Neurogenesis in the subventricular zone and rostral migratory stream of the neonatal and adult primate forebrain.

Throughout life, the anterior part of the postnatal rodent subventricular zone (SVZa), surrounding the lateral ventricles, contains a prolific source of neuronal progenitor cells that retain their capacity to concurrently generate neurons and migrate along the rostral migratory stream (RMS) to the olfactory bulb, where they differentiate into interneurons. This study was designed to determine whether the SVZ and RMS of the postnatal primate also harbor a specialized population of neuronal progenitors with the capacity to divide while they migrate. In order to reveal the spatial-temporal changes in the distribution and composition of the neuronal progenitor cells in the primate SVZ and RMS, seven rhesus monkeys, ranging in age from 2 days to 8 years, were given a single injection of the cell proliferation marker bromodeoxyuridine (BrdU) 3 h before they were perfused. The phenotypic identity of the BrdU(+) cells was revealed by double labeling sagittal sections with cell type-specific markers. From birth onward the distribution of BrdU(+) cells with a neuronal phenotype is extensive and largely overlapping with that of the rodent. Similar to the rodent brain the neuronal progenitors are most numerous in neonates. The BrdU(+) neurons in the primate forebrain extend lateral and ventral to the lateral ventricle and all along the RMS. The cytoarchitectonic arrangement and appearance of the neuronal progenitor cells is quite varied in the primate compared to the rodent; in some locations the cells are aligned in parallel arrays resembling the neuronal chains of the adult rodent RMS, whereas in other positions the cells have a homogeneous "honeycomb" arrangement. The chains are progressively more pervasive in older primates. Akin to the RMS of adult rodents, in the primate SVZ and RMS the astrocytes often form long tubes enveloping the chains of neuronal progenitors. Our study demonstrates that the primate forebrain, similar to the rodent forebrain, harbors a specialized population of mitotically active neuronal progenitor cells that undergo extensive rearrangements while continuing to proliferate throughout life.

Infusion of brain-derived neurotrophic factor into the lateral ventricle of the adult rat leads to new neurons in the parenchyma of the striatum, septum, thalamus, and hypothalamus.

The findings that brain-derived neurotrophic factor (BDNF) promotes in vitro the survival and/or differentiation of postnatal subventricular zone (SVZ) progenitor cells and increases in vivo the number of the newly generated neurons in the adult rostral migratory stream and olfactory bulb prompted us to investigate whether the infusion of BDNF influences the proliferation and/or differentiation of cells in other regions of the adult forebrain. We examined the distribution and phenotype of newly generated cells in the adult rat forebrain 16 d after intraventricular administration of BDNF in conjunction with the cell proliferation marker bromodeoxyuridine (BrdU) for 12 d. BDNF infusion resulted in numerous BrdU(+) cells, not only in the SVZ lining the infused lateral ventricle, but moreover, in specific parenchymal structures lining the lateral and third ventricles, including the striatum and septum, as well as the thalamus and hypothalamus, in which neurogenesis had never been demonstrated previously during adulthood. In each region, newly generated cells expressed the neuronal marker microtubule-associated protein-2, or neuron-specific tubulin, identified by the antibody TuJ1. The percentage of the newly generated cells expressing TuJ1 ranged from 27 to 42%, suggesting that the adult forebrain has a more profound capacity to produce neurons than recognized previously. The extent of cell proliferation after BDNF infusion was correlated with the level of expression of full-length TrkB, the high-affinity receptor for BDNF, despite the fact that the BrdU(+) cells were not themselves TrkB(+). Collectively, our results demonstrate that the adult brain parenchyma may recruit and/or generate new neurons, which could replace those lost as a result of injury or disease.

Increased number of BrdU-labeled neurons in the rostral migratory stream of the estrous prairie vole.

In the mammalian forebrain, most neurons originate from proliferating cells in the ventricular zone lining the lateral ventricles, including a discrete area of the subventricular zone in which neurogenesis continues into adulthood. The majority of the cells generated in the anterior portion of the subventricular zone (SVZa) are neuronal precursors with progeny that migrate to the olfactory bulb (OB) along a pathway known as the rostral migratory stream (RMS). The list of factors that influence the proliferation and survival of neurons in the adult brain remains incomplete, but previous studies have implicated neurotrophins in mammals and estrogen in birds. This study examined the effect of estrus induction on the proliferation of SVZa neurons in female prairie voles. Prairie voles, unlike many other rodents, are induced into estrus by chemosensory cues from a male. This olfactory-mediated process results in an increase in serum estrogen levels and the consequent induction of behavioral estrus (sexual receptivity). Female prairie voles induced into estrus by male exposure had a 92% increase in BrdU-labeled cells in the SVZa compared to females exposed to a female. Double-label immunocytochemical studies demonstrated that 80% of the BrdU-labeled cells in the RMS displayed a neuronal phenotype. Ovariectomized females exposed to a male did not show an increase in serum estrogen or BrdU labeling in the RMS. Conversely, ovariectomized females injected with estrogen were sexually receptive and had more BrdU-labeled cells in the RMS than oil-injected females. These data suggest that, in female prairie voles, estrus induction is associated with increased numbers of dividing cells in the RMS, possibly via an estrogen-mediated process.

