Gonadal steroids and astroglial plasticity

Summary 1. Recent evidence indicates that astroglia participate in the metabolism of gonadal hormones, in the synthesis of neurosteroids, and in the plastic responses of neurons to gonadal steroids. The role of astroglia on plastic responses of neural tissue to gonadal hormones and neurosteroids is examined in this review.2. Gonadal steroids and neurosteroids promote astroglia plasticity in several areas of the central nervous system, including the hypothalamus, the striatum, and the hippocampus.3. Gonadal steroids and neurosteroids modulate astroglia proliferation and the formation of reactive astroglia after brain injury.4. Astroglia is a source of trophic factors that may mediate effects of gonadal steroids on neural tissue.5. Astroglia is involved in the promotion of synaptic plastic changes by gonadal hormones.6. The effect of gonadal hormones on astroglial plasticity is dependent on specific membrane interactions with neurons and on the expression of the embryonic highly polysialylated isoform of the neural cell adhesion molecule on neuronal membranes.7. In conclusion, coordinated responses of neurons and astroglia appear to be involved in the modulation of neural function and response to injury by gonadal hormones and neurosteroids.     

Reciprocal Modulation Between Microglia and Astrocyte in Reactive Gliosis Following the CNS Injury

Reactive gliosis, also known as glial scar formation, is an inflammatory response characterized by the proliferation of microglia and astrocytes as well as astrocytic hypertrophy following injury in the central nervous system (CNS). The glial scar forms a physical and molecular barrier to isolate the injured area from adjacent normal nervous tissue for re-establishing the integrity of the CNS. It prevents the further spread of cellular damage but represents an obstacle to regrowing axons. In this review, we integrated the current findings to elucidate the tightly reciprocal modulation between activated microglia and astrocytes in reactive gliosis and proposed that modification of cellular response to the injury or cellular reprogramming in the glial scar could lead advances in axon regeneration and functional recovery after the CNS injury.     

Ganglioside function in the development and repair of the nervous system

Gangliosides play important roles in the normal physiological operations of the nervous system, in particular that of the brain. Changes in ganglioside composition occur in the mammalian brain not only during development, but also in aging and in several neuropathological situations. Gangliosides may modulate the ability of the brain to modify its response to cues or signals from the microenvironment. For example, cultured neurons are known to respond to exogenous ganglioside with changes characteristic of cell differentiation. Gangliosides can amplify the responses of neurons to extrinsic protein factors (neuronotrophic factors) that are normal constituents of the neuron's environment. The systemic administration of monosialoganglioside also potentiates trophic actions in vivo and improves neural responses following various types of injury to the adult mammalian central nervous system. The possible molecular mechanism(s) underlying the ganglioside effects may reflect an action in modulating ligand-receptor linked transfer of information across the plasma membrane of the cell.     

LPA receptor expression in the central nervous system in health and following injury

Lysophosphatidic acid (LPA) is released from platelets following injury and also plays a role in neural development but little is known about its effects in the adult central nervous system (CNS). We have examined the expression of LPA receptors 1-3 (LPA_1–3) in intact mouse spinal cord and cortical tissues and following injury. In intact and injured tissues, LPA₁ was expressed by ependymal cells in the central canal of the spinal cord and was upregulated in reactive astrocytes following spinal cord injury. LPA₂ showed low expression in intact CNS tissue, on grey matter astrocytes in spinal cord and in ependymal cells lining the lateral ventricle. Following injury, its expression was upregulated on astrocytes in both cortex and spinal cord. LPA₃ showed low expression in intact CNS tissue, viz. on cortical neurons and motor neurons in the spinal cord, and was upregulated on neurons in both regions after injury. Therefore, LPA_1–3 are differentially expressed in the CNS and their expression is upregulated in response to injury. LPA release following CNS injury may have different consequences for each cell type because of this differential expression in the adult nervous system.     

The Role of eNSCs in Neurodegenerative Disease

Recent progress in biology has shown that many if not all adult tissues contain a population of stem cells. It is believed that these cells are involved in the regeneration of the tissue or organ in which they reside as a response to the natural turnover of differentiated cells or to injury. In the adult mammalian brain, stem cells in the subventricular zone and the dentate gyrus may also play a role in the replacement of neurons. A positive beneficial response to injury does not necessarily require cell replacement. New findings suggest that some populations of endogenous neural stem cells in the central nervous system may have adopted a function different from cell replacement and are involved in the protection of neurons in diverse paradigms of disease and injury. In this article, we will focus on the immature cell populations of the central nervous system and the signal transduction pathways that regulate them which suggest new possibilities for their manipulation in injury and disease.     

