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Biomedical subjects

M V Sofroniew

Publications and source records attributed to M V Sofroniew.

At least 55 records · Page 3Linked to original sources
PubMed1993

Serum proteins bypass the blood-brain fluid barriers for extracellular entry to the central nervous system.

Extracellular pathways circumventing the mammalian blood-brain fluid barriers (e.g., blood-brain and blood-CSF barriers) have been investigated in the rat by immunohistochemical localization of the endogenous serum proteins albumin, IgG, complement C-9, and IgM and by the exogenous tracer protein horseradish peroxidase (HRP). A demonstrable extracellular pathway into the central nervous system (CNS) is evident at the level of the subarachnoid space/pial surface. Immunoreaction products for the serum proteins and reaction product of intravenously administered HRP are identified over the entire pial surface, in the Virchow-Robin spaces and subpial cortical grey matter, and within phagocytes occupying the subarachnoid space/pial surface and perivascular clefts throughout the CNS. From specific circumventricular organs (e.g., median eminence, area postrema, subfornical organ), well known to lie outside the blood-brain barrier (BBB), each of the blood-borne proteins readily enters adjacent white and grey matter and the ventricular system for subsequent rostrocaudal labeling of the ependymal cell lining. Similar immunohistochemical and blood-borne HRP results are obtained in the CNS of the neonatal rat. Peroxidase delivered into the aorta of postmortem adult rats confirms the presence of a BBB in brain sites containing blood vessels impermeable to blood-borne HRP and the absence of a BBB in sites revealed as leaky to blood-borne HRP in the live rat. The results suggest blood-borne macromolecules, including those of the immune and complement systems, have potential widespread, extracellular distribution within the CNS and cerebrospinal fluid from sites deficient in a BBB (e.g., subarachnoid space/pial surface, circumventricular organs). These observations may have important clinical implications regarding experimental and pathologic autoimmune dysfunction within the CNS and impact on the interpretation of potential transcytosis of blood-borne peptides and proteins through the cerebral endothelium in vivo. A summary diagram of suspected extracellular and intracellular pathways circumventing the blood-brain fluid barriers is provided.

Animals↗
PubMed1993

Morphometric evaluation of neurophysin-immunoreactivity in the human brain: pronounced inter-individual variability and evidence for altered staining patterns in schizophrenia.

The neurohypophyseal peptides vasopressin and oxytocin have a variety of well documented behavioural effects. Accordingly, terminals and receptors that respectively contain or bind these peptides have been identified throughout the central nervous system (CNS) in experimental animals. In this study we have mapped the distribution of neurophysin I and II-immunoreactive structures in the human CNS. Neurophysins are portions of the precursor proteins for vasopressin and oxytocin, and are found specifically in structures that contain these peptides. In addition, we have quantitatively compared neurophysin neurons and fibers in the brains of individuals with no history of neurologic or psychiatric abnormality, and in brains of patients dying with psychotic illness categorized as schizophrenia. These latter brains were collected prior to the advent of pharmacologic treatment and were available from the Vogt collection. Our findings show wide variations of morphometric values obtained for neurophysin-stained structures in different CNS regions in normal subjects, but provide evidence for abnormal values in certain brain areas in untreated schizophrenia, in the hypothalamic paraventricular nucleus, internal pallidal segment and substantia nigra. These findings suggest that the function of vasopressin and/or oxytocin may be disturbed in these brain regions in schizophrenia. Further investigation will be required to establish whether these differences contribute to, or are a consequence of the disease mechanism.

Adult↗
PubMed1993

Atrophy but not death of adult septal cholinergic neurons after ablation of target capacity to produce mRNAs for NGF, BDNF, and NT3.

