Retracted: Hypocretin (orexin) cell transplantation diminishes narcoleptic-like sleep behavior in rats.

Arias-Carrión, O.; Drucker-Colín, R.; Murillo-Rodríguez, E. "Hypocretin (orexin) cell transplantation diminishes narcoleptic-like sleep behavior in rats." CNS Neurol. Disord. Drug Targets, 2011,11(7). The above-cited paper has been retracted from CNS & Neurological Disorders-Drug Targets at the request of the authors. The authors advised the Journal of their intention to perform additional experiments in order to strengthen their initial results, at which time an amended manuscript may be submitted.

Neuroprotective effects of extremely low-frequency electromagnetic fields on a Huntington's disease rat model: effects on neurotrophic factors and neuronal density.

There is evidence to suggest that the neuroprotective effect of exposure of extremely low-frequency electromagnetic fields (ELF-EMF) may be due, at least in part, to the effect of these fields on neurotrophic factors levels and cell survival, leading to an improvement in behavior. This study was undertaken to investigate the neuroprotective effects of ELFEF in a rat model of 3-nitropropionic acid (3NP)-induced Huntington's disease. Behavior patterns were evaluated, and changes in neurotrophic factor, cell damage, and oxidative stress biomarker levels were monitored in Wistar rats. Rats were given 3NP over four consecutive days (20 mg/kg body weight), whereas ELFEF (60 Hz and 0.7 mT) was applied over 21 days, starting after the last injection of 3NP. Rats treated with 3NP exhibited significantly different behavior in the open field test (OFT) and the forced swim test (FST), and displayed significant differences in neurotrophic factor levels and oxidative stress biomarkers levels, together with a neuronal damage and diminished neuronal density, with respect neuronal controls. ELFEF improved neurological scores, enhanced neurotrophic factor levels, and reduced both oxidative damage and neuronal loss in 3NP-treated rats. ELFEF alleviates 3NP-induced brain injury and prevents loss of neurons in rat striatum, thus showing considerable potential as a therapeutic tool.

Aspects of the narcolepsy-cataplexy syndrome in O/E3-null mutant mice.

Orexins (hypocretins) are peptide neurotransmitters produced by a small group of neurons located exclusively in the lateral hypothalamus (LH). Orexins modulate arousal, and as a result, have profound effects on feeding behavior and the sleep-wake cycle. Loss of orexin producing neurons leads to a narcoleptic phenotype, characterized by sudden transitions from vigilance to rapid eye movement (REM) sleep (direct transition to REM, DREM) observed in electroencephalogram (EEG) and electromyogram (EMG) recordings. In this study, we demonstrate that mice lacking the basic helix-loop-helix transcription factor O/E3 (also known as ebf2) have a decrease in orexin-producing cells in the LH, in addition to a severely impaired orexinergic innervation of the pons. These changes in the orexinergic circuit of O/E3-null animals induce a narcoleptic phenotype, similar to the one arising in orexin-deficient and orexin-ataxin-3 mice. Taken together, our results suggest that O/E3 plays a central role during the establishment of a functional orexinergic circuit by controlling the expression of essential hypothalamic neurotransmitter and the correct development of the nerve fibers arising from the hypothalamus. This is the first report regarding the narcolepsy-cataplexy syndrome in O/E3-null mice, which adds the importance of transcription factors in the regulation of neural subpopulations that control the sleep-wake cycle.

Dopamine D(2)-class receptor supersensitivity as reflected in Ca2+ current modulation in neostriatal neurons.

The loss of dopaminergic neurons followed by dopamine (DA) depletion in the neostriatum is a hallmark of Parkinson's disease. Among other changes, DA D(2)-receptor class (D(2)R-class) supersensitivity is a result of striatal DA depletion. Pharmacological, biochemical and behavioral data have documented this phenomenon, but clear electrophysiological-functional correlates are still lacking. This work describes an electrophysiological correlate of D(2)R-class supersensitivity in DA-depleted striata after unilateral 6-hydroxydopamine (6-OHDA) lesions in the rat substantia nigra compacta (SNc). Ca2+ current modulation mediated by D(2)R-class activation reflected an altered sensitivity. Thus, while the concentration-response relationship (C-R plot) from control striata was better fit with a two sites model, the C-R plot obtained from DA-depleted striata was better fit by a three sites model, exhibited a considerable leftward shift, and presented an increased maximal response. Because Ca2+ current modulation by D(2)R-class activation is involved in the control of spiny neurons excitability and their synaptic GABA release, the present findings may help to explain several functional changes found in the striatal circuitry after dopaminergic denervation.

