Abstract: Clonazepam was initially licensed as an anti-epileptic agent, but its use in a wide variety of psychiatric conditions, including panic disorder (PD) has now been well established. This overview evaluates the current role of clonazepam alone or in combination with antidepressants and/or behavioral therapy in the treatment of PD. We review the data establishing the use of clonazepam in the treatment of PD as well as new information, particularly confirmation of longterm efficacy and safety. We also discuss a regimen for safely tapered withdrawal of clonazepam, the characteristics of the respiratory subtype of PD, and CO2-induced panic attacks as a diagnostic measure and predictor for therapeutic success. It has been shown that panic attacks can more readily be induced by CO2 in PD patients with the respiratory subtype than those with the non-respiratory subtype. More than 25 years after the first report of efficacy in PD in 1984, clonazepam, alone or combined with selective serotonin reuptake inhibitors (SSRIs) and/or behavioral therapy, remains an important therapeutic modality for the management of PD.
Abstract: Transcranial magnetic stimulation (TMS) is a non-invasive technique used recently to treat different neuropsychiatric and neurodegenerative disorders. Despite its proven value, the mechanisms through which TMS exerts its beneficial action on neuronal function remain unclear. Recent studies have shown that its beneficial effects may be at least partly due to a neuroprotective effect on oxidative and cell damage. This study shows that TMS can modulate the Nrf2 transcriptor factor in a Huntington's disease-like rat model induced by 3-nitropropionic acid (3-NP). Western blot analysis demonstrated that 3-NP caused a reduction in Nrf2 in both cytoplasm and nucleus, while TMS applied to 3-NP-treated rats triggered an increase in cytoplasm and nucleus Nrf2 levels. It was therefore concluded that TMS modulates Nrf2 expression and translocation and that these mechanisms may partly explain the neuroprotective effect of TMS, as well as its antioxidant and cell protection capacity.
Abstract: Presenile Dementia or Early Onset Dementia (EOD) is a public health problem, it differs from Senile Dementia, and encloses a significant number of cases; nevertheless, it is still poorly understood and underdiagnosed. This study aims to review the prevalence and etiology of EOD, comparing EOD with Senile Dementia, as well as to show the main causes of EOD and their prevalence in population and non-population based studies. The computer-supported search used the following databases: Pubmed/Medline, ISI Web of Knowledge and Scielo. The search terms were alcohol-associated dementia, Alzheimer's disease, dementia, Creutzfeldt-jakob disease, dementia with lewy bodies, early onset dementia, frontotemporal lobar degeneration, Huntington's disease, mixed dementia, neurodegenerative disorders, Parkinson's disease dementia, presenile dementia, traumatic brain injury, vascular dementia. Only papers published in English and conducted from 1985 up to 2012 were preferentially reviewed. Neurodegenerative diseases are the most common etiologies seen in EOD. Among the general population, the prevalence of EOD was found to range between 0 to 700 per 100.000 habitants in groups of 25-64 years old, with an increasing incidence with age. The progression of EOD was found to range between 8.3 to 22.8 new cases per 100.000 in those aged under 65 years. Alzheimer's disease (AD) is the major etiology, followed by Vascular Dementia (VaD) and Frontotemporal Lobar Degeneration (FTLD). A larger number of epidemiological studies to elucidate how environmental issues contribute to EOD are necessary, thus, we can collaborate in the planning and prevention of services toward dementia patients.
Abstract: This study aimed to elucidate electrophysiological and cortical mechanisms involved when 15 healthy right-handed subjects executed an index finger flexion and extension task before and after hand immobilization, using qEEG beta band (13-30Hz) asymmetry. This beta band is involved in motor activity and sensorial factors. Our hypothesis is that an increase in beta band asymmetry in pre-frontal, motor and parietal areas will occur in post-hand immobilization, because these areas need to reorganize for new planning, preparation and voluntary motor control. We found increase in beta band asymmetry during post-treatment task. We concluded that beta band asymmetry plays an important role in the analysis of cortical changes in several brain areas when associated to motor task. Furthermore, we assume that 48h of hand immobilization change cortical functioning.
Abstract: There is no sense organ specifically dedicated to time perception, as there is for other senses such as hearing and vision. However, this subjective sense of time is fundamental to our conception of reality and it creates the temporal course of events in our lives. Here, we explored neurobiological relations from the clinical perspective, examining timing ability in patients with different neurological and psychiatric conditions (e.g. Parkinson's disease, depression, bipolar disorder, anxiety disorders and schizophrenia). The neural bases of present distortions in time perception and temporal information processing still remain poorly understood. We reviewed: a) how the brain is capable of encoding time in different environments and multiple tasks, b) different models of interval timing, c) brain structures and neurotransmitters associated with time perception, d) the relationship between memory and time perception, e) neural mechanisms underlying different theories in neural and mental processes, and f) the relationship between different mental diseases and time perception. Bibliographic research was conducted based on publications over the past thirteen years written in English in the databases Scielo, Pubmed/MEDLINE, ISI Web of Knowledge. The time perceptions research are executed to evaluate time perception in mental diseases and can provide evidence for future clinical applications.
Abstract: Ischemic acute kidney injury (AKI) is usually accompanied by neuroinflammation-induced encephalopathy. However, the specific mechanism remains unclear. Toll-like receptors (TLR), specifically TLR-4 has been linked to ischemic reperfusion injury in different organs like kidney, brain and liver. Here, we induced an ischemic reperfusion kidney injury in Sprague Dawley rats. All animals were evaluated using behavioral tests which revealed locomotor activity and motor disturbances in the AKI group. The brains were then examined by immunostaining with ionized calcium binding adaptor molecule 1 (microglial marker) and TLR-4 antibodies. The histological analysis revealed significant up-regulation of TLR-4 in the hippocampus and striatum in the AKI group. These data demonstrate for the first time, the triggering effect of TLR-4 on AKI-induced neuroinflammation in the brain that may lead to AKI-induced encephalopathy. This would also generate a novel hypothesis that using TLR blockers may have a role in preventing AKI effects on the brain.
Abstract: The compression of the fourth ventricle (CV-4) is one of the more well known procedures in the cranial manipulation curriculum and practice. Cranial manipulation has received criticism because of the subtle, difficult to learn techniques, controversy over whether or not cranial bone structures move, and what if any clinical effects have been shown. The aim of this study was to measure the effects of CV-4 in 10 healthy subjects through quantitative electroencephalography (qEEG), specifically in alpha band. Participants were randomly distributed in control, sham-CV4 and CV4 conditions using a cross-over design. qEEG activity was recorded for each of the 10 subjects in each of the 3 conditions. There was a significant increase in the alpha absolute power between pre and post in the CV-4 condition. There appears to be potential for understanding the effect of the CV-4 if these finding are replicated in further clinical trials.
