Neurogenesis Research Articles

While it has been hypothesized that adult neurogenesis (NG) plays a role in the encoding of temporal information at long time-scales, the temporal relationship of immature cells to the highly rhythmic network activity of the hippocampus has been largely unexplored. Here, we present a theory for how the activity of immature adult-born granule cells relates to hippocampal oscillations. Our hypothesis is that theta rhythmic (5–10 Hz) excitatory and inhibitory inputs into the hippocampus could differentially affect young and mature granule cells due to differences in intrinsic physiology and synaptic inhibition between the two cell populations. Consequently, immature cell activity may occur at broader ranges of theta phase than the activity of their mature counterparts. We describe how this differential influence on young and mature granule cells could separate the activity of differently aged neurons in a temporal coding regime. Notably, this process could have considerable implications on how the downstream CA3 region interprets the information conveyed by young and mature granule cells. To begin to investigate the phasic behavior of granule cells, we analyzed in vivo recordings of the rat dentate gyrus (DG), observing that the temporal behavior of granule cells with respect to the theta rhythm is different between rats with normal and impaired levels of NG. Specifically, in control animals, granule cells exhibit both strong and weak coupling to the phase of the theta rhythm. In contrast, the distribution of phase relationships in NG-impaired rats is shifted such that they are significantly stronger. These preliminary data support our hypothesis that immature neurons could distinctly affect the temporal dynamics of hippocampal encoding.

Background Monosialotetrahexosylganglioside (GM1) is a kind of ganglioside extracted from the neural cells of pig brain, which involves in the pathophysiological processes of neurogenesis, and plays an important role in neural formation, growth and differentiation. GM1 is widely used in the treatment for vascular brain injury and traumatic brain and spinal cord injury, promoting and protecting the recovery of nerve cells. Besides, it can improve the behavior disorders of patients with Parkinson's disease. However, as it is widely used in clinical practice, its adverse reaction has been gradually discovered. There is some evidence to suggest Guillain-Barre syndrome (GBS) may occur after GM1 injection intravenously. Both clinical manifestations and possible mechanism of GBS associated with GM1 are unclear, and need further study. Methods Three cases of GBS associated with GM1 were clinically observed including cerebrospinal fluid (CSF) testing and nerve conduction studies. These cases were analyzed and subjected to assessment with literature review. Results Three male patients (with the age 39-65) of GBS were observed after injection of GM1 intravenously. At 9-14 days, they developed weakness of all limbs and were unable to stand upright with decreased muscle tone in limbs and absent deep tendon reflexes, accompanied by dyspnea (1 case), albuminocytological dissociation (1 case) and axonal degeneration of peripheral nerve (1 case). Conclusion GBS may occur occasionally in patients treated with GM1 injection intravenously for 9-14 days, and the prognosis is not favorable. The possible mechanism is that exogenous gangliosides could be immunogenic and may occasionally result in neural axonal degeneration.

Several lines of evidence support the role of hippocampal neurogenesis in the successful treatment of depression. Two recent translational studies add

Vitamin D (vitD), vitD binding protein-derived macrophage activating factor (DBP-MAF), and vitD receptor (VDR) are essential for adult neurogenesis [1], and this effect could be responsible for the recently reported effects of DBP-MAF on autism spectrum disorders (ASD) [2]. In order to test this hypothesis, we challenged a human neuronal cell line (SH-SY5Y, IZSLER) with DBP-MAF (Immuno Biotech), and we studied cAMP formation (cAMP EIA kit, Abnova), cell proliferation (MTT assay, Sigma Aldrich), apoptosis (human caspase 3 act, Invitrogen) and cell morphology. SH-SY5Y cells represent a validated in vitro model of human neurons in neurodegenerative diseases [3]. DBP-MAF induced rapid (15 min) formation of cAMP in a dose-dependent manner (0.4-40 ng/ml) as well as increase in cell proliferation at 24-48 and 72 h. Cell morphology was consistent with neurogenesis and an increase in the number of cells with high synthetic activity was observed. No apoptosis following DBP-MAF treatment was observed. Our results open the way to exploit these newly described effects to treat neurodegenerative disorders from Parkinson’s and Alzheimer’s diseases to Myalgic Encephalomyelitis and ASD.