Why seeing is believing: merging auditory and visual worlds

Vision may dominate our perception of space not because of any inherent physiological advantage of visual over other sensory connections in the brain, but because visual information tends to be more reliable than other sources of spatial information, and the central nervous system integrates information in a statistically optimal fashion. This review discusses recent experiments on audiovisual integration that support this hypothesis. We consider candidate neural codes that would enable optimal integration and the implications of optimal integration for perception and plasticity.     

Shaping the dynamics of a bidirectional neural interface

Progress in decoding neural signals has enabled the development of interfaces that translate cortical brain activities into commands for operating robotic arms and other devices. The electrical stimulation of sensory areas provides a means to create artificial sensory information about the state of a device. Taken together, neural activity recording and microstimulation techniques allow us to embed a portion of the central nervous system within a closed-loop system, whose behavior emerges from the combined dynamical properties of its neural and artificial components. In this study we asked if it is possible to concurrently regulate this bidirectional brain-machine interaction so as to shape a desired dynamical behavior of the combined system. To this end, we followed a well-known biological pathway. In vertebrates, the communications between brain and limb mechanics are mediated by the spinal cord, which combines brain instructions with sensory information and organizes coordinated patterns of muscle forces driving the limbs along dynamically stable trajectories. We report the creation and testing of the first neural interface that emulates this sensory-motor interaction. The interface organizes a bidirectional communication between sensory and motor areas of the brain of anaesthetized rats and an external dynamical object with programmable properties. The system includes (a) a motor interface decoding signals from a motor cortical area, and (b) a sensory interface encoding the state of the external object into electrical stimuli to a somatosensory area. The interactions between brain activities and the state of the external object generate a family of trajectories converging upon a selected equilibrium point from arbitrary starting locations. Thus, the bidirectional interface establishes the possibility to specify not only a particular movement trajectory but an entire family of motions, which includes the prescribed reactions to unexpected perturbations.     

Neurobiology of exercise

Voluntary physical activity and exercise training can favorably influence brain plasticity by facilitating neurogenerative, neuroadaptive, and neuroprotective processes. At least some of the processes are mediated by neurotrophic factors. Motor skill training and regular exercise enhance executive functions of cognition and some types of learning, including motor learning in the spinal cord. These adaptations in the central nervous system have implications for the prevention and treatment of obesity, cancer, depression, the decline in cognition associated with aging, and neurological disorders such as Parkinson's disease, Alzheimer's dementia, ischemic stroke, and head and spinal cord injury. Chronic voluntary physical activity also attenuates neural responses to stress in brain circuits responsible for regulating peripheral sympathetic activity, suggesting constraint on sympathetic responses to stress that could plausibly contribute to reductions in clinical disorders such as hypertension, heart failure, oxidative stress, and suppression of immunity. Mechanisms explaining these adaptations are not as yet known, but metabolic and neurochemical pathways among skeletal muscle, the spinal cord, and the brain offer plausible, testable mechanisms that might help explain effects of physical activity and exercise on the central nervous system.     

Cell Therapy for CNS Trauma

Cell therapy plays an important role in multidisciplinary management of the two major forms of central nervous system (CNS) injury, traumatic brain injury and spinal cord injury, which are caused by external physical trauma. Cell therapy for CNS disorders involves the use of cells of neural or non-neural origin to replace, repair, or enhance the function of the damaged nervous system and is usually achieved by transplantation of the cells, which are isolated and may be modified, e.g., by genetic engineering, when it may be referred to as gene therapy. Because the adult brain cells have a limited capacity to migrate to and regenerate at sites of injury, the use of embryonic stem cells that can be differentiated into various cell types as well as the use of neural stem cells has been explored. Preclinical studies and clinical trials are reviewed. Advantages as well as limitations are discussed. Cell therapy is promising for the treatment of CNS injury because it targets multiple mechanisms in a sustained manner. It can provide repair and regeneration of damaged tissues as well as prolonged release of neuroprotective and other therapeutic substances.     

Neural interfaces for upper-limb prosthesis control: opportunities to improve long-term reliability

Building on a long history of innovation in neural-recording interfaces, the Defense Advanced Research Projects Agency (DARPA) has launched a program to address the key challenges related to transitioning advanced neuroprosthesis technology to clinical use for amputated service members. The goal of the Reliable Neural Technology (RE-NET) Program is to develop new technology to extract information from the nervous system at a scale and rate needed to reliably control modern robotic prostheses over the lifetime of the amputee. The RE-NET program currently encompasses three separate efforts: histology for interface stability over time (HIST), reliable peripheral interfaces (RPIs), and reliable central nervous system (CNS) interfaces (RCIs).     