The anandamide membrane transporter inhibitor, VDM-11, modulates sleep and c-Fos expression in the rat brain.

Endogenous cannabinoids or endocannabinoids are lipid molecules that have a variety of biological actions, most notably via activation of the cannabinoid receptors. The family of endocannabinoids includes arachidonoylethanolamide (ANA) which modulates different behaviors, such as sleep. However, it is unknown whether pharmacological elevation of ANA endogenous levels might induce sleep. VDM 11 [(5 Z,8 Z,11 Z,14 Z)-N-(4-hydroxy-2-methylphenyl)-5,8,11,14-eicosatetraenamide] is commonly used as an inhibitor of ANA cellular uptake, and thereby to potentiate its actions. In this study we have examined whether VDM-11 exerts any effect on the sleep-wake cycle and c-Fos expression in brain areas. When assayed alone in rats, VDM-11 (10 or 20 microg/5 microL, i.c.v.) at the beginning of the lights-off period, reduced wakefulness and increased sleep. The CB(1) cannabinoid receptor antagonist, SR141716A, partially reversed the effects of VDM-11 on sleep. Additionally, VDM-11 enhanced c-Fos expression in sleep-related brain areas such as the anterior hypothalamic area, paraventricular thalamic nucleus, and pedunculopontine tegmental nucleus. It is concluded that VDM-11 displays sleep-inducing properties and these effects slightly, albeit significantly, are reversed using SR141716A. Furthermore, c-Fos data suggest a possible underlying neuroanatomical substrate of the sleep-inducing properties of VDM-11. We report evidence suggesting that VDM-11 might be considered for the development of new pharmacological and pharmaceutical approaches to treat sleep disorders such as insomnia.

[Neurogenesis as a therapeutic strategy to regenerate central nervous system]. / Neurogénesis como estrategia terapéutica para regenerar el sistema nervioso central.

INTRODUCTION: In the past few years, it has been demonstrated that the adult mammalian brain maintains the capacity to generate new neurons from neural stem/progenitor cells. These new neurons integrate into pre-existing systems through a process referred to as 'neurogenesis in the adult brain'. DEVELOPMENT: This discovery has modified our understanding of how the central nervous system functions in health and disease. Until today, a great effort has been made attempting to decipher the mechanisms regulating adult neurogenesis, which might help to induce neuronal endogenous cell replacement in various neurological diseases. CONCLUSIONS: In this revision, we will attempt to shed some light on the neurogenesis process with respect to diseases of the central nervous system and we will describe some therapeutic potentials in relation to neurodegenerative diseases.

Neurogénesis como estrategia terapéutica para regenerar el sistema nervioso central / Neurogenesis as a therapeutic strategy to regenerate central nervous system

La investigación generada en los últimos años ha demostrado que el cerebro adulto de mamíferosmantiene la capacidad de generar nuevas neuronas a partir de células troncales/progenitoras neuronales. Las nuevas neuronas se integran a las redes preexistentes a través de un proceso denominado ‘neurogénesis en el cerebro adulto’. Desarrollo.Este descubrimiento ha modificado nuestra comprensión de cómo el sistema nervioso central funciona en la salud y en la enfermedad. Hasta ahora se ha realizado un gran esfuerzo para descifrar los mecanismos que regulan la neurogénesis en el adulto, lo cual puede permitir realizar un reemplazo neuronal endógeno en diversos trastornos neurológicos. Conclusiones.Esta revisión se centra en la neurogénesis que se presenta en respuesta a trastornos del sistema nervioso central y aborda su potencial terapéutico en las enfermedades neurodegenerativas

In the past few years, it has been demonstrated that the adult mammalian brain maintains the capacityto generate new neurons from neural stem/progenitor cells. These new neurons integrate into pre-existing systems through a process referred to as ‘neurogenesis in the adult brain’. Development. This discovery has modified our understanding of how the central nervous system functions in health and disease. Until today, a great effort has been made attempting to decipher themechanisms regulating adult neurogenesis, which might help to induce neuronal endogenous cell replacement in various neurological diseases. Conclusions. In this revision, we will attempt to shed some light on the neurogenesis process with respect to diseases of the central nervous system and we will describe some therapeutic potentials in relation to neurodegenerativediseases

[Neurogenesis in the adult brain]. / Neurogénesis en el cerebro adulto.

