Melatonin increases proliferation of cultured neural stem cells obtained from adult mouse subventricular zone

Abstract: Melatonin, a circadian rhythm–promoting molecule secreted mainly by the pineal gland, has a variety of biological functions and neuroprotective effects including control of sleep–wake cycle, seasonal reproduction, and body temperature as well as preventing neuronal cell death induced by neurotoxic substances. Melatonin also modulates neural stem cell (NSC) function including proliferation and differentiation in embryonic brain tissue. However, the involvement of melatonin in adult neurogenesis is still not clear. Here, we report that precursor cells from adult mouse subventricular zone (SVZ) of the lateral ventricle, the main neurogenic area of the adult brain, express melatonin receptors. In addition, precursor cells derived from this area treated with melatonin exhibited increased proliferative activity. However, when cells were treated with luzindole, a competitive inhibitor of melatonin receptors, or pertussis toxin, an uncoupler of Gi from adenylate cyclase, melatonin‐induced proliferation was reduced. Under these conditions, melatonin induced the differentiation of precursor cells to neuronal cells without an upregulation of the number of glia cells. Because stem cell replacement is thought to play an important therapeutic role in neurodegenerative diseases, melatonin might be beneficial for stimulating endogenous neural stem cells.     

Task difficulty in the Morris water task influences the survival of new neurons in the dentate gyrus

Adult neurogenesis continues throughout life in the mammalian hippocampus. The precise function of the adult generated neurons remains uncertain although there is growing evidence that they are involved in hippocampus‐dependent learning and memory. Training rats on a hidden platform version of the Morris water task has been shown to increase or decrease the survival of newly produced cells in the dentate gyrus (DG) compared to training on a visible platform version. Here we investigated whether the difficulty of the task is related to the degree or direction of the change in neurogenesis. We trained rats on either a visible platform version of the Morris water task or one of three different hidden platform paradigms: four training trials per session version, two training trials per session, and reduced‐cue (a version in which the majority of the distal cues were removed from the room). BrdU was administered 6 days prior to training and rats were perfused 24 h after the last training session. As expected, training on the four trial hidden platform version increased cell survival compared to training on the visible platform version. However, training on the more difficult reduced‐cue hidden platform version resulted in a decrease in cell survival. Rats that received fewer trials per session did not differ in terms of cell survival in comparison to rats trained on the visible platform version. These findings demonstrate that altering the difficulty of the spatial task has an impact on the corresponding change in cell survival. The lack of obvious distal cues likely changed the strategy used by the rats to determine the location of the platform and resulted in a decrease, instead of an increase in cell survival in the hippocampus. In conclusion, different types of hippocampus‐dependent learning can differentially impact cell survival. © 2009 Wiley‐Liss, Inc.     

Harnessing neuroplasticity: modern approaches and clinical future

ABSTRACT

Background and purpose: Neurological diseases and injuries to the nervous system may cause inadvertent damage to neuronal and synaptic structures. Such phenomenon would lead to the development of neurological and neurodegenerative disorders which might affect memory, cognition and motoric functions. The body has various negative feedback systems which can induce beneficial neuroplastic changes in mediating some neuronal damage; however, such efforts are often not enough to ameliorate the derogatory changes.

Materials and methods: Articles discussing studies to induce beneficial neuroplastic changes were retrieved from the databases, National Center for Biotechnology Information (NCBI) and MEDLINE, and reviewed.

Results: This review highlights the significance of neuroplasticity in restoring neuronal functions and current advances in research to employ this positive cellular event by inducing synaptogenesis, neurogenesis, clearance of toxic amyloid beta (Aβ) and tau protein aggregates, or by providing neuroprotection. Compounds ranging from natural products (e.g. bilobalides, curcumin) to novel vaccines (e.g. AADvac1, RG7345) have been reported to induce long-lasting neuroplasticity in vitro and in vitro. Activity-dependent neuroplasticity is also inducible by regimens of exercises and therapies with instances in human studies proving major successes. Lastly, mechanical stimulation of brain regions through therapeutic hypothermia or deep brain stimulation has given insight on the larger scale of neuroplasticity within the nervous system.

Conclusion: Harnessing neuroplasticity may not only offer an arm in the vast arsenal of approaches being taken to tackle neurological disorders, such as neurodegenerative diseases, but from ample evidence, it also has major implications in neuropsychological disorders.     

Septo-temporal gradients of neurogenesis and activity in 13-month-old rats

Recent studies suggest that hippocampal function is partially dissociable along its septo-temporal axis: the septal hippocampus is more critical for spatial processing, while the temporal hippocampus may be more important for non-spatial-related behavior. In young adults, water maze training specifically activates new neurons in the temporal hippocampus, but it is unknown whether subregional differences are maintained in older animals, which have reduced neurogenesis levels. We therefore examined gradients of activity-related Fos expression and neurogenesis in 13-month-old rats and found that neurogenesis occurs relatively evenly throughout the dentate gyrus. Water maze experience significantly increased Fos expression in the suprapyramidal blade and Fos was highest in the septal pole of the dentate gyrus whether the animal learned a platform location, swam in the absence of a platform or remained in their cage. No Fos+ young neurons were found using typical markers of immature neurons. However, Fos expression in the subgranular zone, where adult-born neurons predominate, was disproportionally high in the temporal dentate gyrus. These findings indicate that adult-born neurons in the temporal hippocampus are preferentially activated compared with older neurons.     