The effect of unilateral excitotoxic ablation of hippocampal neurons was investigated on (1) the local production of mRNA for NGF and related neurotrophins, (2) the amount of NGF protein in the septal region, and (3) the viability and appearance of afferent septal cholinergic neurons in adult rats. After near complete ablation of hippocampal neurons, total levels of NGF, brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT3) mRNA measured by quantitative Northern blot analysis in the hippocampal remnant fell significantly, to less than 25% of control values by 28 d and to less than 9% by 300 d. In the septal region ipsilateral to such lesions, NGF protein levels measured by ELISA fell significantly, to about 35% of control values, but the number of immunohistochemically detected cholinergic neurons did not decline significantly for up to 500 d. Instead, the cholinergic neurons persisted in an atrophied state, exhibiting severe shrinkage and reduced staining for the transmitter-synthesizing enzyme ChAT. The parameters of cell size and ChAT staining intensity correlated significantly with the amount of hippocampal tissue present. These findings indicate that in adult rats, target-derived NGF, BDNF, and NT3 do not regulate the survival of septal cholinergic neurons in proportion to the number of target neurons present. Moreover, the findings suggest that one or more of these target-derived neurotrophins regulate the structural and chemical phenotype of these neurons in the adult.

Animals↗
PubMed1992

Neuronal loss or replacement in the injured adult cerebral neocortex induces extensive remodeling of intrinsic and afferent neural systems.

The question of how the cerebral cortex responds over time to changes in cortical neuronal number was addressed by inducing excitotoxic cortical neuronal loss, either alone or followed by homotypic fetal cortical cell suspension grafts, in adult rats. Following neuronal cell loss, rapid gliosis and inflammation temporarily maintained tissue volume. As gliosis subsided, tissue shrinkage occurred until the ratio of glia to neurons approached that of normal neocortex. After neuronal loss, total cortical glutamate uptake and glutamic acid decarboxylase activity dropped markedly and remained low, and there was a gradual but considerable reduction in the total size of afferent fiber networks. However, when expressed as concentrations per unit of tissue or protein, histological and neurochemical cortical markers showed increases during the phase of tissue shrinkage and in the long-term equilibrated to near normal levels. Retrograde tracing studies showed that the reduction in total afferent fiber network is accompanied by the atrophy of afferent neuronal cell bodies. Grafts of fetal cortical cells placed after excitotoxic lesions provided long-term reconstitution of cortical tissue mass, maintained afferent fiber systems, and prevented both the atrophy and surrounding cellular gliosis of some afferent neuronal cell bodies for over a year, but were unable to innervate the main cortical target regions in the host. Thus after neuronal loss or replacement, the adult cerebral neocortex and its afferent systems remodel to a density of neurons, glia, and afferent fibers similar to that found in intact tissue, illustrating structural plasticity toward a dynamic equilibrium.

Afferent Pathways↗
PubMed1991

Evidence for subdivisions in the human suprachiasmatic nucleus.

The human suprachiasmatic nucleus was analysed by immunohistochemical demonstration of various substances in combination with 3-dimensional computerized reconstruction and video overlay facilities. In the human, the suprachiasmatic nucleus is not as compact as in the rodent. Its boundaries are not easily delineated using conventional stains, and it shows no obvious cytoarchitectonic structure. However, based on its chemoarchitecture, the human suprachiasmatic nucleus can be apportioned into five major subdivisions: Dorsal, comprising a crescent shaped mass of densely packed neurophysin/vasopressin-neurons as well as neurotensin-neurons, and also containing 3-fucosyl-N-acetyl-lactosamine (FAL)-positive neurons in its medial part. Central, occupying the core of the nucleus and consisting precisely of a region devoid of neurophysin/vasopressin neurons but demarcated by calbindin, synaptophysin, and a circumscribed cluster of vasoactive intestinal polypeptide-neurons and containing neurotensin neurons as well. Anteroventrally this division also contains some intermingled neurons positive for neurotensin, neuropeptide Y, somatostatin, and FAL. Ventral, extending from the anterior extreme of the preoptic recess caudolaterally to a field between the optic chiasm and the anteroventral margin of the supraoptic nucleus. This subdivision is specified by synaptophysin, calbindin, and substance P immunoreactivity and is almost free of glial fibrillary acidic protein. From its rostral portion, fibers immunoreactive for calbindin, vasoactive intestinal polypeptide, synaptophysin, and substance P protrude deeply into the optic chiasm. Medial, comprising a thin band between the subependymal zone and the dorsal subdivision, containing scattered somatostatin neurons. External, extending as a band around the dorsal and lateral borders of the nucleus, containing astrocytes expressing the FAL-epitope and scattered neurophysin/vasopressin and neurotensin neurons. These findings indicate that the human suprachiasmatic nucleus contains well-defined subdivisions with different, chemically specific, connections and provides a basis for comparing these subdivisions with the structure and function of subdivisions previously described for the suprachiasmatic nucleus in experimental animals. In addition, the findings strengthen the concept that the human suprachiasmatic nucleus generates and expresses circadian rhythms in a manner similar to that documented for the suprachiasmatic nucleus in experimental animals, and suggest that different subdivisions may subserve specific functional roles.