INTRODUCTION: The discovery that new neurons continue to be generated in the adult brain has modified the concept of brain plasticity and has brought to light new mechanisms that ensure the homeostasis of the nervous system. DEVELOPMENT: Neurogenesis, that is to say, the process involving the generation of new neurons, has been shown to occur in the hippocampus and in the olfactory bulb in adult mammals, which suggests that neuronal stem cells persist throughout the entire lifespan. The primary precursors have been identified in specialised regions called neurogenic niches. Interestingly, the cells that give rise to the new neurons in the adult brain express markers for glial cells, a cell lineage that is a long way from that of neurons. Studies conducted during the development of the brain have shown that radial glial cells not only give rise to astrocytes but also neurons, oligodendrocytes and ependymal cells. In addition, it is known that radial glial cells are also the precursors of neuronal stem cells in the adult brain. CONCLUSIONS: Overall, these data support the idea that stem cells develop from a neuroepithelial-glial radial-astrocytic lineage. Thus, identifying the primary precursors, both in the developing brain and in the adult brain, is essential to understand the functioning of the nervous system and, from there, to develop strategies for neuronal replacement in the adult brain when needed.

Neurogénesis en el cerebro adulto / Neurogenesis in the adult brain

Introducción. El descubrimiento de que nuevas neuronas continúan generándose en el cerebro adulto ha modificado el concepto de plasticidad cerebral y ha revelado nuevos mecanismos que garantizan la homeostasis del sistema nervioso. Desarrollo. La neurogénesis, proceso que involucra la generación de nuevas neuronas, se ha demostrado en el hipocampo y en el bulbo olfatorio de mamíferos adultos, lo cual sugiere la persistencia de células troncales neuronales a lo largo de toda la vida. Los precursores primarios se han identificado en zonas especializadas denominadas nichos neurogénicos. De manera interesante, la célula que da origen a las nuevas neuronas en el cerebro adulto expresa marcadores de células gliales, un linaje celular lejano al de las neuronas. Trabajos realizados durante el desarrollo del cerebro han demostrado que la glía radial no sólo origina astrocitos, sino también neuronas, oligodendrocitos y células ependimales. Además, se sabe que la glía radial también es la precursora de las células troncales neuronales del cerebro adulto. Conclusiones. En conjunto, estos datos soportan la idea de que las células troncales se desarrollan de un linaje neuroepitelial-glía radial-astrocítico. Así, la identificación de los precursores primarios, tanto en el cerebro en desarrollo como en el cerebro adulto, es fundamental para comprender el funcionamiento del sistema nervioso y, con esto, desarrollar estrategias de reemplazo neuronal en el cerebro adulto que lo requiera

Introduction. The discovery that new neurons continue to be generated in the adult brain has modified the concept of brain plasticity and has brought to light new mechanisms that ensure the homeostasis of the nervous system. Development. Neurogenesis, that is to say, the process involving the generation of new neurons, has been shown to occur in the hippocampus and in the olfactory bulb in adult mammals, which suggests that neuronal stem cells persist throughout the entire lifespan. The primary precursors have been identified in specialised regions called neurogenic niches. Interestingly, the cells that give rise to the new neurons in the adult brain express markers for glial cells, a cell lineage that is a long way from that of neurons. Studies conducted during the development of the brain have shown that radial glial cells not only give rise to astrocytes but also neurons, oligodendrocytes and ependymal cells. In addition, it is known that radial glial cells are also the precursors of neuronal stem cells in the adult brain. Conclusions. Overall, these data support the idea that stem cells develop from a neuroepithelial- glial radial-astrocytic lineage. Thus, identifying the primary precursors, both in the developing brain and in the adult brain, is essential to understand the functioning of the nervous system and, from there, to develop strategies for neuronal replacement in the adult brain when needed

Frontal and limbic metabolic differences in subjects selected according to genetic variation of the SLC6A4 gene polymorphism.

Allelic variants in the promoter region of the serotonin transporter (5-HTT) gene have been implicated in several psychiatric disorders and personality traits. In particular, two common alleles in a variable repeat sequence of the promoter region (SLC6A4) have been differentially associated with a display of abnormal levels of anxiety and affective illness in individuals carrying the "s" allele. The aim of this study was to compare the basal cerebral metabolic activity of non-psychiatric subjects in fronto-limbic structures to determine whether differences exist in basal metabolic activity within this functional polymorphism. PET scans with fluorine-18 fluorodeoxyglucose as radiotracer were performed in 71 non-psychiatric subjects previously screened for psychopathology and subsequently genotyped for SLC6A4; PET images were compared with SPM2 according to s/s (n = 27), s/l (n = 25), and l/l (n = 19) groups considering a significance threshold in a priori selected areas of P < 0.001 and an extent threshold > or =5 voxels. The analysis showed an effect of interest among the three genotype groups in right anterior cingulate gyrus (ACC), left middle frontal gyrus, and left posterior cingulate gyrus (PCC). Comparison between l/l vs. s/s showed increased metabolism for l/l in left middle frontal gyrus and an increase for s/s in right ACC and left PCC. Comparison between s/s vs. s/l showed an increase for s/s in left PCC and right ACC. Increased basal metabolism in fronto-limbic structures for the s/s group may be conceived as an "overactive metabolic state" of these structures, possibly related to an increased susceptibility for developing an anxiety-depression spectrum disorder.