Abstract: Coenzyme Q10 (CoQ10) plays a pivotal role in mitochondrial respiratory chain which is the cell power supply. CoQ10 serves as a physiological electron (e-) shuttle from complexes I and II to complex III, as well as a potent antioxidant. Neurons are characterized by high rates of metabolic activity and need to respond promptly to activity-dependent fluctuations in bioenergetic demand. Consequently, it is not surprising that mitochondrial alterations can promote neuronal dysfunction and degeneration. In several neurological disorders, dysfunction of the respiratory chain leads to reduced ATP levels and increased generation of reactive oxygen species. CoQ10 supplementation has been widely used to treat aging, stroke, neuromuscular diseases, Parkinson's disease, Alzheimer's disease, progressive supranuclear palsy, autosomal recessive cerebellar ataxias, amyotrophic lateral sclerosis and Huntington's disease. Here we discuss a large number of preclinical and clinical trials for CoQ10. The mechanisms underlying the disease-modifying effects of CoQ10 are the principle subject of the current integrative review. The rational applications as a therapeutic agent in neurological disorders are discussed.
Abstract: Regulation of the sleep-waking cycle is complex and involves diverse brain circuits and molecules. On one hand, an interplay among many neuroanatomical and neurochemical systems including acetylcholine, dopamine, noradrenaline, serotonin, histamine, and hypocretin has been shown to control the waking state. On the other hand the sleep-onset is governed by the activity of sleep-promoting neurons placed in the anterior hypothalamus that utilize GABA to inhibit wake-promoting regions. Moreover, brainstem regions inhibited during wakefulness (W) and slow wave sleeps (SWS) become active during rapid eye movement (REM) sleep. Further complexity has been introduced by the recognition of sleep-promoting molecules that accumulate in the brain in prolonged W as well as the physiological role of gene expression during sleep. The sleep-wake cycle is currently undergoing intense research with many new findings leading to new paradigms concerning sleep regulation, brain organization and sleep function. This review provides a broader understanding of our present knowledge in the field of sleep research.
Abstract: Regular physical activity participation seems to be linked to brain metabolism and to be one factor responsible for different effects of high intensity exercise on cognition. Due to this, we investigated the effect of an intermittent maximal exercise intervention on a neuropsychological test requiring sustained and selective attention in a group of low and high physically active subjects.
Abstract: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive procedure whereby a pulsed magnetic field stimulates electrical activity in the brain. Anxiety disorders are the most common of all mental health problems for which effective, mechanism-based treatments remain elusive. Consequently, more advanced non-invasive therapeutic methods are required. A possible method to modulate brain activity and potentially viable for use in clinical practice is rTMS. Here, we focus on the main findings of rTMS from animal models of anxiety and the experimental advances of rTMS that may become a viable clinical application to treat anxiety disorders, one of the most common causes of disability in the workplace in the world. Key advances in combining rTMS with neuroimaging technology may aid such future developments. This article is part of a Special Issue entitled 'Anxiety and Depression'.
Abstract: The saccadic movement is an important behavioral measure used to investigate several cognitive processes, including attention and sensorimotor integration. The present study aimed at investigating changes in beta coherence over frontal, motor, occipital, and parietal cortices during the performance of two different conditions of a prosacadic paradigm. The conditions involved a different pattern of stimulus presentation: a fixed and random stimulus presentation. Twelve healthy volunteers (three male, mean age of 26.25 (SD=4.13) performed the task, while their brain activity pattern was recorded using quantitative electroencephalography. The results showed an interaction between factors condition and moment for the pair of electrode C3/C4. We observed a main effect for moment to CZ/C4, FZ/F3, and P3/PZ. We also found a main effect for condition to FZ/F4, P3/P4, and O1/O2. Our results demonstrated an important role of the inter-connection of the two hemispheres in visual search and movement preparation. The study demonstrates an automation of action and reduction of the focus of attention during the task. We also found that the inter-hemispheric beta coherence plays an important role in the differentiation of the two conditions, and that beta in the right frontal cortex is able to differentiate the conditions, demonstrating a greater involvement of procedural memory in fixed condition. Our results suggest a neuronal specialization in the execution of prosacadic paradigm involving motor task sequence.
Abstract: This study aimed at analyzing the relationship between slow- and fast-alpha asymmetry within frontal cortex and the planning, execution and voluntary control of saccadic eye movements (SEM), and quantitative electroencephalography (qEEG) was recorded using a 20-channel EEG system in 12 healthy participants performing a fixed (i.e., memory-driven) and a random SEM (i.e., stimulus-driven) condition. We find main effects for SEM condition in slow- and fast-alpha asymmetry at electrodes F3-F4, which are located over premotor cortex, specifically a negative asymmetry between conditions. When analyzing electrodes F7-F8, which are located over prefrontal cortex, we found a main effect for condition in slow-alpha asymmetry, particularly a positive asymmetry between conditions. In conclusion, the present approach supports the association of slow- and fast-alpha bands with the planning and preparation of SEM, and the specific role of these sub-bands for both, the attention network and the coordination and integration of sensory information with a (oculo)-motor response.
Abstract: The saccadic paradigm has been used to investigate specific cortical networks involving visuospatial attention. We examined whether asymmetry in theta and beta band differentiates the role of the hemispheres during the execution of two different prosacadic conditions: a fixed condition, where the stimulus was presented at the same location; and a random condition, where the stimulus was unpredictable. Twelve healthy volunteers (3 male; mean age: 26.25) performed the task while their brain activity pattern was recorded using quantitative electroencephalography. We did not find any significant difference for beta, slow- and fast-alpha frequencies for the pairs of electrodes analyzed. The results for theta band showed a superiority of the left hemisphere in the frontal region when responding to the random condition on the right, which is related to the planning and selection of responses, and also a greater activation of the right hemisphere during the random condition, in the occipital region, related to the identification and recognition of patterns. These results indicate that asymmetries in the premotor area and the occipital cortex differentiate memory- and stimulus-driven tasks.