Adolescent↗
PubMed1991

Trophic factor effects on septal cholinergic neurons.

The role of trophic factors in the adult central nervous system (CNS) is poorly understood. One system that may require trophic factors, particularly nerve growth factor (NGF) and brain-derived growth factor (BDNF), for normal function in the adult CNS is the cholinergic projection from the basal forebrain to the hippocampus. To study the nature of this requirement we ablated target neurons in the hippocampus that normally produce NGF and BDNF; we found no loss of cholinergic neurons or cholinergic phenotype in the medial septum in young adult rats. In similarly treated aged rats (24-33 months), some reduction in cholinergic phenotype was found, in the absence of cell death for up to 90 days. Thus, these cholinergic neurons either do not require trophic support for survival, or are able to obtain trophic factors from other sources for the duration of the experiments. In vitro, NGF withdrawal from septal neurons initially grown in the presence of NGF did not result in the death of old cholinergic neurons in these tissue cultures but did result in a down-regulation of transmitter-associated enzymes, accompanied by cholinergic cell shrinkage and a reduction in fiber density. Together, these findings suggest that target-derived factors may not be required for the survival of mature septal cholinergic neurons, but may be involved in maintenance of cholinergic and structural phenotype.

Alzheimer Disease↗
PubMed1991

Developmentally regulated and tissue specific expression of mRNAs encoding the two alternative forms of the LIM domain oncogene rhombotin: evidence for thymus expression.

The T-cell oncogene rhombotin was first identified as a gene near a chromosomal translocation breakpoint in a human T-cell tumour and represents the first example of an oncogene carrying the duplicated cysteine-rich regions (CRR or LIM domains). Transgenic expression of a reporter gene under the control of one of the rhombotin gene promoters subsequently showed high levels of expression in the developing brain. These disparate sites of transcriptional activity suggested that the gene may have been activated de novo specifically in the T cell tumour via the translocation. Here, we assess this possibility by analysing rhombotin gene expression in mouse development by in situ hybridization of whole embryos, Northern filter hybridization, and a sensitive semiquantitative PCR method. The results show that the central nervous system is the major site of rhombotin mRNA production. Low level expression does, however, occur in other tissues including thymus. Furthermore, both promoters are active and differentially regulated during mouse embryogenesis in both brain and thymus. In subregions of the adult brain, different levels of rhombotin activity can be observed, with evidence for regional variation in promoter usage. A detailed analysis of mouse and human T-cell differentiation suggests that fluctuating promoter activities are related to a general T-cell differentiation process rather than to the differentiation of functionally distinct subsets of T-cells. These data suggest that the transforming activity of rhombotin in the T-cell with the chromosomal translocation was not due to de novo transcriptional activation, but rather to a quantitative or qualitative change in expression levels of this CRR-containing oncogene after chromosomal translocation.

Animals↗
PubMed1990

Segmental and developmental regulation of a presumptive T-cell oncogene in the central nervous system.