A two-year study on the effects of nicotine and its withdrawal on mood and sleep.

Acute administration of nicotine has beneficial effects on a variety of neurological and psychiatric disorders. The purpose of this study was to determine the long-term effects of transdermal nicotine on sleep and major depression. Under a single blind protocol study where patients initially received nicotine and then switched to placebo. Fourteen non-smoking patients with major depression (Hamilton Rating > or = 18) served as subjects. Transdermal nicotine (17.5 mg), was administered five days weekly for six months, three days weekly on month 7 and one day per week on month 8. From the 9th to the 24th month, once a week a patch without nicotine substituted the nicotine patch. Sleep and depression was assessed throughout. REM sleep latency changed from 32.6 min. to 78.2 min. at the end of the study, wakefulness decreased, slow wave sleep increased throughout the study and a transient decrease of REM sleep duration upon nicotine withdrawal was observed. Hamilton scores went from an initial mean score of 29.7 to a final score of 10.8. The results support the possible therapeutical effects of long-term transdermal nicotine on sleep and mood, with a carryover effect into the withdrawal period, even though, the conclusions should be taken with caution due to the design applied.

Neurogenesis in the subventricular zone following transcranial magnetic field stimulation and nigrostriatal lesions.

Neurogenesis continues at least in two regions of the mammalian adult brain, the subventricular zone (SVZ) and the subgranular zone in hippocampal dentate gyrus. Neurogenesis in these regions is subjected to physiological regulation and can be modified by pharmacological and pathological events. Here we report the induction of neurogenesis in the SVZ and the differentiation after nigrostriatal pathway lesion along with transcranial magnetic field stimulation (TMFS) in adult rats. Significant numbers of proliferating cells demonstrated by bromodeoxyuridine-positive reaction colocalized with the neuronal marker NeuN were detected bilaterally in the SVZ, and several of these cells also expressed tyrosine hydroxylase. Transplanted chromaffin cells into lesioned animals also induced bilateral appearance of subependymal cells. These results show for the first time that unilateral lesion, transplant, and/or TMFS induce neurogenesis in the SVZ of rats and also that TMFS prevents the motor alterations induced by the lesion.

Normal prism adaptation but reduced after-effect in basal ganglia disorders using a throwing task.

Prism adaptation is a form of visuomotor learning in which the visual and motor systems need to be adjusted because a visual perturbation is produced by horizontally displacing prisms. Despite being known for over two centuries, the neuronal substrates of this phenomenon are not yet completely understood. In this article the possible role of the basal ganglia in this kind of learning was analysed through a study of Huntington's and Parkinson's disease patients. A throwing technique requiring the use of open loop feedback was used. The variables analysed were visuomotor performance, adaptation rate and magnitude, and the after-effect. The results clearly showed that both Huntington's and Parkinson's disease groups learned at the same rate as control subjects. In addition, despite having a disturbed visuomotor performance, both experimental groups showed the same adaptation magnitude as the control group. Finally, the after-effect, which is measured after removing the prisms, is reduced in both patients groups. This reduction leads to a disruption in the normal adaptation-after-effect correlation found in normal volunteers. These results suggest that basal ganglia are not involved in this type of open-looped visuomotor learning. The large number of patients studied as well as the similarity of the findings between both populations support this hypothesis. By contrast, there is an impairment in the after-effect on both basal ganglia patient populations. This impairment may be the result of the deterioration of the perceptual recalibration process involved in visuomotor learning.

Nicotine stimulation of dorsal raphe neurons: effects on laterodorsal and pedunculopontine neurons.