Abstract: Catching an object is a complex movement that involves not only programming but also effective motor coordination. Such behavior is related to the activation and recruitment of cortical regions that participates in the sensorimotor integration process. This study aimed to elucidate the cortical mechanisms involved in anticipatory actions when performing a task of catching an object in free fall.
Abstract: Although dopaminergic system represents the cornerstone in rewarding, other neurotransmitters can modulate both the reward system and the psychomotor effects of addictive drugs. Many hypotheses have been proposed for a better understanding of the reward system and its role in drug addiction. However, after many years of investigation, no single theory can completely explain the neural basis of drug addiction. Recent reports introduce novel neurotransmitters into the game e.g. dynorphins, orexins, histamine, gheralin and galanin. The interacting functions of these neurotransmitters have shown that the reward system and its role in drug dependence, is far more complicated than was thought before. Individual variations exist regarding response to drug exposure, vulnerability for addiction and the effects of different cues on reward systems. Consequently, genetic variations of neurotransmission are thought to influence reward processing that in turn may affect distinctive social behavior and susceptibility to addiction. However, the individual variations can not be based mainly on genetics; environmental factors seem to play a role too. Here we discuss the current knowledge about the orquestic regulation of different neurotransmitters on reward-seeking behavior and their potential effect on drug addiction.
Abstract: The brain is capable of elaborating and executing different stages of information processing. However, exactly how these stages are processed in the brain remains largely unknown. This study aimed to analyze the possible correlation between early and late stages of information processing by assessing the latency to, and amplitude of, early and late event-related potential (ERP) components, including P200, N200, premotor potential (PMP) and P300, in healthy participants in the context of a visual oddball paradigm. We found a moderate positive correlation among the latency of P200 (electrode O2), N200 (electrode O2), PMP (electrode C3), P300 (electrode PZ) and the reaction time (RT). In addition, moderate negative correlation between the amplitude of P200 and the latencies of N200 (electrode O2), PMP (electrode C3), P300 (electrode PZ) was found. Therefore, we propose that if the secondary processing of visual input (P200 latency) occurs faster, the following will also happen sooner: discrimination and classification process of this input (N200 latency), motor response processing (PMP latency), reorganization of attention and working memory update (P300 latency), and RT. N200, PMP, and P300 latencies are also anticipated when higher activation level of occipital areas involved in the secondary processing of visual input rise (P200 amplitude).
Abstract: A key feature of Parkinson's disease is the dopaminergic neuronal cell loss in the substantia nigra pars compacta. Besides inflammation, oxidative stress and apoptosis, a recent hypothesis suggested that degeneration of dopaminergic neurons occurs secondary to abnormal mitosis in these 'postmitotic neurons', ending up in apoptosis. Hence, recent therapies tried to prevent this mitotic cycle in dopaminergic neurons. However, most of the advocated therapies e.g., siRNA-induced silencing of cell cycle regulators, seems far from clinical application. In consequence, the use of anti-mitotic drugs could be a more practical alternative. Colchicine is one clinically approved drug that beyond its anti-mitotic effects has anti-inflammatory, anti-oxidant and anti-apoptotic properties. Moreover, clinical surveys proved that patients receiving colchicine for treating musculoskeletal disorders have lower incidence of Parkinson's disease. In addition, the difficult penetration of colchicines to the blood brain barrier disappears in parkinsonian patients due to depression of the p-glycoprotein efflux system. Based on these clinical data we explored the neuroprotective effects of colchicine in the rat rotenone model of Parkinson's disease. Thirty Sprague Dawley rats aged 3 months were divided into 3 equal groups. The first group received daily intraperitoneal injections of 0.5% carboxymethyl cellulose 3 mL/kg. The second group received rotenone suspended in 0.5% carboxymethyl cellulose intraperitoneally at a dose of 3 mg/kg, daily. The third group received the same rotenone regimen plus daily oral colchicine at a dose of 20 μg/kg. All animals were evaluated regarding locomotor disturbance through a blinded investigator who monitored akinesia, tremors and performance on grid test. After 35 and 70 days the animals were sacrificed and their brains were immunostained against anti-tyrosine hydroxylase. Results showed protective effects of colchicine against rotenone induced neurotoxicity as evident by behavioral tests and immunostaining analysis. Thus, this study provides, for the first time, experimental evidence that colchicine protects against the neurotoxic effects of rotenone on dopaminergic neurons, warranting further investigation as a therapeutic option for Parkinson's disease patients.
Abstract: Nestin is an intermediate filament protein expressed in neuroepithelial stem cells during development and it is later replaced by cell specific neuronal or glial filaments. Nevertheless, nestin⺠cells remain within adult tissues and they can be regarded as potential neural stem cell (NSC). Nestin⺠cells have been detected in Schwann cells related with sensory corpuscles of rodent and they have been demonstrated to be NSC. We have investigated the existence of nestin⺠in human cutaneous cells Meissner and Pacinian corpuscles through the use of immunohistochemistry techniques and in situ hybridization. S100 protein (also regarded as a marker for NSC) and vimentin (the intermediate filament of mature Schwann cells in sensory corpuscles) were also investigated. The results show that the adult human cutaneous sensory Meissner and Pacinian corpuscles contains a small population of Schwann-related cells (vimentinâº) which on the basis of their basic immunohistochemical characteristics (S100 proteinâº, nestinâº) can be potential NSCs. Cells sharing identical immunohistochemical profile were also found in the close vicinity of Meissner corpuscles. Because their localization they are easily accessible and may represent a peripheral niche of NSC to be used for therapeutic goals.
Abstract: Arias-Carrión, O.; Drucker-ColÃn, R.; Murillo-RodrÃguez, 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.
Abstract: A possible viral etiology has been documented in the genesis of motor neuron disorders and acquired peripheral neuropathies, mainly due to the vulnerability of peripheral nerves and the anterior horn to certain viruses. In recent years, several reports show association of HIV infection with Amyotrophic Lateral Sclerosis - Syndrome, Motor Neuron Diseases and peripheral neuropathies.
Abstract: During the last decade skin biopsy has been confirmed as a tool to provide diagnostic information on some peripheral neuropathies. Most studies were focused on intraepithelial nerve fibers and few studies have investigated large myelinated fibers or whether corpuscles in human skin change quantitatively or qualitatively in pathologies of the peripheral or central nervous system. The main objective of this article is to provide a comprehensive review of Meissner's corpuscles including their distribution, density and age changes, development, molecular composition, cellular anatomy and physiology. We also describe their involvement in several pathologies and suggest including this dermal structure in the routine study of skin biopsies, looking for changes to be used as potential markers for several disorders. Finally the article draws the main aspects of how to study Meissner's corpuscles in skin biopsies and gives a view on future perspectives for implementing their use in clinical practice.