Fetal striatal transplantation emerged as a new strategy to promote reparative responses in Huntington’s disease (HD) patients1. Mechanisms that support neuroblasts survival and replenishment of damaged cells within the HD brain in hypoxia remain to be elucidated. This study investigated how human fetal striatal neuroblasts (HSP cells) respond to hypoxia, using the hypoxia-mimetic agent cobalt chloride (CoCl2)2. We analyzed CoCl2 effect on hypoxia-related proteins, such as HIF-1α and VEGF, and on a neuroprotective factor, such as Seladin-1. Moreover, we evaluated FGF2 (50 ng/ml) and ET1 (100 nM) proliferative/survival effects in HSP cells in normoxic and hypoxic conditions. These growth factors could be important mediators under pathological conditions for striatal neuroblasts function and response to hypoxia. Dose-response experiments with increasing concentration of CoCl2 (50-750 um) showed an increase of HSP cell proliferation at 24-48h, with maximal effects observed at 400 um, while cell survival was impaired at 72h. Hypoxia increased protein expressions of HIF-1α and VEGF, whereas decreased Seladin-1 levels. FGF2 and ET1 significantly stimulated HSP cells proliferation both in normoxic and hypoxic condition, counteracting the apoptotic CoCl2 effect at 72h. FGF2 and ET1 neuroprotective effect was abolished by the selective inhibition of their receptors (FGFR1, ETA and ETB). In particular, ET1 stimulated HSP cells survival through ETA receptor in normoxic condition and through ETB receptor during hypoxia. Our results support the idea that FGF2 and ET1 promote neurogenesis and survival of HSP cells, through receptor-mediated mechanisms, when grafted into the hypoxic HD brain.

Ciliary neurotrophic factor (CNTF) is a potent survival molecule for a large number of neuronal and glial cells. We previously found that in mouse hypothalamus CNTF is expressed by ependymal cells and tanycyctes lining the third ventricle and in a few scattered glial cells (Severi et al., 2012). Exogenously administered CNTF produces an anorectic effect via activation of hypothalamic neurons, and also stimulates neurogenesis in mouse hypothalamus. Thus, we evaluated CNTF expression in the hypothalamus of mice feeding a high fat diet (HFD, 50% of calories as fat) and in mice kept in a calorie restriction (CR) regimen (60% of individual mean food intake). RT-PCR showed a significant increase of both CNTF and CNTF receptor α (CNTFRα) mRNAs in the hypothalamus of the HFD mice; conversely, CR mice exhibited a significant decrease of CNTF and CNTFRα. Immunohistochemistry showed that in the HFD mice the hypothalamic increase of CNTF was restricted to the tanycytes located in the ependymal layer bordering the median eminence and sending their processes to the arcuate, ventromedial and dorsomedial nuclei, the tuberal part of the hypothalamus strongly involved in energy balance regulation. Stimulation of cells bearing the CNTFRα induces specific activation of the signal transducer and activator of transcription 3 (STAT3) signalling system. Intraperitoneal treatment with recombinant CNTF and detection of the nuclear expression of phospho-STAT3 (P-STAT3) confirmed an increased responsiveness of HFD mice hypothalamus to CNTF and, conversely, a decreased expression of the receptor in the mice kept in the CR regimen. Interestingly, only in the HFD mice CNTF was able to activate a large population of neurons dispersed in the arcuate, ventromedial and dorsomedial nuclei.