Previous studies showed that nicotine suppresses the ponto-geniculo-occipital (PGO) spikes of rapid eye movement (REM) sleep in cats. This effect may depend on stimulation of dorsal raphe nucleus (DRN) serotoninergic neurons that inhibit the pedunculopontine (PPT) and laterodorsal tegmental (LDT) cholinergic neurons, generators of PGO spikes. For testing this hypothesis 37 experiments were performed in rat midbrain slices. Nicotine (2 mM), administered locally into DRN, significantly increased the firing rate of 81.1% DRN neurons and serotonin release while simultaneously and significantly decreasing the firing rate of 80.8% LDT neurons and of 81.8% PPT neurons. The inhibition of LDT neurons by nicotine administered into DRN was blocked by the 5-HT1A receptor antagonist WAY-100635 (140 nM) administered into LDT. These results indicate that nicotine inhibits the activity of LDT and PPT neurons and consequently the generation of PGO spikes through stimulation of DRN serotoninergic neurons.

Inhibition of the ERK pathway prevents HIVgp120-induced REM sleep increase.

Approximately 35% of HIV-infected subjects, both children and adults, exhibit alterations in the sleep-waking cycle. HIV surface glycoprotein gp120 has been postulated to contribute to this abnormality. For example, it has been reported that HIVgp120 modifies sleep in freely-moving rats and that it also activates the ERK pathway in brain slices. The goal of this work was to determine if sleep changes induced by HIVgp120 in normal rats are mediated by the MAPK pathway. Our results show that a single intraventricular administration of HIVgp120 selectively increases REMS and that such an increase can be prevented by U0126, an inhibitor of ERK activating enzyme, MEK. In contrast, SB202190, a MAPK-p38 inhibitor, had no effect on HIVgp120-induced increase in REMS. These results suggest that HIVgp120 increases REMS in the rat by specifically affecting the ERK signal transduction pathway.

Subcutaneous administration of nicotine changes dorsal raphe serotonergic neurons discharge rate during REM sleep.

In the present study nicotine (0.1 mg/kg, s.c.) increased discharge rate of putative dorsal raphe (DRN) serotonergic neurons of behaving rats during REM sleep (362.61%), without any significant change during waking and non-REM sleep. Since serotonergic DRN neurons gate PGO onset, these results suggest that nicotine-induced suppression of PGO spikes during REM sleep previously reported is achieved through stimulation of dorsal raphe serotonergic cells.

Discharge modulation of rat dorsal raphe neurons during sleep and waking: effects of preoptic/basal forebrain warming.

In cats, putative serotonergic neurons (PSNs) recorded from the dorsal raphe nucleus (DRN) across the sleep-wake cycle exhibit the so-called rapid eye movement sleep-off (REM-off) discharge pattern. Since, the sleep-wake discharge patterns of DRN neurons in behaving rats is poorly known, the present study examined this neuronal populations. The PSNs recorded in this study exhibited: (1) progressive decrease in discharge rate from waking to NREM to REM sleep; (2) long action potential duration, and (3) reduction of discharge rate after systemic administration of a selective 5-HT(1A) agonist, (+/-)-8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide (8-OH-DPAT). Evidence supports the hypothesis that NREM sleep is modulated by thermoregulatory mechanisms localized in the preoptic area and adjacent basal forebrain (POA/BF). We previously reported that POA/BF warming suppresses the discharge of wake-promoting neurons in the posterior hypothalamus and the basal forebrain. Since the DRN is one component of the brainstem arousal system and receives projections from POA/BF, we examined the effects of local POA/BF warming by 1.5-2.0 degrees C during waking on the discharge of DRN neurons. POA/BF warming reduced the discharge in 14 of 19 PSNs and in 12 of 17 other wake-related neurons in the DRN. DRN neuronal discharge reduction occurred without accompanying EEG frequency or behavioral changes. These results suggest that PSNs recorded in DRN in unrestrained and unanesthetized rats exhibit a "wake-active REM-off" discharge pattern and further support the hypothesis that the POA/BF warm-sensitive hypnogenic system induces sleep by a coordinated inhibition of multiple arousal systems including that modulated by the DRN.

Nicotine, brain nicotinic receptors, and neuropsychiatric disorders.

Neuronal nicotinic acetylcholine receptors (nAChRs) represent a large family of ligand-gated cation channels with diverse structures and properties. In contrast to the muscular nAChRs, the physiological functions of neuronal nAChRs are not well defined to date. Behavioral studies indicate that brain nAChRs participate in complex functions such as attention, memory, and cognition, whereas clinical data suggest their involvement in the pathogenesis of certain neuropsychiatric disorders (Alzheimer's and Parkinson's diseases, Tourette's syndrome, schizophrenia, depression, etc.). For the majority of these disorders, the use of nAChRs' agonists may represent either a prophylactic (especially for Alzheimer's and Parkinson's diseases) or a symptomatic treatment. The possible mechanisms underlying these beneficial effects as well as the characteristics and potential therapeutic use of new, subtype-selective nAChRs agonists are presented.