Complementary encoding of spatial information in hippocampal astrocytes

Calcium dynamics into astrocytes influence the activity of nearby neuronal structures. However, because previous reports show that astrocytic calcium signals largely mirror neighboring neuronal activity, current information coding models neglect astrocytes. Using simultaneous two-photon calcium imaging of astrocytes and neurons in the hippocampus of mice navigating a virtual environment, we demonstrate that astrocytic calcium signals encode (i.e., statistically reflect) spatial information that could not be explained by visual cue information. Calcium events carrying spatial information occurred in topographically organized astrocytic subregions. Importantly, astrocytes encoded spatial information that was complementary and synergistic to that carried by neurons, improving spatial position decoding when astrocytic signals were considered alongside neuronal ones. These results suggest that the complementary place dependence of localized astrocytic calcium signals may regulate clusters of nearby synapses, enabling dynamic, context-dependent variations in population coding within brain circuits.

A combination of functional imaging of astrocytes and neurons in the mouse hippocampus with information theory analysis shows that calcium dynamics in topographically-organized subcellular regions of astrocytes encode information about an animal’s position that is complementary and synergistic to that encoded in the spike output of surrounding neurons.     

AMPA受体介导的神经元和星形胶质细胞网络编程小鼠胡须感觉适应

动物感觉输入的适应性影响了它们对外界环境改变的意识和反应.感觉通路各层次,诸如感受器、传入神经和中枢系统等,反应活性的降低可能与感觉适应性相关联.在感觉适应过程中,皮层局部网络中神经元和星形胶质细胞对信号的编程机制仍有待进一步研究.利用活体双光子成像、电生理记录即药理学方法,我们分析了小鼠barrel皮层神经元和星形胶质应答重复的胡须感觉输入动力学.相同特征的胡须感觉刺激诱发了神经元和星形胶质细胞反应活性的降低,并且它们的活动在空间上和时间上去同步化,神经元和星形胶质细胞之间的缺少协调性.这种神经元和星形胶质细胞功能在空间和时间性质上的下调被局部施加AMPA受体脱敏感抑制剂所逆转.因此,在胡须感觉适应过程中,barrel皮层神经元和星形胶质细胞反应活性的下降和去同步化是由AMPA受体脱敏感参与介导完成的.     

Astrocytes and energy metabolism

Astrocytes are glial cells, which play a significant role in a number of processes, including the brain energy metabolism. Their anatomical position between blood vessels and neurons make them an interface for effective glucose uptake from blood. After entering astrocytes, glucose can be involved in different metabolic pathways, e.g. in glycogen production. Glycogen in the brain is localized mainly in astrocytes and is an important energy source in hypoxic conditions and normal brain functioning. The portion of glucose metabolized into glycogen molecules in astrocytes is as high as 40%. It is thought that the release of gliotransmitters (such as glutamate, neuroactive peptides and ATP) into the extracellular space by regulated exocytosis supports a significant part of communication between astrocytes and neurons. On the other hand, neurotransmitter action on astrocytes has a significant role in brain energy metabolism. Therefore, understanding the astrocytes energy metabolism may help understanding neuron-astrocyte interactions.     

Spinal Astrogliosis in Pain Models: Cause and Effects

Pathological pain has been subjected to intense research to shed light on the underlying mechanisms of key symptoms, such as allodynia and hyperalgesia. The main focus has by and large concerned plasticity of spinal cord neurons and the primary afferent nerves relaying peripheral information to the spinal cord. Animal pain models display an increased presence of reactive astrocytes in the spinal cord, but in contrast to neurons, little is known about how they contribute to abnormal pain sensation. However, astrocytes are now beginning to receive greater attention, and as new information is emerging, it appears that astrocytes undertake critical roles in manifesting pathological pain. Through the secretion of diffusible transmitters, such as interleukins, ATP, and NO, astrocytes may augment primary afferent neuronal signaling or sensitize second order neurons in the spinal cord. In addition, astrocytes might lead to altered pain perception by a direct modulation of synaptic transmission between neurons in the nociceptive pathway or through the creation of astrocytic networks capable of transducing signals for extended distances across and along the spinal cord. Future research in astrocyte activation and signaling may therefore reveal novel drug targets for managing pathological pain.     