Vascular endothelial growth factor increases neurogenesis after traumatic brain injury

Activation of endogenous stem cells has been proposed as a novel form of therapy in a variety of neurologic disorders including traumatic brain injury (TBI). Vascular endothelial growth factor (VEGF) is expressed in the brain after TBI and serves as a potent activator of angiogenesis and neurogenesis. In this study, we infused exogenous VEGF into the lateral ventricles of mice for 7 days after TBI using mini-osmotic pumps to evaluate the effects on recovery and functional outcome. The results of our study show that VEGF significantly increases the number of proliferating cells in the subventricular zone and in the perilesion cortex. Fate analysis showed that most newborn cells differentiated into astrocytes and oligodendroglia and only a few cells differentiated into neurons. Functional outcome was significantly better in mice treated with VEGF compared with vehicle-treated animals after TBI. Injury size was significantly smaller at 90 days after TBI in VEGF-treated animals, suggesting additional neuroprotective effects of VEGF. In conclusion, VEGF significantly augments neurogenesis and angiogenesis and reduces lesion volumes after TBI. These changes are associated with significant improvement in recovery rates and functional outcome.     

A review of the potential to restore vision with stem cells

Vision research involving stem cells is a rapidly evolving field. Animal experiments have shown that in response to environmental cues, stem cells can repopulate damaged retinas, regrow neuronal axons, repair higher cortical pathways, and restore pupil reflexes, light responses and basic pattern recognition. Viable corneas have been grown from stem cells and transplanted into humans. Similarly, human trials to repair damaged retinas in retinitis pigmentosa and age‐related macular degeneration patients have produced preliminary successes. This review attempts to place the collective contributions toward stem cell/vision research into a broader clinical model of how stem cells might ultimately be used to restore the entire visual pathway.     

Attenuated plasticity in neurons and astrocytes in the mouse model of Sanfilippo syndrome type B

Sanfilippo syndrome type B (MPS III B) is a neurodegenerative disorder characterized by profound mental retardation and early death. It is caused by deficiency of a lysosomal enzyme involved in heparan sulfate (HS) degradation. Because HS accumulation can be a major feature of this disease, we have examined crucial molecular systems associated with HS function. Using a knockout mouse with disruption of the gene responsible for HS degradation, we evaluated the effects of possible HS accumulation on neuroplasticity that are within the spectrum of action of fibroblast growth factors (FGFs) and their receptor (FGFR). We found that levels of mRNA for the FGFR-1 were attenuated in the mutant mice by the age of 6 months, whereas the mRNAs for FGF-1 and FGF-2 were reduced or unchanged in the brain regions tested. Neurogenesis, in which FGF-2 is involved, was inhibited in the MPS III B mouse brain at both young and adult ages. We also examined the expression of the glial fibrillary acidic protein (GFAP) gene and GFAP-positive cell density in both normal and injured conditions to study the functional response of astrocytes to insult. We found that, although the mutation alone caused drastic induction of reactive astrocytes, acute injury to the mutant brains failed to induce additional reactive astrocytes. Our results showed important alterations in the expression of several genes involved in the maintenance of neuroplasticity in the MPS III B. This in turn may result in reduction of neuronal health and brain function.     

Selective enhancement of spatial learning under chronic psychosocial stress

The hippocampus has long been proved to be implicated in several learning and memory processes. Being integrated into the limbic-hypothalamus-pituitary-adrenal axis, the hippocampus also plays an active role in the regulation of the stress response. Long lasting elevated levels of glucocorticoids resulting from a prolonged stress exposure affect hippocampal functions and structure, inducing learning and memory alterations and suppressing cell proliferation in the adult dentate gyrus. Here, adult male tree shrews (Tupaia belangeri) exposed to chronic psychosocial stress were tested repeatedly on a holeboard apparatus using two different learning tasks devised to evaluate hippocampal-dependent and hippocampal-independent cognitive function. We show that chronic stress enhanced learning in animals performing the hippocampal-dependent task, whereas no stress-induced effect was found in the hippocampal-independent task. Additionally, after five weeks of stress, cell proliferation was reduced in the hippocampal dentate gyrus. These results indicate that specific memory processes not only may remain intact, but indeed are facilitated by chronic stress, despite elevated cortisol levels and suppressed hippocampal cell proliferation.     

Depletion of norepinephrine decreases the proliferation,but does not influence the survival and differentiation,of granule cell progenitors in the adult rat hippocampus

The dentate gyrus region retains the ability to generate neurons throughout adulthood. A few studies have examined the neurotransmitter regulation of adult hippocampal neurogenesis and have shown that this process is regulated by serotonin and glutamate. Given the strong noradrenergic innervation of the adult hippocampus and the ability of norepinephrine to influence proliferation during development, we examined the influence of norepinephrine on adult hippocampal neurogenesis. Our study indicates that depletion of norepinephrine by the selective noradrenergic neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromo benzylamine hydrochloride (DSP-4), results in a 63% reduction in the proliferation of dentate gyrus progenitor cells identified through 5-bromo-2'-deoxyuridine (BrdU) labelling. In contrast, the survival of BrdU-positive cells labelled prior to treatment with DSP-4 is not influenced by norepinephrine depletion. The differentiation of BrdU labelled progenitors into neurons or glia was also not sensitive to noradrenergic depletion. These results indicate that the proliferation, but not the survival or differentiation, of adult hippocampal granule cell progenitors is affected by norepinephrine depletion.