Although most proto-oncogenes such as c-myc are involved in cell proliferation, being expressed in a wide range of tissues as well as in progenitors of transformed cells, others may normally function in cellular differentiation. We now report on a gene on human chromosome 11, at the junction of the T-cell tumour-associated chromosomal translocation t(11; 14) (p15; q11) and known as the 11p15 gene or Ttg, which is believed to be involved in the pathogenesis of the tumour. It has two transcriptional promoters (both retained by the translocated allele) and is expressed in tumour cells with neuro-endocrine properties, suggesting that normal expression may occur in nerve cells. Using fusion constructs of one 11p15 promoter and lacZ in transgenic mice, we found that the gene is expressed in a segment-specific manner in rhombomeres of the developing mouse hind-brain. During subsequent development, the gene is more widely expressed, again in precisely defined regional patterns, but in post-mitotic neurons confined to the central nervous system. Thus, this presumptive T-cell oncogene is both developmentally regulated and segmentally restricted in a tissue different from that in which the original tumour arose.

Animals↗
PubMed1990

Loss of true blue labelling from the medial septum following transection of the fimbria-fornix: evidence for the death of cholinergic and non-cholinergic neurons.

Many neurons in the medial septal nucleus lose their transmitter-associated enzyme staining following axotomy in the proximal fimbria-fornix (FF), but it is not clear if these neurons have died or persist in a shrunken and subfunctional state. To investigate this further, septal neurons projecting through the FF were labelled with the fluorescent dye, True blue, by retrograde transport from multiple bilateral injection sites in the hippocampus. True blue-labelled neurons and cholinergic neurons immunohistochemically stained for choline acetyltransferase (ChAT) were then quantitatively compared in neighbouring sections through the medial septum 28 days after complete unilateral transections of the proximal FF. The number of True blue and ChAT positive cells ipsilateral to the FF lesion showed significant (P less than 0.001) declines of 51.4% and 71.1%, respectively, relative to the unlesioned side. Cell loss was considerably more severe among large neurons, such that 78.0% and 92.7% of True blue and ChAT labelled cells larger than the normal mean, but only 40.1% and 68.0% of True blue and ChAT labelled cells smaller than the normal mean size were lost. This indicates either that larger neurons were more prone to cell loss, or that some (but not all) large neurons persisted in a shrunken form. Histograms showed no increase in cell number in any of the smaller size categories and a substantial decrease in most cases, indicating that shrinkage alone could not account for the loss of all large neurons. Since True blue can remain present in brainstem cholinergic neurons surviving for over 365 days after axotomy, loss of True blue suggests breakdown of membrane integrity and cell death.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Survival of adult basal forebrain cholinergic neurons after loss of target neurons.

Target cells are thought to regulate the survival of afferent neurons during development by supplying limiting amounts of neurotrophic factors, but the degree to which afferent neurons remain dependent on target-derived support in the adult is uncertain. In this study, uninjured basal forebrain cholinergic neurons did not die after excitotoxic ablation of their target neurons in young adult rats, indicating that they are either not dependent on neurotrophic factors for survival or can obtain trophic support from other sources after target neurons are lost. This finding suggests that cholinergic cell death in neurodegenerative conditions such as Alzheimer's disease is not due solely to a loss of target neurons or factors provided by them.

Acetylcholinesterase↗
PubMed1990

Re-expression of Nerve Growth Factor Receptor after Axonal Injury Recapitulates a Developmental Event in Motor Neurons: Differential Regulation when Regeneration is Allowed or Prevented.

Motor neurons in the brainstem and spinal cord transiently express nerve growth factor receptors (NGFr) during development, but not in normal adult animals. In this study, NGFr was immunohistochemically identified in hypoglossal motor neurons after different types of peripheral axonal injury in adult rats. NGFr is re-expressed in motor neurons 7 days after a nerve crush injury, and has disappeared again by 28 days. These times correspond, respectively, to the active phase of regeneration, and a time by which regeneration has largely been completed, as determined by electrical activation of tongue muscle twitch. In contrast, 7 days after nerve transection and ligation of the proximal stump to prevent regeneration, there is no re-expression of NGFr, but 28 days after such treatment NGFr is present in a few neurons. By this time, neuroma formation has begun proximal to the end of the cut and ligated nerve. Together, these findings suggest that motor neurons transiently re-express NGFr during regeneration and not in response to axonal transection per se. The signal triggering re-expression thus seems more likely to be the introduction of a message from the site of injury, rather than the loss of a target-derived message. Although the function of NGFr in developing and regenerating motor neurons is not known, its expression appears to be associated with periods of axonal growth and maturation.