Is the Outgrowth of Transplant-Derived Axons Guided by Host Astrocytes and Myelin Loss?

Loss of cortical neurons may lead to sever and sometimes irreversible deficits in motor function in a number of neuropathological conditions. Absence of spontaneous axonal regeneration following trauma in the adult central nervous system (CNS) is attributed to inhibitory factors associated to the CNS white matter and to the non-permissive environment provided by reactive astrocytes that form a physical and biochemical barrier scar. Neural transplantation of embryonic neurons has been widely assessed as a potential approach to overcome the generally limited capacity of the mature CNS to regenerate axons or to generate new neurons in response to cell loss. We have recently shown that embryonic (E14) mouse motor cortical tissue transplanted into the damaged motor cortex of adult mice developed efferent projections to appropriate cortical and subcortical host targets including distant areas such as the spinal cord, with a topographical organization similar to that of intact motor cortex. Several parameters might account for the outgrowth of axonal projections from embryonic neurons within a presumably non-permissive adult brain, among which are astroglial reactions and myelin formation. In the present study, we have examined the role of astrocytes and myelin in the axonal outgrowth of transplanted neurons.     

Effects of glutathione depletion on the viability of human NT2-derived neuronal and astroglial cultures

The level of glutathione (GSH) is often reduced in brains that are affected by neurodegeneration. It is not known, however,whether this is a cause or a consequence of the disease. Here we have examined the effects of GSH depletion on the viability of human neurons cultured in either the presence or the absence of astrocytes, both derived from NT2/D1 cells. We established that the endogenous concentration of GSH is 10 times lower in neurons than in astrocytes (1.42 versus 18.9 pmol microg protein(-1)) and that pure neuronal cultures begin to die by apoptosis within 24 h of GSH depletion. By contrast, neurons that are co-cultured with astrocytes remain viable for several days, even with a profoundly decreased GSH content. However, they die rapidly when challenged additionally with nitrative stress. In addition, astrocytes survive for prolonged periods of time (>12 days) under severely reduced GSH concentrations. Our study shows clear differences in the content and sensitivity to depletion of GSH in neurons and astrocytes and establishes the significance of neuronal-glial interactions for the maintenance of neuronal viability under reduced GSH content. However, with chronic GSH depletion, these interactions might not be sufficient to protect neurons from other injurious factors (i.e. reactive oxygen and nitrogen species), which indicates that defective GSH metabolism might facilitate the progression of neurodegeneration.     

Endocannabinoids mediate neuron-astrocyte communication

Cannabinoid receptors play key roles in brain function, and cannabinoid effects in brain physiology and drug-related behavior are thought to be mediated by receptors present in neurons. Neuron-astrocyte communication relies on the expression by astrocytes of neurotransmitter receptors. Yet, the expression of cannabinoid receptors by astrocytes in situ and their involvement in the neuron-astrocyte communication remain largely unknown. We show that hippocampal astrocytes express CB1 receptors that upon activation lead to phospholipase C-dependent Ca2+ mobilization from internal stores. These receptors are activated by endocannabinoids released by neurons, increasing astrocyte Ca2+ levels, which stimulate glutamate release that activates NMDA receptors in pyramidal neurons. These results demonstrate the existence of endocannabinoid-mediated neuron-astrocyte communication, revealing that astrocytes are targets of cannabinoids and might therefore participate in the physiology of cannabinoid-related addiction. They also reveal the existence of an endocannabinoid-glutamate signaling pathway where astrocytes serve as a bridge for nonsynaptic interneuronal communication.     

