Differential immunochemical markers reveal the normal distribution of brain macrophages and microglia in the developing rat brain.

Brain macrophages and microglia play important roles in central nervous system (CNS) development, especially during regressive events in which particular neuronal and glial constituents are eliminated. The purpose of this study is to provide a complete map of brain macrophage and microglia distribution in all regions of the neuraxis from birth to sexual maturity. We have utilized morphology and immunostaining with the specific antibodies OX-42 and ED1 to distinguish between brain macrophages and microglia. Brain macrophages are large, round cells, 10-15 microns in diameter, with few or no cytoplasmic processes; these cells are ED1- and OX-42-immunopositive. Microglia have small cell bodies with numerous, ramified cytoplasmic processes. These cells are OX-42-positive, and ED1-negative. We found a specific pattern of distribution of brain macrophages, targeting specific cortical and subcortical areas transiently, including developing fiber tracts. These cells disappeared completely by the third postnatal week. In contrast, OX-42-positive microglia exhibited a gradual increase in number and were distributed uniformly throughout gray matter and within white matter tracts. These cells remain in the adult CNS, constituting the resident microglia population. We suggest that these two distinct phagocytic cell populations perform unique functions in the developing brain, including remodeling of restricted CNS areas by brain macrophages that is part of a normal morphological process.     

Reactive microglia with membrane features of mononuclear phagocytes.

An inflammatory response was induced by the implantation of cover-slips into the brains of rabbits. The cytomorphology of the glass-adhering cells, their phagocytic properties and their enzymatic activity were characterized and these features were correlated with the presence of membrane markers. Mononuclear cells with foamy cytoplasm, with marked phagocytic potential and strong activity of nonspecific esterases consistently showed IgG- and C-receptor activity. Multinuclear giant cells, which increased in number after prolonged implantation, exhibited comparable features. In contrast, mononuclear cells of fusiform appearance with a low activity of nonspecific esterases and a poor phagocytic potential lacked the IgG-receptor. A close relationship between the mononuclear phagocytic cell and reactive microglia is postulated. The authors conclude that the inflammatory response observed under their test conditions was characterized by the prevalence of phagocytic cells with membrane characteristics of the monocyte-macrophage series.     

The role of microglia in the healthy brain

Microglia were recently shown to play unexpected roles in normal brain development and adult physiology. This has begun to dramatically change our view of these resident "immune" cells. Here, we briefly review topics covered in our 2011 Society for Neuroscience minisymposium "The Role of Microglia in the Healthy Brain." This summary is not meant to be a comprehensive review of microglia physiology, but rather to share new results and stimulate further research into the cellular and molecular mechanisms by which microglia influence postnatal development, adult neuronal plasticity, and circuit function.     

Responses of microglia and neural progenitors to mechanical brain injury.

Neural cells have distinct responses to CNS injury; however, neural progenitor response to CNS injury is not yet documented. Stab injury combined with injection of bromodeoxyuridine (BrdU), a thymidine analog, into adult rat cortex above the lateral ventricle for 10 min resulted in activated microglia/macrophage infiltration along with nuclear factor kappa B (NF kappa B)/p65 activation at the lesion site. Most NF kappa B/p65+ cells displayed a phagocytic morphology. Under these conditions, profound cell apoptosis took place in the injured corpus callosum, but not in the subventricular/ventricular zone (SVZ/VZ). The SVZ/VZ-derived neural progenitors in both injected and non-injected contralateral hemispheres showed strong BrdU immunostaining, indicating that SVZ/VZ-derived neural progenitors of both hemispheres may undergo DNA synthesis in response to unilateral brain injury.     

The response of neurons and microglia to blast injury in the rat brain

Rats subjected to a single non-penetrative blast were examined for possible neuronal damage and glial reaction by immunohistochemistry and electron microscopy. The most dramatic feature in rats killed between 1 and 14 days after the blast was the widespread response of microglial cells in various parts of the brain in which the cells were hypertrophied and their surface antigens, like complement type three receptors (CR3), were upregulated. The blast wave also induced the vigorous expression of major histocompatibility complex (MHC) class I and II (Ia) antigens. In rats killed 21 days after the blast, the elevated immunoreactivity of microglia had subsided and at 28 days both the microglial external morphology and immunoreactivity were comparable to those of normal animals. In rats killed 4–7 days after the blast, the neurons in the cerebral and cerebellar cortex appeared normal except for the occurrence of some ‘darkened dendrites’. The incidence of ‘darkened’ den-drites was most common in rats killed at day 14 but they were absent at 21 and 28 days. Microglial cells were closely associated with some of the ‘darkened’ dendrites. Results in this study show that a non-penetrative blast in rats provokes a widespread microglial activation suggesting increased endocytosis and immunological responses. However, it remains uncertain whether such a drastic response was a direct activation of the cells by the blast wave or elicited indirectly by some chemical factors released from the damaged brain tissues.     