Abstract: Regulation of the sleep-wake cycle involves diverse brain circuits and molecules. Further complexity has been introduced by the recognition of sleep-promoting factors that accumulate in the brain naturally or during prolonged waking. The variety of sleep-inducing molecules includes peptides, cytokines, and lipids. With regard to the lipids, current evidence indicates the existence of endogenous lipids, called endocannabinoids, that mimic the pharmacological actions of the psychoactive ingredient of marijuana and that are likely to be essential factors in sleep promotion. This Mini-Review presents current knowledge concerning the role of endogenous compounds with sleep-promoting properties.
Abstract: Neuregulin-1 (Nrg1) is genetically linked to schizophrenia, a disease caused by neurodevelopmental imbalance in dopaminergic function. The Nrg1 receptor ErbB4 is abundantly expressed on midbrain dopaminergic neurons. Nrg1 has been shown to penetrate blood-brain barrier, and peripherally administered Nrg1 activates ErbB4 and leads to a persistent hyperdopaminergic state in neonatal mice. These data prompted us to study the effect of peripheral administration of Nrg1 in the context of Parkinson's disease, a neurodegenerative disorder affecting the dopaminergic system in the adult brain. We observed that systemic injections of the extracellular domain of Nrg1β(1) (Nrg1β(1)-ECD) increased dopamine levels in the substantia nigra and striatum of adult mice. Nrg1β(1)-ECD injections also significantly protected the mouse nigrostriatal dopaminergic system morphologically and functionally against 6-hydroxydopamine-induced toxicity in vivo. Moreover, Nrg1β(1)-ECD also protected human dopaminergic neurons in vitro against 6-hydroxydopamine. In conclusion, we have identified Nrg1β(1)-ECD as a neurotrophic factor for adult mouse and human midbrain dopaminergic neurons with peripheral administratability, warranting further investigation as therapeutic option for Parkinson's disease patients.
Abstract: This study investigated the effects of bromazepam on qEEG when 14 healthy subjects were asked to perform a visuomotor task (i.e., motor vehicle driving task). The subjects were exposed to two experimental conditions: the placebo (PL) and 6 mg of bromazepam (Br 6 mg), following a randomized, double-blind design on different days. Specifically, we observe absolute power extracted from qEEG data for theta band. We expected to see a decrease in absolute theta power in the temporal and parietal areas due to the influence of bromazepam for the experimental group when compared with the placebo group. We found a main effect for the condition factor for electrodes T3, T4, P3 and P4. We also observed a main effect for the period factor for electrodes P3 and P4. We observed that the ingestion of 6 mg of bromazepam induces different patterns in theta power at the temporal and parietal sites. We concluded that 6 mg of bromazepam was an important factor in the fluctuation of the activities in the temporal and parietal areas. We then hypothesize about the specific role of this drug during the execution of a visuomotor task and within the sensorimotor integration process.
Abstract: The present study examined absolute alpha power using quantitative electroencephalogram (qEEG) in bilateral temporal and parietal cortices in novice soldiers under the influence of methylphenidate (MPH) during the preparatory aiming period in a practical pistol-shooting task. We anticipated higher bi-hemispheric cortical activation in the preparatory period relative to pre-shot baseline in the methylphenidate group when compared with the control group because methylphenidate has been shown to enhance task-related cognitive functions.
Abstract: Unlike for depression, only few studies are available today investigating the therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) for anxiety disorders. This review aims to provide information on the current research approaches and main findings regarding the therapeutic use of rTMS in the context of various anxiety disorders. Although positive results have frequently been reported in both open and randomized controlled studies, our review of all identified studies indicates that at present no conclusive evidence of the efficacy of rTMS for the treatment for anxiety disorders is provided. Several treatment parameters have been used, making the interpretation of the results difficult. Moreover, sham-controlled research has often been unable to distinguish between response to rTMS and sham treatment. However, there is a limitation in the rTMS methods that likely impacts only the superficial cortical layers. It is not possible to directly stimulate more distant cortical areas, and also subcortical areas, relevant to the pathogenesis of anxiety disorders, though such effects in subcortical areas are thought to be indirect, via trans-synaptic connections. We thus recommend further studies to clearly determine the role of rTMS in the treatment of anxiety disorders. Key advances in combining TMS with neuroimaging technology may aid in such future developments.
Abstract: Activation of the complement system promotes the removal of pathogens and tissue damage products from the brain and may also be involved in neuronal cell death in neurodegenerative diseases. Here, we analyzed the expression of C1q, the initial recognition subcomponent of the classic complement cascade, in the substantia nigra pars compacta (SNc) in Parkinson disease (PD) and control cases using immunohistochemistry and in situ hybridization. Microglia were determined to be the only cells that expressed C1q in the SNc and other brain areas. In the SNc of PD cases, there was increased deposition of extracellular neuromelanin in the parenchyma, resulting from degeneration of dopaminergic neurons. Neuromelanin granules and blebs of degenerated neurons seemed to be opsonized by C1q and phagocytosed by C1q-positive microglia and macrophages in the parenchyma and in the perivascular spaces. Neuromelanin-laden C1q-positive cells were also attached to the luminal surfaces of blood vessels in the SNc in PD. Thus, we present evidence suggesting that microglia are capable of phagocytosing and clearing cellular debris of degenerating neurons from the SNc through a C1q-mediated pathway in PD.
Abstract: Clinical studies have indicated that the primary pharmacological activity of modafinil (MOD) is inducing wakefulness; however, the brain targets that underlie its wake-promoting activity have not been described. In the present study, we show that MOD injected into sleep-wake related brain areas promoted alertness. If administered (10, 20, or 30 μg/1 μL) into either anterior hypothalamus (AH) or pedunculopontine tegmental nucleus (PPTg) at 08:00, 12:00 or 16:00 h, MOD enhanced wakefulness whereas diminished slow wave sleep as well as rapid eye movement sleep. In addition, microinjection of MOD (10, 20, or 30 μg/1 μL) either into AH or PPTg after total sleep deprivation prevented the sleep rebound. Taken together, these observations suggest that AH and PPTg play a key role in the wake-inducing effects of MOD and encourage further experimentation to draw a possible mechanism of action.