Journal Article↗
PubMed1989

Nerve growth factor receptor immunoreactivity in the rat suprachiasmatic nucleus.

Using a monoclonal antibody, nerve growth factor receptor has been immunohistochemically identified within the suprachiasmatic nucleus of adult rats. Labelling was most intense in the ventral, lateral and caudal portions of the nucleus and appeared primarily associated with fibers and terminals. These were among the most intensely labelled fibers and terminals in the forebrain.

Animals↗
PubMed1989

A primate model of Huntington's disease: cross-species implantation of striatal precursor cells to the excitotoxically lesioned baboon caudate-putamen.

Ibotenic acid was injected unilaterally into the baboon caudate-putamen (CP) to achieve a neural degeneration model in the primate, with a neuropathology similar to Huntington's disease. Four to six weeks later injections of cell suspensions of striatal precursor cells, obtained by dissection of the fetal rat striatal region (13-15 days gestational age), were made into the excitotoxically lesioned CP of 3 baboons immunosuppressed by Cyclosporin A. Morphological analysis indicated that in one of the baboons, which had the largest lesion of the CP and the shortest survival time (6 weeks after implantation), there was a surviving striatal implant. The implanted neurons grew in high densities in cellular aggregates within the host gliotic CP. These neurons had a neuronal size phenotypical for rat striatum, i.e. on average about a 25% smaller neuronal cell diameter than a similar population in the baboon caudate-putamen. Glial-fibrillary-acid-protein immunoreactivity was present on large astrocytes within the striatal implant, with a distinct border towards the lesion-induced astrogliosis of the host. Neuronal markers for acetylcholinesterase and Leu-enkephalin were distributed in a typical patchy manner in the striatal implants along with fiber staining for tyrosine-hydroxylase-like immunoreactivity (TH) possibly derived from afferent host dopaminergic axons. Some of these fibers in the implants came from intrinsic TH-positive neuronal somata, probably of neocortical fetal origin and transiently expressing the enzyme. In conclusion, the results indicate that neuronal replacement can be achieved by cross-species implantation of fetal striatal precursor cells to the previously neuron depleted primate CP under immunosuppression but that the survival and growth of such implants may be variable and subject to unfavourable trophic conditions.

Animals↗
PubMed1989

A direct catecholaminergic projection from the brainstem to the neurohypophysis of the rat.

The presence of the catecholamines dopamine and noradrenaline in the posterior pituitary is well documented. Dopaminergic terminals are thought to derive from cells in the periventricular hypothalamus including the rostral arcuate nucleus, but the origin of the noradrenergic terminals is uncertain. The majority of central noradrenaline-containing neurons are in the brainstem and lesions of the ventral noradrenergic tract significantly reduce the noradrenaline content of the neural lobe. We have explored the possibility of a direct noradrenergic projection from the brainstem to the neural lobe using as a retrograde tract tracer horseradish peroxidase alone or in combination with immunohistochemical detection of tyrosine hydroxylase. Horseradish peroxidase was injected into the neural lobes of 20 rats using a ventral approach, and the animals were perfusion fixed 12 h later. In all 20 cases, cells retrogradely labelled with horseradish peroxidase were found not only in the periventricular zone and magnocellular nuclei of the hypothalamus but also in the A2 region of the brainstem. In all six cases simultaneously processed for horseradish peroxidase and tyrosine hydroxylase immunohistochemistry, retrogradely labelled cells in both the arcuate nucleus and A2 region were found to be tyrosine hydroxylase-positive. These findings demonstrate the presence of a direct projection from catecholaminergic neurons in the A2 region of the brainstem to the neurohypophysis. Since catecholaminergic neurons in this region are known to be noradrenergic and lesions of the ventral noradrenergic tract deplete the neurohypophysis of noradrenaline, these neurons may represent an important source of noradrenaline in the neurohypophysis.

Adrenergic Fibers↗