小胶质细胞和放射性脑损伤

放射治疗是有效的肿瘤治疗手段,尤其在神经系统肿瘤,由于其部位的限制和血脑屏障的存在,手术和化学治疗的效果常不理想,而有的肿瘤如生殖细胞瘤、脑干胶质瘤等,放疗可能是唯一的治疗选择.     

小胶质细胞和放射性脑损伤

放射治疗是有效的肿瘤治疗手段,尤其在神经系统肿瘤,由于其部位的限制和血脑屏障的存在,手术和化学治疗的效果常不理想,而有的肿瘤如生殖细胞瘤、脑干胶质瘤等,放疗可能是唯一的治疗选择.     

小胶质细胞和放射性脑损伤

放射治疗是有效的肿瘤治疗手段,尤其在神经系统肿瘤,由于其部位的限制和血脑屏障的存在,手术和化学治疗的效果常不理想,而有的肿瘤如生殖细胞瘤、脑干胶质瘤等,放疗可能是唯一的治疗选择.     

小胶质细胞和放射性脑损伤

放射治疗是有效的肿瘤治疗手段,尤其在神经系统肿瘤,由于其部位的限制和血脑屏障的存在,手术和化学治疗的效果常不理想,而有的肿瘤如生殖细胞瘤、脑干胶质瘤等,放疗可能是唯一的治疗选择.     

小胶质细胞和放射性脑损伤

放射治疗是有效的肿瘤治疗手段,尤其在神经系统肿瘤,由于其部位的限制和血脑屏障的存在,手术和化学治疗的效果常不理想,而有的肿瘤如生殖细胞瘤、脑干胶质瘤等,放疗可能是唯一的治疗选择.     

小胶质细胞和放射性脑损伤

放射治疗是有效的肿瘤治疗手段,尤其在神经系统肿瘤,由于其部位的限制和血脑屏障的存在,手术和化学治疗的效果常不理想,而有的肿瘤如生殖细胞瘤、脑干胶质瘤等,放疗可能是唯一的治疗选择.     

小胶质细胞和放射性脑损伤

放射治疗是有效的肿瘤治疗手段,尤其在神经系统肿瘤,由于其部位的限制和血脑屏障的存在,手术和化学治疗的效果常不理想,而有的肿瘤如生殖细胞瘤、脑干胶质瘤等,放疗可能是唯一的治疗选择.     

小胶质细胞和放射性脑损伤

放射治疗是有效的肿瘤治疗手段,尤其在神经系统肿瘤,由于其部位的限制和血脑屏障的存在,手术和化学治疗的效果常不理想,而有的肿瘤如生殖细胞瘤、脑干胶质瘤等,放疗可能是唯一的治疗选择.     

The imbalanced brain: from normal behavior to schizophrenia.

An outstanding problem in psychiatry concerns how to link discoveries about the pharmacological, neurophysiological, and neuroanatomical substrates of mental disorders to the abnormal behaviors that they control. A related problem concerns how to understand abnormal behaviors on a continuum with normal behaviors. During the past few decades, neural models have been developed of how normal cognitive and emotional processes learn from the environment, focus attention and act upon motivationally important events, and cope with unexpected events. When arousal or volitional signals in these models are suitably altered, they give rise to symptoms that strikingly resemble negative and positive symptoms of schizophrenia, including flat affect, impoverishment of will, attentional problems, loss of a theory of mind, thought derailment, hallucinations, and delusions. This article models how emotional centers of the brain, such as the amygdala, interact with sensory and prefrontal cortices (notably ventral, or orbital, prefrontal cortex) to generate affective states, attend to motivationally salient sensory events, and elicit motivated behaviors. Closing this feedback loop between cognitive and emotional centers is predicted to generate a cognitive-emotional resonance that can support conscious awareness. When such emotional centers become depressed, negative symptoms of schizophrenia emerge in the model. Such emotional centers are modeled as opponent affective processes, such as fear and relief, whose response amplitude and sensitivity are calibrated by an arousal level and chemical transmitters that slowly inactivate, or habituate, in an activity-dependent way. These opponent processes exhibit an Inverted-U, whereby behavior becomes depressed if the arousal level is chosen too large or too small. The negative symptoms are owing to the way in which the depressed opponent process interacts with other circuits throughout the brain.     

小胶质细胞和放射性脑损伤

放射治疗是有效的肿瘤治疗手段,尤其在神经系统肿瘤,由于其部位的限制和血脑屏障的存在,手术和化学治疗的效果常不理想,而有的肿瘤如生殖细胞瘤、脑干胶质瘤等,放疗可能是唯一的治疗选择.     