Abstract: Neurogenesis occurs in the adult brain in a constitutive manner under physiological circumstances within two regions: the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles. In contrast to these two so-called neurogenic areas, other regions of the brain were considered to be primarily non-neurogenic in nature, implying that no new neurons were formed there under normal conditions. Recently, low proliferative activity was reported in the hypothalamus and the cell layers surrounding the third ventricle. This review summarizes recent evidence for adult neurogenesis in the hypothalamus, and points out the potential contributions of these new neurons to neural processing. We also discussed some technical considerations in investigating neurogenesis in the adult hypothalamus. It is believed that the hypothalamus could serve as a new source and target for stem cell transplantation.
Abstract: Mutations in the N-terminus of the gene encoding α-synuclein (α-syn) are linked to autosomal dominantly inherited Parkinson's disease (PD). The vast majority of PD patients develop neuropsychiatric symptoms preceding motor impairments. During this premotor stage, synucleinopathy is first detectable in the olfactory bulb (OB) and brain stem nuclei; however its impact on interconnected brain regions and related symptoms is still less far understood. Using a novel conditional transgenic mouse model, displaying region-specific expression of human mutant α-syn, we evaluated effect and reversibility of olfactory synucleinopathy. Our data showed that induction of mutant A30P α-syn expression increased transgenic deposition into somatodendritic compartment of dopaminergic neurons, without generating fibrillar inclusions. We found reversibly reduced levels of dopamine and metabolites in the OB, suggesting an impact of A30P α-syn on olfactory neurotransmitter content. We further showed that mutant A30P expression led to neurodegenerative changes on an ultrastructural level and a behaviorally hyperactive response correlated with novelty, odor processing and stress associated with an increased dopaminergic tone in midbrain regions. Our present data indicate that mutant (A30P) α-syn is directly implicated in reduction of dopamine signaling in OB interneurons, which mediates further alterations in brain regions without transgenic expression leading functionally to a hyperactive response. These modulations of neurotransmission may underlie in part some of the early neuropsychiatric symptoms in PD preceding dysfunction of the nigrostriatal dopaminergic system.
Abstract: Although several electrophysiological studies have demonstrated the role of theta band during the execution of different visuospatial attention tasks, this study is the first to directly investigate the role of theta power during the planning, execution and cognitive control of saccadic eye movements (SEMs). The current study aims at addressing this issue by investigating absolute theta power over the frontal cortex during the execution of random and fixed SEMs. Twelve healthy volunteers, performed two tasks involving different conditions in the planning, execution and cognitive control of SEMs while their brain activity pattern was recorded using quantitative electroencephalography. We found an interaction between SEM condition and electrode (F3, F4, Fz), and a main effect of time point and electrode. Our key finding revealed that the stimulus presentation induces different patterns over frontal theta power increase between the left and right hemisphere. We conclude that right and left frontal regions are an important factor to discriminate between memory- versus stimulus-driven SEMs, and speculate on their different contributions to visuospatial attention.
Abstract: Experimental models of Parkinson's disease (PD) are of great importance for improving the design of future clinical trials. Various neurotoxic models are available, including 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), paraquat and rotenone. However, no model is considered perfect; each has its own limitations. Based on epidemiological data, a new trend of using environmental toxins in PD modeling seems attractive and has dominated public discussions of the disease etiology. A search for new environmental toxin-based models would improve our knowledge of the pathology of the condition. Here, we discuss some toxins of natural origin (e.g. cycad-derived toxins, epoxomicin, Nocardia asteroides bacteria, Streptomyces venezuelae bacteria, annonacin and DOPAL) that possibly represent a contributory environmental component to PD.
Abstract: This study aimed to investigate the acute modulatory effect of bromazepam, a benzodiazepine derivative drug, on alpha and beta bands (8-35Hz) in primary motor areas (M1) through event-related spectral perturbation (ERSP). Ten healthy subjects were submitted to a cross-over double-blind design. Subjects performed a visuomotor task where they had to identify rapidly the ball launched horizontally and catch it quickly, while electroencephalographic activity was acquired. We found a statistically significant difference on the time windows of 2920 ms for 13Hz in the electrodes C3 and Cz, and on the time window of 2000 ms for 18Hz in the electrodes C3, when compared the bromazepam and placebo conditions. We concluded that the acute effects of bromazepam provoked changes in information process in the left M1 represented by electrode C3 in both 13 Hz and 18 Hz. Our paradigm is relevant for a better understanding of the brain dynamics due to the information related to bromazepam effects on sensorimotor processes. We consider this report an invitation to conduct more studies in order to associate electro-cortical activity and psychometric tests.
Abstract: The endocannabinoid system comprises amides, esters and ethers of long chain polyunsaturated fatty acids. Narachidonoylethanolamide (anandamide; ANA) and 2-arachidonoylglycerol (2-AG) are endogenous cannabinoids (endocannabinoids) ligands for the cannabinoid family of G-protein-coupled receptors named CB1 and CB2. Endocannabinoids are released upon demand from lipid precursors in a receptor-dependent manner and behave as retrograde signaling messengers, as well as modulators of postsynaptic transmission, interacting with other neurotransmitters systems. The two principal enzymes that are responsible for the metabolism of ANA and 2-AG are fatty acid amide hydrolase and monoacylglycerol lipase, respectively. Pharmacological experiments have shown that the administration of endocannabinoids induce cannabimimetic effects, including sleep promotion. This review will focus on some of the current evidence of the pharmacological potential of the endocannabinoid system on sleep modulation.
Abstract: Neuregulin-1 (NRG1) belongs to a large family of growth and differentiation factors with a key role in the development and maintenance of the brain. Genetic association of NRG1 within brain disorders such as Alzheimer's disease, schizophrenia and neuroprotective properties of certain NRG1 isoforms have led to a variety of studies in corresponding disease models. In the present work, we investigated NRG1 with regard to its peripheral and central biodistribution after systemic application. We first-time radiolabeled the entire biologically active extracellular domain of NRG1 isotype-β1 (NRG1-β1 ECD; aa 2-246) with iodine-125 and administered it peripherally to healthy adult C57Bl6 mice. Blood kinetics and relative organ distribution of (125)I-labeled NRG1-β1 ECD were determined. The blood level of NRG1-β1 ECD peaked within the first hour after intraperitoneal (i.p.) application. The brain-blood ratios of (125)I-labeled NRG1-β1 ECD were time-dependently 150-370% higher compared to the brain impermeable control, (131)I-labeled bovine serum albumin. Autoradiographs of brain slices demonstrated that (125)I-labeled NRG1-β1 ECD accumulated in several regions of the brain e.g. frontal cortex, striatum and ventral midbrain containing the substantia nigra. In addition we found histochemical and biochemical evidence that phosphorylation of the NRG1 prototype receptor ErbB4 was increased in these regions after systemic application of NRG1-β1 ECD. Our data suggest that NRG1-β1 ECD passes the blood-brain barrier and activates cerebral ErbB4 receptors.