The properties of hNT cells following transplantation into the subventricular zone of the neonatal forebrain.

Neurons derived from the human teratocarcinoma cell line (hNT) establish structural polarity and a fully mature phenotype following transplantation into the rodent brain. Here we describe the transplantation of hNT cells into the anterior part of neonatal subventricular zone (SVZa), which is a prolific region of neuronal progenitor cells. Ordinarily, the progeny of endogenous or homotopically transplanted SVZa cells migrate to the olfactory bulb (OB) along a restricted pathway, the rostral migratory stream (RMS), and differentiate into interneurons. To compare the phenotype of cultured hNT cells to their transplanted cohorts, hNT cells labeled by the fluorescent dye PKH26 were cultured for 1 day and stained with cell-type-specific antibodies. Clusters as well as individual hNT cells were immunoreactive for TuJ1, an antibody that recognizes neuron-specific class III beta-tubulin. The distribution and phenotype of the transplanted hNT cells were examined. The majority of transplanted PKH26-labeled hNT cells were found at their site of implantation in the SVZa, while a small proportion of the transplanted hNT cells was situated in the migratory pathway leading to the OB and in the subependymal zone and granule cell layer of the olfactory bulb. Many of the transplanted hNT cells, both within the SVZa and within the RMS, revealed a neuronal phenotype. Collectively, these results reveal the capacity of hNT cells to respond, at least partially, to cues that ordinarily govern the migration of SVZa-derived cells and maintain their neuronal identity.

Neurogenesis and neuronal migration in the neonatal rat forebrain anterior subventricular zone do not require GFAP-positive astrocytes.

A prolific neuronal progenitor cell population in the anterior portion of the neonatal rat forebrain subventricular zone, the SVZa, is specialized for the production of olfactory bulb interneurons. At all ages, SVZa-derived cells traverse a tangential migratory pathway, the rostral migratory stream (RMS), while en route to the olfactory bulb. Unlike other neuronal progenitor cells of the forebrain, migrating progeny of SVZa progenitors express neuronal-specific proteins and continue to divide into adulthood. Recent studies indicate that in the adult, migrating SVZa-derived cells are ensheathed by astrocytes, although the function of these astrocytes has not been determined. To explore the possible role(s) of astrocytes in the rat SVZa and RMS, we examined the expression of astroglial-specific genes in the postnatal SVZa and RMS using RT-PCR, in situ hybridization, and immunohistochemistry during (Postnatal Days 1-10) and after the period of peak olfactory bulb interneuron generation. We also examined the expression of neuronal-specific genes throughout the rostral-caudal extent of the postnatal subventricular zone to determine if differential cell type-specific gene expression could distinguish the neurogenic SVZa as a region distinct from the remainder of the SVZ. We found little to no astrocyte-specific gene expression in the P0-P7 SVZa, although the neuron-specific isoforms of tubulin (T alpha 1 and beta-III tubulin) were expressed abundantly in the SVZa and RMS. In contrast, astrocyte-specific genes were strongly expressed in the SVZ posterior to the SVZa. GFAP expressions begins to appear in some restricted areas of the rostral migratory stream after the first postnatal week. These data suggest that astroglia are not involved in the generation or migration of most olfactory bulb interneurons. Moreover, the scarcity of glial markers in the neonatal SVZa indicates that the forebrain subventricular zone includes a distinct neurogenic anterior region containing predominantly committed neuronal progenitor cells.

Intraventricular administration of BDNF increases the number of newly generated neurons in the adult olfactory bulb.

We have previously demonstrated that the most rostral part of the subventricular zone (SVZ) is a source of neuronal progenitor cells whose progeny are destined to become interneurons of the olfactory bulb. To determine whether the number of newly generated neurons in the adult olfactory bulb could be increased by the administration of an exogenous factor, brain-derived neurotrophic factor (BDNF) was infused for 12 days into the right lateral ventricle of adult rat brains. The production of new cells was monitored by either the intraventricular infusion or intraperitoneal injection of the cell proliferation marker BrdU. In both experimental paradigms we observed significantly more BrdU-labeled cells in the olfactory bulbs on the BDNF-infused side than in the olfactory bulb of PBS-infused animals. Analysis of the BDNF-infused brains of animals injected intraperitoneally with BrdU demonstrated a 100% increase in the number of BrdU-labeled cells in the bulb, the preponderance ( approximately 90%) of which were double-labeled with a neuron-specific antibody. These results demonstrate that the generation and/or survival of new neurons in the adult brain can be increased substantially by an exogenous factor. Furthermore, the SVZ, and in particular the rostral part, may constitute a reserve pool of progenitor cells available for neuronal replacement in the diseased or damaged brain.

Neuronal progenitor cells of the neonatal subventricular zone differentiate and disperse following transplantation into the adult rat striatum.