Morphology of neuroglia in the hypothalamus of the opossum (Didelphis virginiana), armadillo (Dasypus novemcinctus mexicanus) and cat (Felis domestica)

The hypothalamus of the opossum (Didelphis virginiana), the armadillo (Dasypus novemcinctus mexicanus), and the cat (Felis domestica) was studied using Del Rio Hortega's silver carbonate technique, as modified by Scharenberg ('60). This technique demonstrates astrocytes, oligodendroglia, and neuronal perikarya, but does not impregnate microglia. The morphology of macroglia was observed in ten comparable nuclei in each of the three species. The subpial and subependymal areas were also examined. Astrocytes display more cell body angularity and have more processes in most hypothalamic regions of the cat when compared to similar regions of the opossum and armadillo. In the anterior hypothalamic nucleus, the ventromedial and the dorsomedial hypothalamic nuclei, and the medial mammillary nucleus of all three species, astrocytes send processes to neurons, but neuronal and astrocytic perikarya are usually not directly contiguous. However, oligodendrocytes in a perisomatic position on neurons are a consistent feature in these nuclei. A closer relationship appears to exist between astrocytes and neurons in the neurosecretory nuclei. In the supraoptic nucleus and paraventricular nucleus of all three species a basket-like structure, designated a ?pericellular envelope”? was observed surrounding neuronal perikarya. This structure is composed of astrocytic and oligodendroglial cell bodies and processes, and is most highly developed in the cat. A dense astrocytic plexus was observed in the suprachiasmatic nucleus of the cat, and in the comparable nuclei of the armadillo and opossum. The most prominent macroglial cell type of the lateral hypothalamic and lateral mammillary nuclei of all three species is the interfascicular oligodendrocyte. The posterior hypothalamic nucleus of each species has many perisomatic oligodendrocytes, and in the armadillo and cat astrocytes are closely related to the larger neurons. A subpial plexus, consisting of a palisade of small glial cells with many processes, is present in the hypothalamus of the three species. Ependymal cells have long projecting processes throughout the length of the third ventricle in the armadillo hypothalamus, but such processes are only apparent in the region of the infundibular nucleus and median eminence in the opossum and cat.     

脑缺氧缺血后激活的信号转导通路

 脑缺氧缺血后,神经元和星形胶质细胞中调节细胞存活与死亡的信号转导通路被激活,主要包括：MAPK信号转导通路,PI3-K/Akt信号转导通路,JAK-STAT信号转导通路和转录因子NF- κB参与的信号转导通路等.在缺氧缺血的神经元和星形胶质细胞中,同一信号转导通路的激活表现出不同的时程变化,作用也不尽相同,这可能是这两种细胞对抗缺氧缺血损伤能力差异的基础.深入分析比较信号转导通路的细节差异,将为我们理解损伤/保护机理,寻求保护神经细胞的策略提供实验依据     

Spinal cord injury: emerging beneficial role of reactive astrocytes' migration

Spinal cord injury (SCI), despite considerable progress in palliative care, has currently no satisfying therapeutic leading to functional recovery. Inability of central nervous system severed axons to regenerate after injury is considered to originate from both limited intrinsic capabilities of neurons and inhibitory effect of the local environment. Precisely, the so-called "glial scar" formed by reactive astrocytes in response to injury exerts a well-known axon-outgrowth inhibitory effect. However, recent studies revealed that role of reactive astrocytes after SCI is more complex. During the first weeks after injury, reactive astrocytes indeed protect the tissue and contribute to a spontaneous relative functional recovery. Compaction of the lesion center and seclusion of inflammatory cells by migrating reactive astrocytes seem to underlie this beneficial effect. Stimulation of reactive astrocytes migration in the sub-acute phase of SCI might thus represent a new approach to improve the functional outcome of patients.     

Is the Outgrowth of Transplant-Derived Axons Guided by Host Astrocytes and Myelin Loss?

Loss of cortical neurons may lead to sever and sometimes irreversible deficits in motor function in a number of neuropathological conditions. Absence of spontaneous axonal regeneration following trauma in the adult central nervous system (CNS) is attributed to inhibitory factors associated to the CNS white matter and to the non-permissive environment provided by reactive astrocytes that form a physical and biochemical barrier scar. Neural transplantation of embryonic neurons has been widely assessed as a potential approach to overcome the generally limited capacity of the mature CNS to regenerate axons or to generate new neurons in response to cell loss. We have recently shown that embryonic (E14) mouse motor cortical tissue transplanted into the damaged motor cortex of adult mice developed efferent projections to appropriate cortical and subcortical host targets including distant areas such as the spinal cord, with a topographical organization similar to that of intact motor cortex. Several parameters might account for the outgrowth of axonal projections from embryonic neurons within a presumably non-permissive adult brain, among which are astroglial reactions and myelin formation. In the present study, we have examined the role of astrocytes and myelin in the axonal outgrowth of transplanted neurons.Key Words: motor cortex, neuronal transplantation, embryonic cells, GFP, GFAP, PLP     

Nutrition during brain activation: does cell-to-cell lactate shuttling contribute significantly to sweet and sour food for thought?