Abstract: Functional electrical stimulation (FES) is a technique used for rehabilitation of motor and sensory dysfunction and consisted in the application of neuromuscular electrical stimulation concurrently with a functional activity. Previous studies suggest that sensory motor processing during FES stimulation of hand is similar to that of voluntary hand movement.
Abstract: Oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) are amides of fatty acids and ethanolamine named N-acylethanolamines or acylethanolamides. The hydrolysis of OEA and PEA is catalyzed by the fatty acid amide hydrolase (FAAH). A number of FAAH inhibitors that increase the levels of OEA and PEA in the brain have been developed, including URB597. In the present report, we examined whether URB597, OEA or PEA injected into wake-related brain areas, such as lateral hypothalamus (LH) or dorsal raphe nuclei (DRN) would promote wakefulness (W) in rats.
Abstract: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive procedure whereby a pulsed magnetic field stimulates electrical activity in the brain. Parkinson's disease (PD) is a neurodegenerative process characterized by numerous motor and nonmotor clinical manifestations for which effective, mechanism-based treatments remain elusive. Consequently, more advanced non-invasive therapeutic methods are required. A possible method of rehabilitation that may be effective and potentially viable for use in clinical practice is rTMS. Here, we focus on the basic foundation of rTMS, the main findings of rTMS from animal models, the effects of rTMS on sensorimotor integration in patients with PD, and the experimental advances of rTMS that may become a viable clinical application to treat the disease.
Abstract: The endocannabinoid anandamide (ANA) participates in the control of cell death inducing the formation of apoptotic bodies and DNA fragmentation. The aim of this study was to evaluate whether the ANA degrading enzyme, the fatty acid amide hydrolase (FAAH), would induce cellular death. Experiments were performed in cerebellar granule neurons cultured with the FAAH inhibitor, URB597 (25, 50 or 100 nM) as well as endogenous lipids such as oleoylethanolamide (OEA) or palmitoylethanolamide (PEA) and cellular viability was determined by MTT test. Neurons cultured with URB597 (25, 50 or 100 nM) displayed a decrease in cellular viability. In addition, if cultured with OEA (25 nM) or PEA (100 nM), cellular death was found. These results further suggest that URB597, OEA or PEA promote cellular death.
Abstract: Some patients are no longer able to communicate effectively or even interact with the outside world in ways that most of us take for granted. In the most severe cases, tetraplegic or post-stroke patients are literally 'locked in' their bodies, unable to exert any motor control after, for example, a spinal cord injury or a brainstem stroke, requiring alternative methods of communication and control. But we suggest that, in the near future, their brains may offer them a way out. Non-invasive electroencephalogram (EEG)-based brain-computer interfaces (BCI) can be characterized by the technique used to measure brain activity and by the way that different brain signals are translated into commands that control an effector (e.g., controlling a computer cursor for word processing and accessing the internet). This review focuses on the basic concepts of EEG-based BCI, the main advances in communication, motor control restoration and the downregulation of cortical activity, and the mirror neuron system (MNS) in the context of BCI. The latter appears to be relevant for clinical applications in the coming years, particularly for severely limited patients. Hypothetically, MNS could provide a robust way to map neural activity to behavior, representing the high-level information about goals and intentions of these patients. Non-invasive EEG-based BCIs allow brain-derived communication in patients with amyotrophic lateral sclerosis and motor control restoration in patients after spinal cord injury and stroke. Epilepsy and attention deficit and hyperactive disorder patients were able to downregulate their cortical activity. Given the rapid progression of EEG-based BCI research over the last few years and the swift ascent of computer processing speeds and signal analysis techniques, we suggest that emerging ideas (e.g., MNS in the context of BCI) related to clinical neurorehabilitation of severely limited patients will generate viable clinical applications in the near future.
Abstract: Zonisamide is widely used as an antiepileptic drug. Two studies published recently in Experimental Neurology focus on the drug's neuroprotective effect. In the present commentary, we discuss the significance of their findings and aspects of zonisamide in neuroprotection.
Abstract: Progressive supranuclear palsy is a sporadic and progressive neurodegenerative disease, most often presenting as a symmetric, akinetic-rigid syndrome with postural instability, vertical supranuclear gaze palsy and frontal lobe deficits. It belongs to the family of tauopathies and involves both cortical and subcortical structures. Although the exact pathophysiology is not yet fully understood, several lines of evidence point to a crucial contribution from both genetic predisposition and mitochondrial dysfunction. Recently gained insights into the pathophysiology of this disease have led to several hypothesis-driven therapeutic approaches aiming at disease-modification rather than mere symptomatic neurotransmitter-replacement therapy. Agents targeting mitochondrial dysfunction have already shown a positive effect in a phase II study and further studies to verify and expand these results are ongoing. Clinical studies with agents targeting tau dysfunction such as tau-kinase inhibitors, tau-aggregation inhibitors and microtubule stabilizers are in preparation or ongoing. This review presents the current pathophysiological concepts driving these exciting therapeutic developments.
Abstract: The development and application of single neuron electroporation largely advanced the use of traditional genetics in investigations of the central nervous system. This quick and accurate manipulation of the brain at individual neuron level allowed the gain and loss of functional analyses of different genes and/or proteins. This manuscript reviewed the development of the technique and discussed some technical aspects in practical manipulations. Then the manuscript summarized the potential applications with this technique. Last but not least, the technique showed prospective future when combined with other modern methods in neuroscience research.
Abstract: Memory is an essential element to adaptive behavior since it allows consolidation of past experience guiding the subject to consider them in future experiences. Among the endogenous molecules that participate in the consolidation of memory, including the drug-seeking reward, considered as a form of learning, is dopamine. This neurotransmitter modulates the activity of specific brain nucleus such as nuclei accumbens, putamen, ventral tegmental area (VTA), among others and synchronizes the activity of these nuclei to establish the neurobiological mechanism to set the hedonic element of learning. We review the experimental evidence that highlights the activity of different brain nuclei modulating the mechanisms whereby dopamine biases memory towards events that are of motivational significance.