We have investigated the suitability of a recently identified and characterized population of neuronal progenitor cells for their potential use in the replacement of degenerating or damaged neurons in the mammalian brain. The unique population of neuronal progenitor cells is situated in a well-delineated region of the anterior part of the neonatal subventricular zone (referred to as SVZa). This region can be separated from the remaining proliferative, gliogenic, subventricular zone encircling the lateral ventricles of the forebrain. Because the neurons arising from the highly enriched neurogenic progenitor cell population of the SVZa ordinarily migrate considerable distances and ultimately express the neurotransmitters GABA and dopamine, we have examined whether they could serve as an alternative source of tissue for neural transplantation. SVZa cells from postnatal day 0-2 rats, prelabeled by intraperitoneal injections of the cell proliferation marker BrdU, were implanted into the striatum of adult rats approximately 1 mo after unilateral denervation by 6-OHDA. To examine the spatio-temporal distribution and phenotype of the transplanted SVZa cells, the experimental recipients were perfused at short (less than 1 wk), intermediate (2-3 wk) and long (5 mo) postimplantation times. The host brains were sectioned and stained with an antibody to BrdU and one of several cell-type specific markers to determine the phenotypic characteristics of the transplanted SVZa cells. To identify neurons we used the neuron-specific antibody TuJ1, or antimembrane-associated protein 2 (MAP-2), and anti-GFAP was used to identify astrocytic glia. At all studied intervals the majority of the surviving SVZa cells exhibited a neuronal phenotype. Moreover, morphologically they could be distinguished from the cells of the host striatum because they resembled the intrinsic granule cells of the olfactory bulb, their usual fate. At longer times, a greater number of the transplanted SVZa cells had migrated from their site of implantation, often towards an outlying blood vessel, and the density of cells within the core of the transplant was reduced. Furthermore, there were rarely signs of transplant rejection or a glial scar surrounding the transplant. In the core of the transplant there were low numbers of GFAP-positive cells, indicating that the transplanted SVZa cells, predominantly TuJ1-positive/MAP2-positive, express a neuronal phenotype. Collectively, the propensity of the SVZa cells to express a neuronal phenotype and to survive and integrate in the striatal environment suggest that they may be useful in the reconstruction of the brain following CNS injury or disease.

Histopathological data on six cases of hypothyroidism accompanying muscular chronic disease.

This study was carried out on 6 patients with myxedema that showed major muscular alterations. Light and electron microscopic examinations of the striated muscle structure revealed myxedematous myopathy lesions. Considering the existence of several hypotheses regarding the pathogeny of muscular alterations, the authors discuss the likelihood of a myogenic syndrome induced by an immunity deficit in hypothyroidism.

[Benign solitary thyroid nodule (BSTN)]. / Nodulul tiroidian solitar benign.

Out of a series of 210 patients (193 women and 17 men) with BSTN, 62% presented an warm nodule, 25.2% a hot nodule and 11.9% a cold nodule. The highest incidence of the nodule was noticed round the age of 40-50 years. The most common site was the middle and lower area of the right thyroid lobe. The thyroid scintigram provided orientative data regarding the nature of BSTN, the treatment indication being the surgical intervention. Histopathologically, polymorphic aspects ranging from anizofollicular adenoma, adenomatous proliferations areas and hyperfunctional aspect to degenerative sclerous alterations and lymphoplasmocitary infiltrations were noticed. The current hypotheses regarding the etiopathogeny of nodule forming process are discussed. Based on some data in the literature, we consider the nodularization of the thyroid gland as a reactional zone functional desynchronization in the conditions of some great variations of the iodate intaxe.

[Hypophysary and ovarian anatomopathological alterations in menopause]. / Modificari anatomopatologice hipofizare si ovariene în climacteriu.

A simultaneous hystopatological investigation of hypophysis and ovary in 80 women aged between 48 and 60 years was carried out. The obtained data pointed out that about menopause the hypophysis increases its activity and the ovaries present important pIenomena of sclerosis which could be determined by the hypersecretion of gonadotropic hormones. The decrease in sensitivity of the hormone-sensitive areas to the negative feed-back of estrogens would contribute to the setting up of the hypothalamic hypertonia on gonadotropic axis. The hypothesis is suggested, on one hand, by the fact that the degenerative ovarian insufficiency and the ovarian vascular alterations in menopause represent singular phenomena in the constellation of all the other endocrine glands and, on the other hand, by the fact that hypophysis, in menopause, increases its activity.

[Cervicomediastinal and thoracic goiters]. / Gusile cervicomediastinale si toracice.

Between 1950 and 1979 approximately 2400 patients with thyropathies have been operated in the I-st Surgical Clinic of Jassy. Of these 100 had cervico-mediastinal goiters, of which 79 were of the plunging cervico-mediastinal type, 18 were of the mediastino-cervical type and 3 were mediastinal goiters. The surgical treatment was applied in 98 patients, cervicotomy being sufficient to relieve the symptoms in 92 of the cases. The mixed approach (cervicosternotomy, or cervico-thoracic approach) were necessary in 5 cases, and the thoracic approach was selected in one case with an independent posterior mediastinal goiter. The immediate postoperative evolution, as well as the late evolution was good in most of the cases. Postoperative mortality was of 2 percent.