Three-dimensional imaging of the unsectioned adult spinal cord to assess axon regeneration and glial responses after injury

Studying regeneration in the central nervous system (CNS) is hampered by current histological and imaging techniques because they provide only partial information about axonal and glial reactions. Here we developed a tetrahydrofuran-based clearing procedure that renders fixed and unsectioned adult CNS tissue transparent and fully penetrable for optical imaging. In large spinal cord segments, we imaged fluorescently labeled cells by 'ultramicroscopy' and two-photon microscopy without the need for histological sectioning. We found that more than a year after injury growth-competent axons regenerated abundantly through the injury site. A few growth-incompetent axons could also regenerate when they bypassed the lesion. Moreover, we accurately determined quantitative changes of glial cells after spinal cord injury. Thus, clearing CNS tissue enables an unambiguous evaluation of axon regeneration and glial reactions. Our clearing procedure also renders other organs transparent, which makes this approach useful for a large number of preclinical paradigms.     

神经干细胞的研究现状及运用前景

近年来的研究表明胚胎期和成年期动物的神经组织及人脑中可以分离出神经干细胞.神经干细胞能不断增殖并且具有分化成神经元、星型胶质细胞和少突胶质细胞的能力.神经干细胞的这种特性为中枢神经系统退行性病变和损伤的治疗打下了基础.对神经干细胞的分布、生物学特性、鉴定、增殖与分化及其治疗中枢神经系统疾病中的应用前景进行了综述.     

Neochlorogenic Acid Inhibits Lipopolysaccharide-Induced Activation and Pro-inflammatory Responses in BV2 Microglial Cells

Neurochemical Research - Microglia is the resident innate immune cells that sense pathogens and tissue injury in the central nervous system. Microglia becomes activated in response to injury,...     

Neural stem cells as biological minipumps: a faster route to cell therapy for the CNS?

One strategy for the use of neural stem cells (NSCs) in treating neurological disorders is as transplantable "biological minipumps", in which genetically engineered neural stem cells serve as sources of secreted therapeutic (neuroprotective or tumoricidal) agents. Neural stem cells are highly mobile within the brain and demonstrate a tropism for various types of central nervous system (CNS) pathology, making them promising candidates for targeted gene delivery vehicles. Although neural stem cells have also been proposed as a potential source of replacement neurons and astrocytes to repopulate injured or degenerating neural circuits, the challenges involved in rebuilding damaged brain architecture are substantial and remain an active area of investigation. In contrast, the use of NSCs as biological minipumps does not rely on neuronal differentiation, axonal targeting, or synaptogenesis. This strategy may be a faster route to cell-based therapy of the CNS and is poised to move into human clinical trials. This review considers two types of neurologic disease that may be suitable targets for this alternative approach to NSC therapy: glial brain tumors and traumatic brain injury. We examine some of the key scientific and technical issues that must be addressed for the successful use of NSCs as minipumps.     

Electrode failure: tissue, electrical, and material responses

The development of invasive, rehabilitative neuroprosthetics for humans requires reliable neural probes that are capable of recording large ensembles of neurons for a long period of time. Recent advances in the development of neuroprosthetics in animals and humans have shown that communication and control can be directly derived from the central nervous system (CNS) for restoring lost motor ability. This proof of concept has opened the possibility of new therapies for the millions of individuals suffering from neurological disorders of the nervous system. The success of these therapies hinges on the ability to reliably access the relevant signals from the brain with high quality for the lifetime of the patient. As a result, research has focused on the cascade of events that follow chronic implantation of microelectrodes and temporal degradation in the signal and electrode quality: signal-to-noise ratio, noise floor, peak amplitude, and neuronal yield. Implanted microelectrodes have been reported to suffer from time-dependent degradation in signal quality due to unknown issues related to tissue interfaces.     

Glial and axonal regeneration following spinal cord injury

Spinal cord injury (SCI) has been regarded clinically as an irreversible damage caused by tissue contusion due to a blunt external force. Past research had focused on the analysis of the pathogenesis of secondary injury that extends from the injury epicenter to the periphery, as well as tissue damage and neural cell death associated with secondary injury. Recent studies, however, have proven that neural stem (progenitor) cells are also present in the brain and spinal cord of adult mammals including humans. Analyses using spinal cord injury models have also demonstrated active dynamics of cells expressing several stem cell markers, and methods aiming at functional reconstruction by promoting the potential self-regeneration capacity of the spinal cord are being explored. Furthermore, reconstruction of the neural circuit requires not only replenishment or regeneration of neural cells but also regeneration of axons. Analysis of the tissue microenvironment after spinal cord injury and research aiming to remove axonal regeneration inhibitors have also made progress. SCI is one of the simplest central nervous injuries, but its pathogenesis is associated with diverse factors, and further studies are required to elucidate these complex interactions in order to achieve spinal cord regeneration and functional reconstruction.     