Abstract: The clinical motor dysfunction in Parkinson's disease is primarily the consequence of a progressive degeneration of dopaminergic neurons in the substantia nigra of the nigrostriatal pathway. The degeneration of this tract provokes a depletion of dopamine in the striatum, where it is required as a permissive factor for normal motor function. Despite intense investigations, no effective therapy is available to prevent the onset or to halt the progression of the neuronal cell loss. Therefore, recent years have seen research into the mechanisms of endogenous repair processes occurring in the adult brain, particularly in the substantia nigra. Neurogenesis occurs in the adult brain in a constitutive manner under physiological circumstances within two regions: the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles. In contrast to these two so-called neurogenic areas, the remainder of the brain is considered to be primarily nonneurogenic in nature, implying that no new neurons are produced there under normal conditions. The occurrence of adult neurogenesis in the substantia nigra under the pathological conditions of Parkinson's disease, however, remains controversial. Here, we review the published evidence of whether adult neurogenesis exists or not within the substantia nigra, where dopaminergic neurons are lost in Parkinson's disease.
Abstract: The clinical motor dysfunction in Parkinson s disease (PD) is primarily linked to the depletion of dopamine in the striatum consecutive to the loss of the large dopaminergic neurons in the substantia nigra. Despite intense investigations, no effective therapy is available to prevent the onset, or to halt the progression of the neuronal cell loss. Here, we hypothesize that autologous adult neural stem cells (NSCs) are an attractive source for cell therapy to treat PD. They overcome the ethical issues inherent to the use of human fetal tissue or embryonic stem cells. NSCs derived from adult tissue also open the possibility for autologous transplantation, where NSCs are taken out from the patient, expanded and differentiated in vitro and re-implanted back as dopaminergic precursor cells.
Abstract: Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep-onset rapid eye movement (REM) sleep periods. Narcolepsy is now identified to be a neurodegenerative disease, as there is a massive loss of neurons containing the neuropeptide, hypocretin/orexin. Orexin neurons are solely located in the hypothalamus, particularly in its perifornical, dorsomedial and lateral portions. Orexin fibers widely project throughout the brain and generally have excitatory effects on their postsynaptic cells. Patients with narcolepsy have a severe reduction in the levels of orexins in the cerebrospinal fluid, a finding consistent with orexin neuronal loss. Experimental models have been generated in order to study the physiology of the orexin system and narcolepsy. The discovery of orexin deficiency in narcolepsy is redefining the clinical entity of narcolepsy and offering novel diagnostic procedures. This article reviews the current understanding of narcolepsy and discusses the opportunity to explore the potential use of transplants as a therapeutical tool in order to treat narcolepsy.
Abstract: Since their discovery in 1998, it has been shown that the orexin (hypocretin) peptides are involved in almost all of the functions historically associated with the lateral hypothalamus. These peptides are produced by only some thousand neurons restricted to the posterolateral hypothalamus. A decade later, the orexin neurons have emerged as an important mode of signalling in the hypothalamus. Orexins were recognized as regulators of feeding behaviour. The subsequent finding that an orexin deficiency causes narcolepsy in humans and animals indicates that these hypothalamic neuropeptides also have a crucial role in regulating sleep and wakefulness. Recent studies of orexin-producing neurons and their efferent and afferent systems, as well as phenotypic characterizations of mice with genetic alterations in the orexin system, have suggested further roles for orexin in the coordination of emotion, energy homeostasis, reward, drug addiction and arousal. In this special issue, we will discuss the role of orexins in sleep-wake regulation and its involvement in narcolepsy.
Abstract: Regulation of the sleep-waking cycle is complex, involving multiple neurological circuits and diverse endogenous molecules. Interplay among assorted neuroanatomical and neurochemical systems such as acetylcholine, dopamine, noradrenaline, serotonin, histamine, and hypocretin maintain the waking (W) state. The sleep-onset is governed by the interacting forces of the sleep drive, which steadily increases with duration of W, and circadian fluctuations. Sleep-promoting neurons located in the anterior hypothalamus release GABA and inhibit wake-promoting regions in the hypothalamus and brainstem and participate in the generation of slow wave sleep (SWS). During rapid eye movement (REM) sleep, brainstem regions typically inhibited during W and SWS become active. In this regard, ascending projections from cholinergic neurons in the brainstem activate the thalamus which in turn increases the firing of the neurons in the cortex. Finally, sleep-promoting substances that accumulate in the brain during natural or prolonged W implicate a further complexity in the mechanism of modulation of the sleep-wake cycle. This review provides a broad understanding of our present knowledge in the field of sleep research.
Abstract: Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep-onset rapid eye movement (REM) sleep periods. It is now identified as a neurodegenerative disease because there is a massive loss of specific neurons in the brain. These neurons contain the neuropeptides hypocretin-1 and hypocretin-2, which are also known as orexin-A and orexin-B. Cerebrospinal fluid hypocretin-1 measurements are diagnostic for primary narcolepsy. The cause of neural loss could be autoimmune since most patients have the HLA DQB1 0602 allele that predisposes to the disorders. The discovery of hypocretin deficiency is redefining the clinical entity of narcolepsy and offering novel diagnostic procedures. This article reviews the current understanding of narcolepsy and discusses the implications of hypocretin discovery.
Abstract: Basic and clinical research suggests a potential role for repetitive transcranial magnetic stimulation (rTMS) in the treatment of Parkinson's disease. However, compared to the growing number of clinical studies on its putative therapeutic properties, the studies on the basic mechanisms of rTMS are surprisingly scarce.
Abstract: Neural stem cells hold the key to innovative new treatments for age-associated degeneration and traumatic injury to the brain and spinal cord. We hypothesized that the in vivo induced pluripotent stem cells or neural stem cells through "forced gene expression" can be used to repair damaged brain areas or treat degenerative diseases. Hopefully, these in vivo patient-specific stem cells can bring a new avenue for cell replacement therapies.
Abstract: 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.