Objective To investigate the possible abnormal changes of adult neurogenesis in the rostral migratory stream(RMS) , in the olfactory bulb and in learning or memory of renovascular hypertensive rat, and to evaluate the possible efficacies produced by intervention of exogenous melatonin. Methods Renovascular hypertensive rat model was established by clamping bilateral renal arteries. Rats were randomly divided into four groups with 10 rats per group: hypertensive, sham-operated, melatonin-treated and normal groups. Morris water maze was used to detect the abilities of learning and memory, and immunohistochemistry for bromodeoxyuridine(BrdU), bromodeoxyuridine plus glial fibrillary acidic protein (BrdU+ GFAP) and bromodeoxyuridine plus neurofilament (BrdU+ NT) was utilized to examine the changes of the adult neurogenesis in RMS and in the olfactory bulb of each rat. Results The escape latency of hypertensive group ((29.95±20.11) s) recorded in Morris water maze test was the longest in a significant comparison to those of normal group((20.58±19.18)s), sham-operated group ((22.11±20.28)s) and melatonin-treated group((23.81±22.25)s)(P<0.05); while the time spent by rats during swimming in the quadrant with being originally put platform of hypertensive((25.51±5.21)s) was the shortest by significant comparison to those of normal((34.67±4.53)s), sham-operated((33.56±6.12)s) and melatonin-treated group ((36.23±3.86)s)(P<0.05). Proliferation of neural stem cells(cells/field): the number of BrdU immunoreactive (BrdU-IR) cells of rats in RMS of hypertensive group(34.08±6.49) was the smallest, significantly compared with those of normal(43.53±7.56), sham-operated(46.11±4.75) and melatonin-treated group(44.30±8.29), (P<0.05). Differentiation of neural stem cells(cells/slice): the number of BrdU+ GFAP-IR cells in olfactory bulb of hypertensive group(2.45±1.32) was largest, significantly compared with those of normal(1.01±0.78), sham-operated(0.68±0.37) and melatonin-treated group(1.35±0.88)(P<0.05); while the number of BrdU+ NF-IR cells in olfactory bulb of hypertensive group(1.15±0.81) was the smallest, significantly compared with those of normal (1.89±0.98), sham-operated(1.63±1.01) and melatonin-treated group(2.30±1.22)(P<0.05). Conclusion Melatonin can ameliorate the abnormal cognitive behaviors induced by hypertension via a mechanism of reversing the progression of neurogenesis disorders both in RMS and in olfactory bulb, indicating that melatonin may prevent the development of dementia triggered by hypertension. Key words: Melatonin; Hypertension; Spatial memory; Rostral migratory stream; Olfactory bulb

OR11-3 IGF-II and neurogenesis: in vitro and in vivo analyses

Objective To study the influence of ginseng total saponins treatment on the expression of cortical neuroregeneration - related factors in rat after traumatic brain injury and to analyze the beneficical effect of GTS for neuro - repair and neuro - restoration after injury.Methods The modified Feeney 's method was used to establish TBI model in rat.GTS(20 mg/kg) was treated at 6h after operation for 7 days.The expression of neurogenesis - promoting factors and neurogenesis inhibitors in the brain cortex ipsilateral to the trauma were measured. NGF,NCAM,Nogo - A,Nogo - B,TN - C190 and TN - C220 were measured with western - blot analysis. GFAP and GDNF were detected by immunofluorescent method.Results The expression of neurogenesis promoting factors ( NGF,NCAM,GDNF) was increased ( 1.232 ± 0.007,1.086 ± 0.024,49.0 ± 3.00) after TBI.The expression of neurogenesis inhibitors ( Nogo - A,Nogo- B,TN-C190,TN -C220) was also enhanced (1.196 ± 0.041,1.297 ± 0.024,0.930± 0.057,0.888 ± 0.012).The GTS treatment after TBI chould further promote the expression of NGF,GDNF and NCAM ( 1.276 ± 0.003,1.184 ± 0.022,68.4 ± 2.79),and reduce the expression of Nogo -A,Nogo-BandTN-C(1.074 ± 0.021,1.126 ± 0.025,0.762 ± 0.022,0.651 ± 0.030).After TBI,GFAP- positive cells were increased to (90.4 ± 3.44) in the cortex.GTS treatment chould slightly decrease GFAP - positive cells to 85.4 ± 2.70,but without significant difference.Conclusions In addition to their neuroprotective effects,GTS may promote neural tissue regeneration and repair by regulating the expression of neurogenesis - related factors,thereby promote recovery of neurological function. Key words: Traumatic brain injury; Cerebral cortex; Nerve regeneration ; Ginseng total saponins

