other available polysaccharides, COS has low molecular weight (Mw), higher degree of deacetylation (DD), higher degree of polymerization (DP), less viscous and complete water solubility, which endowed it with significant biological properties like antimicrobial, antioxidant, anti-inflammatory and antihypertensive, as well as drug/DNA delivery ability. In addition, it is also revealed to exhibit antidiabetic, anti-obesity, anti-HIV-1, anti-Alzheimer's disease, hypocholesterolemic, calcium absorption and hemostatic effects. Furthermore, COS is shown to have higher cellular transduction and completely absorbable via intestinal epithelium due to its cationic sphere exposed on the more exposed shorter N-glucosamine (N-Glc) units. This paper narrates the recent developments in COS biomedical applications while paying considerable attention to its physicochemical properties and its chemical composition. Its pharmacokinetic aspects are also briefly discussed while highlighting potential overdose or lethal dosing. In addition, due to its multiple NGlc unit composition and vulnerability to degradation, its safety is given significant attention. Finally, a suggestion is made for extensive study on COS anti-HIV effects with well-refined batches.

Extracellular regulated protein kinaseis critical for the role of 5-HT1a receptor in modulating nNOS expression and anxiety-related behaviors.

Our previous study found that serotonin 1A receptor (5-HT1aR) is an endogenous suppressor of nNOS expression in the hippocampus, which accounts for anxiolytic effect of fluoxetine. However, the precise molecular mechanism remains unknown. By using 8-OH-DPAT, a selective 5-HT1aR agonist, NAN-190, a selective 5-HT1aR antagonist, and U0126, an Extracellular Regulated Protein Kinases (ERK) phosphorylation inhibitor, we investigated the role of ERK in 5-HT1aR-nNOS pathway. Western blots analysis demonstrated that 5-HT1aR activation up-regulated the level of phosphorylated ERK (P-ERK) beginning at 5 min and down-regulated the expression of nNOS beginning at 20 min. Meanwhile, blockage of 5-HT1aR resulted in a decrease in P-ERK beginning at 20 min and caused an increase in nNOS expression beginning at 6 h. Although U0126 itself did not alter nNOS expression and activity, NO level, and anxiety-related behaviors, the treatment totally reversed 8-OH-DPAT-induced reduction in nNOS expression and function, and anxiolytic effect. Besides, our data showed that ERK phosphorylation was essential for 5-HT1aR activation-induced cAMP responsive element binding protein (CREB) phosphorylation, hippocampal neurogenesis and synaptogenesis of newborn neuron. Our study suggests a crucial role of ERK phosphorylation in the regulation of nNOS expression by 5-HT1aR, which is helpful for understanding the mechanism of 5-HT1aR-based anxiolytic treatment.

Chemogenetic silencing of hippocampal neurons suppresses epileptic neural circuits.

We investigated how pathological changes in newborn hippocampal dentate granule cells (DGCs) lead to epilepsy. Using a rabies virus-mediated retrograde tracing system and a designer receptors exclusively activated by designer drugs (DREADD) chemogenetic method, we demonstrated that newborn hippocampal DGCs are required for the formation of epileptic neural circuits and the induction of spontaneous recurrent seizures (SRS). A rabies virus-mediated mapping study revealed that aberrant circuit integration of hippocampal newborn DGCs formed excessive de novo excitatory connections as well as recurrent excitatory loops, allowing the hippocampus to produce, amplify, and propagate excessive recurrent excitatory signals. In epileptic mice, DREADD-mediated-specific suppression of hippocampal newborn DGCs dramatically reduced epileptic spikes and SRS in an inducible and reversible manner. Conversely, specific activation of hippocampal newborn DGCs increased both epileptic spikes and SRS. Our study reveals an essential role for hippocampal newborn DGCs in the formation and function of epileptic neural circuits, providing critical insights into DGCs as a potential therapeutic target for treating epilepsy.

Long-Term Labeling of Hippocampal Neural Stem Cells by a Lentiviral Vector.

Using a lentivirus-mediated labeling method, we investigated whether the adult hippocampus retains long-lasting, self-renewing neural stem cells (NSCs). We first showed that a single injection of a lentiviral vector expressing a green fluorescent protein (LV PGK-GFP) into the subgranular zone (SGZ) of the adult hippocampus enabled an efficient, robust, and long-term marking of self-renewing NSCs and their progeny. Interestingly, a subset of labeled cells showed the ability to proliferate multiple times and give rise to Sox2+ cells, clearly suggesting the ability of NSCs to self-renew for an extensive period of time (up to 6 months). In addition, using GFP+ cells isolated from the SGZ of mice that received a LV PGK-GFP injection 3 months earlier, we demonstrated that some GFP+ cells displayed the essential properties of NSCs, such as self-renewal and multipotency. Furthermore, we investigated the plasticity of NSCs in a perforant path transection, which has been shown to induce astrocyte formation in the molecular layer of the hippocampus. Our lentivirus (LV)-mediated labeling study revealed that hippocampal NSCs are not responsible for the burst of astrocyte formation, suggesting that signals released from the injured perforant path did not influence NSC fate determination. Therefore, our studies showed that a gene delivery system using LVs is a unique method to be used for understanding the complex nature of NSCs and may have translational impact in gene therapy by efficiently targeting NSCs.

Neuronal nitric oxide synthase and affective disorders.

Affective disorders including major depressive disorder (MDD), bipolar disorder (BPD), and general anxiety affect more than 10% of population in the world. Notably, neuronal nitric oxide synthase (nNOS), a downstream signal molecule of N-methyl-D-aspartate receptors (NMDARs) activation, is abundant in many regions of the brain such as the prefrontal cortex (PFC), hippocampus, amygdala, dorsal raphe nucleus (DRN), locus coeruleus (LC), and hypothalamus, which are closely associated with the pathophysiology of affective disorders. Decreased levels of the neurotransmitters including 5-hydroxytryptamine or serotonin (5-HT), noradrenalin (NA), and dopamine (DA) as well as hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis are common pathological changes of MDD, BPD, and anxiety. Increasing data suggests that nNOS in the hippocampus play a crucial role in the etiology of MDD whereas nNOS-related dysregulation of the nitrergic system in the LC is closely associated with the pathogenesis of BPD. Moreover, hippocampal nNOS is implicated in the role of serotonin receptor 1 A (5-HTR1 A) in modulating anxiety behaviors. Augment of nNOS and its carboxy-terminal PDZ ligand (CAPON) complex mediate stress-induced anxiety and disrupting the nNOS-CAPON interaction by small molecular drug generates anxiolytic effect. To date, however, the function of nNOS in affective disorders is not well reviewed. Here, we summarize works about nNOS and its signal mechanisms implicated in the pathophysiology of affective disorders. On the basis of this review, it is suggested that future research should more fully focus on the role of nNOS in the pathomechanism and treatment of affective disorders.