Abstract: Parkinson's disease is a neurodegenerative disorder characterized by a progressive neuronal loss affecting preferentially the dopaminergic neurons of the nigrostriatal projection. Transplantation of fetal dopaminergic precursor cells has provided the proof of principle that a cell replacement therapy can ameliorate clinical symptoms in affected patients. Recent years have provided evidence for the existence of neural stem cells with the potential to produce new neurons, particularly of a dopaminergic phenotype, in the adult mammalian brain. Such stem cells have been identified in so called neurogenic brain areas, where neurogenesis is constitutively ongoing, but also in primarily non-neurogenic areas, such as the midbrain and the striatum, where neurogenesis does not occur under normal physiological conditions. We review here presently published evidence to evaluate the concept that endogenous neural stem cells may have the potential to be instrumentalized for a non-invasive cell replacement therapy with autologous neurons to repair the damaged nigrostriatal dopaminergic projection in Parkinson's disease.
Abstract: 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'.
Abstract: Dopaminergic neurons of the midbrain are the main source of dopamine (DA) in the brain. DA has been shown to be involved in the control of movements, the signaling of error in prediction of reward, motivation, and cognition. Cerebral DA depletion is the hallmark of Parkinson's disease (PD). Other pathological states have also been associated with DA dysfunction, such as schizophrenia, autism, and attention deficit hyperactivity disorder in children, as well as drug abuse. DA is closely associated with reward-seeking behaviors, such as approach, consumption, and addiction. Recent researches suggest that the firing of DA neurons is a motivational substance as a consequence of reward-anticipation. This hypothesis is based on the evidence that, when a reward is greater than expected, the firing of certain DA neurons increases, which consequently increases desire or motivation towards the reward.
Abstract: Narcolepsy is a chronic disease characterized by excessive somnolence, abrupt transitions from wakefulness to rapid eye movement sleep stage and cataplexy. Experimental evidence show that narcolepsy in humans is a neurodegenerative disease associated with the lost of hypocretin (HCRT) neurons in the lateral hypothalamus. Narcoleptic patients also display a significant diminution in HCRT contents of cerebrospinal fluid. In order to study narcolepsy, several experimental models have been developed. Murine and canine models currently allow us to study this disease. Our laboratory has developed a new experimental rat model of narcolepsy. This model allows us to study the disease from a histological and neurochemical perspective. Elsewhere we have reported that the use of the toxin hypocretin2/saporine (HCRT2/ SAP) selectively destroys hypocretinergic neurons. The loss of these neurons induces a similar behavioural profile as the one observed in other experimental models of narcolepsy. In the present review we describe an overview on narcolepsy, the hypocretinergic system, experimental models in narcolepsy and the use of transplants as an alternative therapeutic tool.
Abstract: Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness, inadvertent transitions from wakefulness to rapid eye movement sleep (so called "sleep-onset REMS period") and cataplexy (sudden bilateral skeletal muscle weakness during waking without impairment of consciousness). This disorder has been recently linked to a loss of hypocretin (HCRT) neurons making narcolepsy a neurodegenerative disease. Neuronal replacement could be used to reverse the symptoms of narcolepsy. Towards this end, we have recently reported that HCRT neurons from rat pups can survive when grafted into the pons of adult rats. Here, we investigate the time-course of survival of grafted HCRT neurons into the pons of adult rats. The HCRT neurons are present only in the lateral hypothalamus, and therefore suspension of cells from this region was derived from 8- to 10-day-old rat pups (donor), and grafted into the pons of adult (60 days old) host rats. Control rats received a transplant that consisted of cells from the cerebellum where no HCRT neurons are present. All adult host rats were sacrificed 1, 3, 6, 9, 12, 24, or 36 days after grafting. Immunohistochemistry was used to identify and count the presence of the HCRT grafted neurons in the target area. The tally of HCRT neurons present in the graft zone 1 day post-grafting was considered to be the baseline. From day 3 to 36 post-transplant there was a steady decline in the number of HCRT neurons. We also noted that on day 36, the HCRT neurons that survived in the pons had morphological features that were similar to mature HCRT neurons in the adult lateral hypothalamus, suggesting that these neurons might be functionally active. Control rats that received grafts of cerebellar tissue did not show HCRT neurons in the target area. These results demonstrate that there is a progressive decline in the number of transplanted neurons, but a significant percentage of HCRT neurons do survive until day 36. This study highlights the potential use of transplants as a therapeutical tool in order to treat narcolepsy.
Abstract: Neurogenesis in the adult mammalian brain continues in the subventricular zone (SVZ). Neuronal precursors from the SVZ migrate along the rostral migratory stream to replace olfactory bulb interneurons. After the destruction of the nigro-striatal pathway (SN-lesion), some SVZ precursors begin to express tyrosine hydroxylase (TH) and neuronal markers (NeuN). Grafting of chromaffin cells (CCs) into the denervated striatum increases the number of TH+ cells (SVZ TH+ cells; Arias-Carrión et al., 2004). This study examines the functional properties of these newly differentiating TH+ cells. Under whole-cell patch-clamp, most SVZ cells recorded from lesioned and grafted animals (either TH+ or TH-) were non-excitable. Nevertheless, a small percentage of SVZ TH+ cells had the electrophysiologic phenotype of mature dopaminergic neurons and showed spontaneous postsynaptic potentials. Dopamine (DA) release was measured in SVZ and striatum from both control and SN-lesioned rats. As expected, 12 weeks after SN lesion, DA release decreased drastically. Nevertheless, 8 weeks after CCs graft, release from the SVZ of SN-lesioned rats recovered, and even surpassed that from control SVZ, suggesting that newly formed SVZ TH+ cells release DA. This study shows for the first time that in response to SN-lesions and CC grafts neural precursors within the SVZ change their developmental program, by not only expressing TH, but more importantly by acquiring excitable properties of mature dopaminergic neurons. Additionally, the release of DA in a Ca(2+)-dependent manner and the attraction of synaptic afferents from neighboring neuronal networks gives further significance to the overall findings, whose potential importance is discussed.
Abstract: 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.
Abstract: The sleep disorder narcolepsy is now considered a neurodegenerative disease because there is a massive loss of neurons containing the neuropeptide, hypocretin, and because narcoleptic patients have very low cerebrospinal fluid levels of hypocretin. Transplants of various cell types have been used to induce recovery in a variety of neurodegenerative animal models. In models such as Parkinson disease, cell survival has been shown to be small but satisfactory. Currently, there are no data indicating whether hypocretin neurons can survive when grafted into host tissue. Here we examined the survival of hypocretin-containing neurons grafted into the pontine reticular formation, a region traditionally regarded to be key for rapid eye movement sleep generation.