Differential T cell response in central and peripheral nerve injury: connection with immune privilege.

The central nervous system (CNS), unlike the peripheral nervous system (PNS), is an immune-privileged site in which local immune responses are restricted. Whereas immune privilege in the intact CNS has been studied intensively, little is known about its effects after trauma. In this study, we examined the influence of CNS immune privilege on T cell response to central nerve injury. Immunocytochemistry revealed a significantly greater accumulation of endogenous T cells in the injured rat sciatic nerve than in the injured rat optic nerve (representing PNS and CNS white matter trauma, respectively). Use of the in situ terminal deoxytransferase-catalyzed DNA nick end labeling (TUNEL) procedure revealed extensive death of accumulating T cells in injured CNS nerves as well as in CNS nerves of rats with acute experimental autoimmune encephalomyelitis, but not in injured PNS nerves. Although Fas ligand (FasL) protein was expressed in white matter tissue of both systems, it was more pronounced in the CNS. Expression of major histocompatibility complex (MHC) class II antigens was found to be constitutive in the PNS, but in the CNS was induced only after injury. Our findings suggest that the T cell response to central nerve injury is restricted by the reduced expression of MHC class II antigens, the pronounced FasL expression, and the elimination of infiltrating lymphocytes through cell death.     

Representation of spectrotemporal sound information in the ascending auditory pathway

The representation of sound information in the central nervous system relies on the analysis of time-varying features in communication and other environmental sounds. How are auditory physiologists and theoreticians to choose an appropriate method for characterizing spectral and temporal acoustic feature representations in single neurons and neural populations? A brief survey of currently available scientific methods and their potential usefulness is given, with a focus on the strengths and weaknesses of using noise analysis techniques for approximating spectrotemporal response fields (STRFs). Noise analysis has been used to foster several conceptual advances in describing neural acoustic feature representation in a variety of species and auditory nuclei. STRFs have been used to quantitatively assess spectral and temporal transformations across mutually connected auditory nuclei, to identify neuronal interactions between spectral and temporal sound dimensions, and to compare linear vs. nonlinear response properties through state-dependent comparisons. We propose that noise analysis techniques used in combination with novel stimulus paradigms and parametric experiment designs will provide powerful means of exploring acoustic feature representations in the central nervous system.     

Elucidating the Role of Injury-Induced Electric Fields (EFs) in Regulating the Astrocytic Response to Injury in the Mammalian Central Nervous System

Injury to the vertebrate central nervous system (CNS) induces astrocytes to change their morphology, to increase their rate of proliferation, and to display directional migration to the injury site, all to facilitate repair. These astrocytic responses to injury occur in a clear temporal sequence and, by their intensity and duration, can have both beneficial and detrimental effects on the repair of damaged CNS tissue. Studies on highly regenerative tissues in non-mammalian vertebrates have demonstrated that the intensity of direct-current extracellular electric fields (EFs) at the injury site, which are 50–100 fold greater than in uninjured tissue, represent a potent signal to drive tissue repair. In contrast, a 10-fold EF increase has been measured in many injured mammalian tissues where limited regeneration occurs. As the astrocytic response to CNS injury is crucial to the reparative outcome, we exposed purified rat cortical astrocytes to EF intensities associated with intact and injured mammalian tissues, as well as to those EF intensities measured in regenerating non-mammalian vertebrate tissues, to determine whether EFs may contribute to the astrocytic injury response. Astrocytes exposed to EF intensities associated with uninjured tissue showed little change in their cellular behavior. However, astrocytes exposed to EF intensities associated with injured tissue showed a dramatic increase in migration and proliferation. At EF intensities associated with regenerating non-mammalian vertebrate tissues, these cellular responses were even more robust and included morphological changes consistent with a regenerative phenotype. These findings suggest that endogenous EFs may be a crucial signal for regulating the astrocytic response to injury and that their manipulation may be a novel target for facilitating CNS repair.     

中枢白细胞介素-1在应激反应中的作用

白细胞介素-1（interleukin-1,IL-1）系统分子广泛分布于中枢神经系统。中枢IL-1具有极其丰富的生物学功能,作为经典炎性细胞因子,在多种生理、病理生理过程中起重要作用。近几年来,中枢IL-1的应激介质作用备受关注。本文综述了中枢IL-1在应激反应中作用的最新进展,包括应激对中枢IL-1系统的影响,中枢IL-1对应激反应的启动和介导作用;参与中枢IL-1-应激介导作用的神经环路和细胞信号转导通路,以及中枢IL-1对应激时脑高级功能和行为反应的影响。