Neuroprotective effect of exogenous microglia in global brain ischemia.

Exogenous microglia pass through the blood-brain barrier and migrate to ischemic hippocampal lesions when injected into the circulation. We investigated the effect of exogenous microglia on ischemic CA1 pyramidal neurons. Microglia were isolated from neonatal mixed brain cultures, labeled with the fluorescent dye PKH26, and injected into the subclavian artery of Mongolian gerbils subjected to ischemia reperfusion neuronal injury. PKH26-labeled microglia migrated to the ischemic hippocampal lesion, resulting in increased numbers of surviving neurons compared with control animals, even when injected 24 h after ischemia. Interferon-gamma stimulation of isolated microglia enhanced the neuroprotective effect. Administration of exogenous microglia resulted in normal performance in a passive avoidance-learning task. Additionally, administration of exogenous microglia increased the expression of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor in the ischemic hippocampus, and thus might have induced neurotrophin-dependent protective activity in damaged neurons. Peripherally injected microglia exhibited a specific affinity for ischemic brain lesions, and protected against ischemic neuronal injury in vivo. It is possible that administration of exogenous microglia can be developed as a potential candidate therapy for central nervous system repair after transitory global ischemia.     

Reactive microglia in the developing brain

Summary Reactive microglia in the developing brain after stab wound was studied by morphological, cytochemical, and autoradiographic methods. Morphologically, early reactive cells are of the M cell type (Matthews 1974). They show an activated nucleus, cytoplasm rich in ribosomes with wide Golgi complex and variable numbers of lipid inclusions. Big clear vacuoles are found in many of these cells. Microtubules not associated with centrioles and filaments may or may not be present. Junctional complexes of the zonula or puncta adherentia types are occasionally found. Strong NADPH dehydrogenase, weak NADH dehydrogenase, strong ATPase, and strong acid phosphatase, in addition to nonspecific esterase activites were demonstrated in many reactive cells. Intravenous infusion of labelled bone marrow cells from a donor showed labelled macrophages and labelled perivascular cells at the site of injury. Intracerebral injection of a small dose of tritiated thymidine at the time of injury resulted in the appearance of labelled macrophages in the following days. These data suggest that many of the reactive cells have an exogenous, more probably monocytic, origin; but a certain amount of endogenous cells also act as macrophages in brain injuries.     

Dynamic motility of microglia: purinergic modulation of microglial movement in the normal and pathological brain

Microglia have highly branched and motile cell processes and constantly screen the brain parenchyma under physiological conditions. In response to pathological stimuli, microglia exhibit morphological changes and migrate toward the lesioned site, where they play important roles in inflammatory reactions and neuronal damage. Within minutes of brain damage, microglial processes rapidly extend toward the injured site. The chemoattractive response is triggered by ATP released at the site of injury and the consequent activation of the purinergic receptor P2Y₁₂R on microglia. In addition to the purinergic signals, various neuronal signaling molecules actively and negatively control microglial motility, which is important for regulating the functional activation of microglia in response to pathology. In this review, we focus on the dynamic motion of microglia and describe several key molecules regulating microglial motility in normal and pathological brain tissues. © 2011 Wiley‐Liss, Inc.     

Adhesion of mononuclear cells from multiple sclerosis patients to cerebral vessels in cryostat sections of normal human brain

Leukocyte extravasation across the blood-brain barrier is a critical event in the pathogenesis of multiple sclerosis (MS). This complex multistep process includes the adhesion of leukocytes to the endothelial cells of the central nervous system microvasculature. To investigate this phenomenon in MS, we developed a modified version of the frozen-section assay. Peripheral blood mononuclear cells (PBM) from 26 MS patients, 26 healthy controls and 10 patients with other inflammatory non- neurological diseases (OIND) were co-incubated with cryostat sections of normal brain white matter, immunohistochemically labelled with anti-CD45 antibody and counterstained with Giemsa stain. CD45-positive PBM adherent to transected microvasculature were counted with an automated image analyzer. MS patients showed an increased number of vessel-bound PBM (48.8 +/- 36.4) with respect to healthy controls (27.4 +/- 20.7, P = 0.01) and OIND patients (22.6 +/- 7.8, P = 0.01). Significant differences were also obtained counting the number of vessel-bound PBM as a percent of total vascular cells between MS patients (12.7 +/- 7.2%) and healthy controls (6.9 +/- 5.4%, P = 0.002) or OIND patients (7.4 +/- 4.4%, P = 0.03). We confirm that PBM from MS patients show an increased potential of binding to cerebral vessels. The frozen-section assay provides a unique tool to study in situ the molecular interactions of leukocytes with brain vascular structures. Copyright Lippincott Williams & Wilkins