Functional activation of astrocytic metabolism is believed, according to one hypothesis, to be closely linked to excitatory neurotransmission and to provide lactate as fuel for oxidative metabolism in neighboring neurons. However, review of emerging evidence suggests that the energetic demands of activated astrocytes are higher and more complex than recognized and much of the lactate presumably produced by astrocytes is not locally oxidized during activation. In vivo activation studies in normal subjects reveal that the rise in consumption of blood-borne glucose usually exceeds that of oxygen, especially in retina compared to brain. When the contribution of glycogen, the brain's major energy reserve located in astrocytes, is taken into account the magnitude of the carbohydrate-oxygen utilization mismatch increases further because the magnitude of glycogenolysis greatly exceeds the incremental increase in utilization of blood-borne glucose. Failure of local oxygen consumption to equal that of glucose plus glycogen in vivo is strong evidence against stoichiometric transfer of lactate from astrocytes to neighboring neurons for oxidation. Thus, astrocytes, not nearby neurons, use the glycogen for energy during physiological activation in normal brain. These findings plus apparent compartmentation of metabolism of glycogen and blood-borne glucose during activation lead to our working hypothesis that activated astrocytes have high energy demands in their fine perisynaptic processes (filopodia) that might be met by glycogenolysis and glycolysis coupled to rapid lactate clearance. Tissue culture studies do not consistently support the lactate shuttle hypothesis because key elements of the model, glutamate-induced increases in glucose utilization and lactate release, are not observed in many astrocyte preparations, suggesting differences in their oxidative capacities that have not been included in the model. In vivo nutritional interactions between working neurons and astrocytes are not as simple as implied by "sweet (glucose-glycogen) and sour (lactate) food for thought."     

Vesicular release of glutamate mediates bidirectional signaling between astrocytes and neurons

The major excitatory neurotransmitter in the CNS, glutamate, can be released exocytotically by neurons and astrocytes. Glutamate released from neurons can affect adjacent astrocytes by changing their intracellular Ca²⁺ dynamics and, vice versa , glutamate released from astrocytes can cause a variety of responses in neurons such as: an elevation of [Ca²⁺]_i, a slow inward current, an increase of excitability, modulation of synaptic transmission, synchronization of synaptic events, or some combination of these. This astrocyte-neuron signaling pathway might be a widespread phenomenon throughout the brain with astrocytes possessing the means to be active participants in many functions of the CNS. Thus, it appears that the vesicular release of glutamate can serve as a common denominator for two of the major cellular components of the CNS, astrocytes and neurons, in brain function.     

How astrocytes feed hungry neurons

For years glucose was thought to constitute the sole energy substrate for neurons; it was believed to be directly provided to neurons via the extracellular space by the cerebral circulation. It was recently proposed that in addition to glucose, neurons might rely on lactate to sustain their activity. Therefore, it was demonstrated that lactate is a preferred oxidative substrate for neurons not only in vitro but also in vivo. Moreover, the presence of specific monocarboxylate transporters on neurons as well as on astrocytes is consistent with the hypothesis of a transfer of lactate from astrocytes to neurons. Evidence has been provided for a mechanism whereby astrocytes respond to glutamatergic activity by enhancing their glycolytic activity, resulting in increased lactate release. This is accomplished via the uptake of glutamate by glial glutamate transporters, leading to activation of the Na⁺/K⁺ ATPase and a stimulation of astrocytic glycolysis. Several recent observations obtained both in vitro and in vivo with different approaches have reinforced this view of brain energetics. Such an understanding might be critically important, not only because it forms the basis of some classical functional brain imaging techniques but also because several neurodegenerative diseases exhibit diverse alterations in energy metabolism.     