Background Recent researches have revealed the intimate relationship between γ-aminobutyric acid (GABA) GABAA receptors pathway and neurogenesis.Neurogenesis occurs not only in fetal and neonatal period but in adult.The neurogenesis in hippocampus has an intimate relationship with cognitive function and memory.Objective To investigate the relationship between the GABAA receptors and the neurogenesis,explore the pharmacology of general anesthetics works through the GABAA.Content This review is mainly focused on the relationship between the GABAA receptors and the neurogenesis and the underlying mechanism.Trend Systematic studies focused on the relationship between the GABAA receptors and the neurogenesis will provide new ideas regarding the studies of the effects of general anesthetic on the cognitive function. Key words: Receptors,GABAA; Neurogenesis; Anesthetics, general

Stimulation of the vagus nerve has been previously reported to promote neural plasticity and neurogenesis in the brain. Several studies also revealed plastic changes in the spinal cord after injuries to somatosensory nerves originating from both the brachial and lumbo-sacral plexuses. However, the neurogenic responses of the brain to the injury of the viscerosensory innervation are not as yet well understood. In the present study, we investigated whether cells in the dentate gyrus of the hippocampus respond to a chemical and physical damage to the vagus nerve in the adult rat. Intraperitoneal capsaicin administration was used to damage non-myelinated vagal afferents while subdiaphragmatic vagotomy was used to damage both the myelinated and non-myelinated vagal afferents. The 5-bromo-2-deoxyuridine (BrdU) incorporation together with cell-specific markers was used to study neural proliferation in subgranular zone, granule cell layer, molecular layer and hilus of the dentate gyrus. Microglia activation was determined by quantifying changes in the intensity of fluorescent staining with a primary antibody against ionizing calcium adapter-binding molecule 1. Results revealed that vagotomy decreased BrdU incorporation in the hilus 15 days after injury compared to the capsaicin group. Capsaicin administration decreased BrdU incorporation in the granular cell layer 60 days after the treatment. Capsaicin decreased the number of doublecortin-expressing cells in the dentate gyrus, whereas vagotomy did not alter the expression of doublecortin in the hippocampus. Both the capsaicin- and the vagotomy-induced damage to the vagus nerve decreased microglia activation in the hippocampus at 15 days after the injury. At 30 days post injury, capsaicin-treated and vagotomized rats revealed significantly more activated microglia. Our findings show that damage to the subdiaphragmatic vagus in adult rats is followed by microglia activation and long-lasting changes in the dentate gyrus, leading to alteration of neurogenesis.

Rats with chronic pilocarpine-induced temporal lobe epilepsy complicated with depression were studied. Anti-5-bromodeoxyuridine immunofluorescence staining and Timms staining showed that neurogenesis within the hippocampal dentate gyrus and mossy fiber sprouting were increased in model rats. Neurogenesis within the hippocampal dentate gyrus was further enhanced, while mossy fiber sprouting was decreased in model rats administered carbamazepine alone or in combination with the 5-hydroxytryptamine 1A receptor agonist, 8-hydroxy-dipropylaminotetralin (0.1 and 1 mg/kg). Among the groups, the effect was the most significant in rats receiving carbamazepine in conjunction with 1 mg/kg 8-hydroxy-dipropylaminotetralin. Thus, high dose 8-hydroxy-dipropylaminotetralin can improve neural plasticity in epileptic rats with depression.

The cerebral cortical expansion index refers to the ratio between left and right cortex width and is recognized as an indicator for cortical hyperplasia. Cerebral ischemia was established in CB-17 mice in the present study, and the mice were subsequently treated with recombinant human erythropoietin via subcutaneous injection. Results demonstrated that cerebral cortical width index significantly increased. Immunofluorescence detection showed that the number of nuclear antigen antibody/5-bromodeoxyuridine-positive cells at the infarction edge significantly increased. Correlation analysis revealed a negative correlation between neurological scores and cortical width indices in rats following ischemic stroke. These experimental findings suggested that recombinant human erythropoietin promoted cerebral cortical hyperplasia, increased cortical neurogenesis, and enhanced functional recovery following ischemic stroke.