Astrocytic production of nerve growth factor in motor neuron apoptosis: implications for amyotrophic lateral sclerosis

Reactive astrocytes frequently surround degenerating motor neurons in patients and transgenic animal models of amyotrophic lateral sclerosis (ALS). We report here that reactive astrocytes in the ventral spinal cord of transgenic ALS-mutant G93A superoxide dismutase (SOD) mice expressed nerve growth factor (NGF) in regions where degenerating motor neurons expressed p75 neurotrophin receptor (p75(NTR)) and were immunoreactive for nitrotyrosine. Cultured spinal cord astrocytes incubated with lipopolysaccharide (LPS) or peroxynitrite became reactive and accumulated NGF in the culture medium. Reactive astrocytes caused apoptosis of embryonic rat motor neurons plated on the top of the monolayer. Such motor neuron apoptosis could be prevented when either NGF or p75(NTR) was inhibited with blocking antibodies. In addition, nitric oxide synthase inhibitors were also protective. Exogenous NGF stimulated motor neuron apoptosis only in the presence of a low steady state concentration of nitric oxide. NGF induced apoptosis in motor neurons from p75(NTR +/+) mouse embryos but had no effect in p75(NTR -/-) knockout embryos. Culture media from reactive astrocytes as well as spinal cord lysates from symptomatic G93A SOD mice-stimulated motor neuron apoptosis, but only when incubated with exogenous nitric oxide. This effect was prevented by either NGF or p75(NTR) blocking-antibodies suggesting that it might be mediated by NGF and/or its precursor forms. Our findings show that NGF secreted by reactive astrocytes induce the death of p75-expressing motor neurons by a mechanism involving nitric oxide and peroxynitrite formation. Thus, reactive astrocytes might contribute to the progressive motor neuron degeneration characterizing ALS.     

Dichotomy of the glial cell response to axonal injury and regeneration

Neurons in the mammalian central nervous system (CNS) have a poor capacity for regenerating their axons after injury. In contrast, neurons in the CNS of lower vertebrates and in the peripheral nervous system (PNS) of mammals are endowed with a high posttraumatic capacity to regenerate. The differences in regenerative capacity have been attributed to the different compositions of the respective cellular environments and to different responses to injury the nonneuronal cells display, which range from supportive and permissive to nonsupportive and hostile for regeneration. The same cell type may support or inhibit regeneration, depending on its state of maturity or differentiation. Astrocytes and oligodendrocytes are examples of cells in which such a dichotomy is manifested. In developing and in spontaneously regenerating nerves, these cells support (astrocytes) and permit (oligodendrocytes) growth. However, in nonregenerating adult mammalian nerves, astrocytes form the nonsupportive scar tissue; and the mature oligodendrocytes inhibit axonal growth. Maturation of these cells may be regulated differently during development than after injury. Among the putative regulators are factors derived from astrocytes, resident microglia; or cytokines produced by macrophages. During development, regulation leads to a temporal separation between axonal growth and maturation of the cellular environment, which might not occur spontaneously after injury in a nonregenerating CNS without intervention at the appropriate time. Data suggest that temporal intervention aimed at the glial cells might enhance the poor regenerative capacity of the mammalian CNS. Possible regulation of the nonneuronal cell response to injury via involvement of protooncogenes is proposed.     

Contribution of astrocytes to synaptic transmission in the rat supraoptic nucleus

Astrocytes, besides supporting metabolic and scaffolding functions, play a prominent role in the modulation of neuronal communication. In particular, they are responsible for clearing synaptically-released glutamate via highly specific transporters located on their plasma membrane. Since glutamate is the main excitatory neurotransmitter in the central nervous system (CNS), astrocytes are likely to play a central role in the regulation of synaptic processing and overall cellular excitability. We recently investigated the influence of astrocytes on glutamatergic and GABAergic transmission in the rat supraoptic nucleus (SON) of the hypothalamus. This nucleus is part of the hypothalamus-neurohypophysial system (HNS), which constitutes a conspicuous example of activity-dependent neuroglial plasticity, in which certains physiological conditions, such as parturition, lactation, and dehydration are accompanied by a structural remodeling of the neurones, their synaptic inputs and their surrounding glia. The use of pharmacological inhibitors of glutamate transporters on this model, in which a physiological change in the astrocyte environment occurs, has brought new insights on the contribution of astrocytes to both excitatory and inhibitory neurotransmissions. The astrocytic environment of neurons appears to control glutamate uptake and diffusion in the extracellular space. This has direct repercussions on the tonic level of activation of presynaptic glutamate receptors and, as a consequence, on the release of neurotransmitter. This short review summarizes data obtained so far, which clearly support the view that astrocytes are indeed a third partner in synaptic transmission, and which show that the supraoptic nucleus represents a remarkable model to study dynamic physiological interactions between astrocytes and neurons.     

Engulfing astrocytes protect neurons from contact-induced apoptosis following injury

Clearing of dead cells is a fundamental process to limit tissue damage following brain injury. Engulfment has classically been believed to be performed by professional phagocytes, but recent data show that non-professional phagocytes are highly involved in the removal of cell corpses in various situations. The role of astrocytes in cell clearance following trauma has however not been studied in detail. We have found that astrocytes actively collect and engulf whole dead cells in an in vitro model of brain injury and thereby protect healthy neurons from bystander cell death. Time-lapse experiments showed that migrating neurons that come in contact with free-floating cell corpses induced apoptosis, while neurons that migrate through groups of dead cells, garnered by astrocytes, remain unaffected. Furthermore, apoptotic cells are present within astrocytes in the mouse brain following traumatic brain injury (TBI), indicating a possible role for astrocytes in engulfment of apoptotic cells in vivo. qRT-PCR analysis showed that members of both ced pathways and Megf8 are expressed in the cell culture, indicating their possible involvement in astrocytic engulfment. Moreover, addition of dead cells had a positive effect on the protein expression of MEGF10, an ortholog to CED1, known to initiate phagocytosis by binding to phosphatidylserine. Although cultured astrocytes have an immense capacity for engulfment, seemingly without adverse effects, the ingested material is stored rather than degraded. This finding might explain the multinuclear astrocytes that are found at the lesion site in patients with various brain disorders.     

Reciprocal pathway between medullary visceral zone and hypothalamic supraoptic nucleus or paraventricular nucleus involved in hyperosmotic regulation

In this study we try to simultaneously investigate the response of neurons and astrocytes of rats following hyperosmotic stimulation and test the possibility that the reciprocal pathways between medullary visceral zone (MVZ) and hypothalamic paraventricular nucleus (PVN) or supraoptic nucleus (SON). Hyperosmotic pressure animal model was established by administering 3% sodium chloride as drinking water to rats. The distribution and expression of the HRP retrogradely labeled neurons, Fos, tyrosine hydroxylase (TH) or vasopressin (VP) positive neuron and glial fibrillary acidic protein (GFAP) positive astrocytes in the MVZ, SON and PVN were observed by quadruplicate-labeling methods of WGA-HRP retrograde tracing combined with anti-Fos, TH (or VP) and GFAP immunohistochemical technique. Fos positive neurons within the MVZ, PVN and SON increased markedly. There were also a large number of GFAP positive structures in the brain and their distribution pattern was fundamentally similar or analogous to Fos positive neurons in the above-mentioned areas. The augmented GFAP reactivities took on hypertrophic cell bodies, thicker and longer processes. Quadruplicate immunohistochemical staining showed that a neuron could be closely surrounded by many astrocytes and they formed neuron-astrocytic complex (N-ASC). Fos+/TH+/HRP+/GFAP+ and Fos+/VP+/HRP+/GFAP+ quadruplicate labeled N-ASC could be found in the MVZ, PVN and SON, respectively. The present results indicated that the neurons and astrocytes might be very active following hyperosmotic pressure and N-ASC as a functional unit might serve to modulate osmotic pressure. There were reciprocal osmoregulation pathways between the MVZ and SON or PVN in the brain.