Neurogenesis and Pattern Integration

Currently, it is accepted that brain injury promotes endogenous neurogenesis in mammals, primarily in the subventricular zone (SVZ), and newborn cells can migrate to the injured area. We examined the pattern of endogenous neurogenesis in adult rats after intracerebral hemorrhage (ICH) that was caused by intrastrial administration of collagenase type IV. Our results showed that ICH induced strong endogenous neurogenesis between 72 hours and 7 days after injury, but that the majority of newborn cells did not survive longer than 3 weeks due to apoptosis-mediated cell death. Furthermore, endogenous neurogenesis remained into a small extent at least 1 year after ICH. Because of the growing interest in new strategies for brain regeneration, these data suggest endogenous neurogenesis and inhibiting apoptosis of newborn neuroblasts as potential strategies to improve the consequences of hemorrhagic stroke in humans.

La terapia de radiacion cerebral esta asociada con muchas consecuencias, incluyendo los trastornos cognitivos. La patogenesis del trastorno cognitivo inducido por la radiacion no esta claro, pero la reduccion de la neurogenesis en el hipocampo puede ser una razon subyacente. Fueron etudiadas 24 ratas macho adultas. La dosis de radiacion absorbida en el mesencefalo fue de 10 Gy, proveniente de una maquina de radioterapia de cobalto con una salida de 115,24 cGy/min. Las ratas fueron divididas en cuatro grupos de seis ratas cada uno, incluyendo un grupo control, fraccion unica de 10 Gy, fraccionada de 10 Gy y finalmente el grupo de anestesia simulado. El numero de celulas nerviosas piramidales se conto en dos regiones de la formacion del hipocampo (CA1 y CA3). La radiacion podria reducir significativamente (p = 0,000) el numero de celulas en dos regiones del hipocampo . Al parecer, la radiacioon fraccionada de 10 Gy es mas eficiente que la fraccion unica, mientras que el rol de la anestesia debe ser cuidadosamente evaluado. Por otra parte la tasa de reduccion de la neurogenesis fue observada en las mismas regiones del hipocampo es decir, con la misma radiosensibilidad de las celulas.

Plasticity changes of uninjured nerves can result in a novel neural circuit after spinal cord injury, which can restore sensory and motor functions to different degrees. Although processes of neural plasticity have been studied, the mechanism and treatment to effectively improve neural plasticity changes remain controversial. The present study reviewed studies regarding plasticity of the central nervous system and methods for promoting plasticity to improve repair of injured central nerves. The results showed that synaptic reorganization, axonal sprouting, and neurogenesis are critical factors for neural circuit reconstruction. Directed functional exercise, neurotrophic factor and transplantation of nerve-derived and non-nerve-derived tissues and cells can effectively ameliorate functional disturbances caused by spinal cord injury and improve quality of life for patients.

Several lines of evidence suggest that in adults, antidepressant therapies enhance neurogenesis in the hippocampus, but how this process occurs has

The present study analyzed the influence of 3-[3-(3-florophenyl-2-propyn-1-ylthio)-1, 2, 5-thiadiazol-4-yl]-1, 2, 5, 6-tetrahydro-1-methylpyridine oxalate (EUK1001), a novel xanomeline derivative of the M1/M4 receptor agonist, on hippocampal neurogenesis in adult C57BL6 mice. Results showed that 15-day EUK1001 treatment via intraperitoneal injection promoted neural cell proliferation in the dentate gyrus, although cell differentiation did not change. The majority of bromodeoxyuridine-positive cells co-expressed the immature neuronal marker doublecortin. In addition, the level of neurogenesis in the subventricular zone was not altered. Brain-derived neurotrophic factor mRNA expression was up-regulated following EUK1001 treatment, but no change was observed in expression of camp-responsive element binding protein 1, paired box gene 6, vascular endothelial growth factor alpha, neurogenic differentiation factor 1, and wingless-related mouse mammary tumor virus integration site 3A mRNA. These experimental findings indicated that EUK1001 enhanced proliferation and survival of hippocampal cells, possibly by increasing brain-derived neurotrophic factor expression.

Researchers recently reported the use of metformin for reversing amenorrhea associated with atypical antipsychotics and for promoting weight loss and improving insulin resistance in patients receiving these medications (JW Psychiatry Jul 9 2012). Now, investigators have examined whether metformin might also promote neurogenesis. The researchers exposed …