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Sample records for rat forebrain subventricular

  1. Mosaic Subventricular Origins of Forebrain Oligodendrogenesis

    PubMed Central

    Azim, Kasum; Berninger, Benedikt; Raineteau, Olivier

    2016-01-01

    In the perinatal as well as the adult CNS, the subventricular zone (SVZ) of the forebrain is the largest and most active source of neural stem cells (NSCs) that generates neurons and oligodendrocytes (OLs), the myelin forming cells of the CNS. Recent advances in the field are beginning to shed light regarding SVZ heterogeneity, with the existence of spatially segregated microdomains that are intrinsically biased to generate phenotypically distinct neuronal populations. Although most research has focused on this regionalization in the context of neurogenesis, newer findings underline that this also applies for the genesis of OLs under the control of specific patterning molecules. In this mini review, we discuss the origins as well as the mechanisms that induce and maintain SVZ regionalization. These come in the flavor of specific signaling ligands and subsequent initiation of transcriptional networks that provide a basis for subdividing the SVZ into distinct lineage-specific microdomains. We further emphasize canonical Wnts and FGF2 as essential signaling pathways for the regional genesis of OL progenitors from NSCs of the dorsal SVZ. This aspect of NSC biology, which has so far received little attention, may unveil new avenues for appropriately recruiting NSCs in demyelinating diseases. PMID:27047329

  2. Mosaic Subventricular Origins of Forebrain Oligodendrogenesis.

    PubMed

    Azim, Kasum; Berninger, Benedikt; Raineteau, Olivier

    2016-01-01

    In the perinatal as well as the adult CNS, the subventricular zone (SVZ) of the forebrain is the largest and most active source of neural stem cells (NSCs) that generates neurons and oligodendrocytes (OLs), the myelin forming cells of the CNS. Recent advances in the field are beginning to shed light regarding SVZ heterogeneity, with the existence of spatially segregated microdomains that are intrinsically biased to generate phenotypically distinct neuronal populations. Although most research has focused on this regionalization in the context of neurogenesis, newer findings underline that this also applies for the genesis of OLs under the control of specific patterning molecules. In this mini review, we discuss the origins as well as the mechanisms that induce and maintain SVZ regionalization. These come in the flavor of specific signaling ligands and subsequent initiation of transcriptional networks that provide a basis for subdividing the SVZ into distinct lineage-specific microdomains. We further emphasize canonical Wnts and FGF2 as essential signaling pathways for the regional genesis of OL progenitors from NSCs of the dorsal SVZ. This aspect of NSC biology, which has so far received little attention, may unveil new avenues for appropriately recruiting NSCs in demyelinating diseases. PMID:27047329

  3. Expression of amyloid precursor protein-like molecule in astroglial cells of the subventricular zone and rostral migratory stream of the adult rat forebrain

    PubMed Central

    Yasuoka, Katsunori; Hirata, Kazuho; Kuraoka, Akio; He, Jian-wen; Kawabuchi, Masaru

    2004-01-01

    In adult mammals, new neurons in the subventricular zone (SVZ) of the lateral ventricle (LV) migrate tangentially through the rostral migratory stream (RMS) to the olfactory bulb (OB), where they mature into local interneurons. Using a monoclonal antibody for the β-amyloid precursor protein (APP) (mAb 22C11), which is specific for the amino-terminal region of the secreted form of APP and recognizes all APP isoforms and APP-related proteins, immunoreactivity was detected in specific subpopulations of cells in the SVZ and RMS of the adult rat forebrain. In the SVZ, APP-like immunoreactivity was detected in the ependymal cells lining the LV and some of the subependymal cells. The latter were regarded as astrocytes, because they were positive for the glial markers, S-100 protein (S-100) and glial fibrillary acidic protein (GFAP). APP-like immunoreactive astrocytes exhibited strong labelling of the perinuclear cytoplasm and often possessed a long, fine process similar to that found with radial glia. The process extended to an APP-like immunoreactive meshwork in the RMS that consisted of cytoplasmic processes of astrocytes forming ‘glial tubes’. Double-immunofluorescent labelling with a highly polysialylated neural cell adhesion molecule (PSA-NCAM) confirmed that the APP-like immunoreactive astrocytes in the SVZ and meshwork in the RMS made close contact with PSA-NCAM-immunopositive neuroblasts, suggesting an interaction between APP-containing cells and neuroblasts. This region of the adult brain is a useful in vivo model to investigate the role of APP in neurogenesis. PMID:15291796

  4. Neurogenesis and widespread forebrain migration of distinct GABAergic neurons from the postnatal subventricular zone

    PubMed Central

    Inta, Dragos; Alfonso, Julieta; von Engelhardt, Jakob; Kreuzberg, Maria M.; Meyer, Axel H.; van Hooft, Johannes A.; Monyer, Hannah

    2008-01-01

    Most forebrain GABAergic interneurons in rodents are born during embryonic development in the ganglionic eminences (GE) and migrate tangentially into the cortical plate. A subset, however, continues to be generated postnatally in the subventricular zone (SVZ). These interneurons populate the olfactory bulb (OB) reached via migration in the rostral migratory stream (RMS). Employing transgenic mice expressing EGFP in 5-HT3-positive neurons, we identified additional migratory pathways in the early postnatal brain. Time-lapse imaging experiments revealed massive migration of EGFP-positive cells from the SVZ into numerous forebrain regions, including cortex, striatum, and nucleus accumbens. The neuronal fate of the migratory EGFP-labeled cells was indicated by their doublecortin (DCX) expression. Birthdating experiments, by using 5-bromo-2′-deoxyuridine (BrdU) and retrovirus-based experiments, provided evidence that migrating neuroblasts were born in the SVZ postnatally and developed a distinct GABAergic phenotype. Our results demonstrate that the SVZ is a reservoir of GABAergic interneurons not only for the OB, but also for other cortical and subcortical areas. PMID:19095802

  5. Proliferating subventricular zone cells in the adult mammalian forebrain can differentiate into neurons and glia.

    PubMed Central

    Lois, C; Alvarez-Buylla, A

    1993-01-01

    Subventricular zone (SVZ) cells proliferate spontaneously in vivo in the telencephalon of adult mammals. Several studies suggest that SVZ cells do not differentiate after mitosis into neurons or glia but die. In the present work, we show that SVZ cells labeled in the brains of adult mice with [3H]thymidine differentiate directly into neurons and glia in explant cultures. In vitro labeling with [3H]thymidine shows that 98% of the neurons that differentiate from the SVZ explants are derived from precursor cells that underwent their last division in vivo. This report identifies the SVZ cells as neuronal precursors in an adult mammalian brain. Images Fig. 1 Fig. 2 Fig. 3 PMID:8446631

  6. Mast cells in the sheep, hedgehog and rat forebrain

    PubMed Central

    MICHALOUDI, HELEN C.; PAPADOPOULOS, GEORGIOS C.

    1999-01-01

    The study was designed to reveal the distribution of various mast cell types in the forebrain of the adult sheep, hedgehog and rat. Based on their histochemical and immunocytochemical characteristics, mast cells were categorised as (1) connective tissue-type mast cells, staining metachromatically purple with the toluidine blue method, or pale red with the Alcian blue/safranin method, (2) mucosal-type or immature mast cells staining blue with the Alcian blue/safranin method and (3) serotonin immunopositive mast cells. All 3 types of brain mast cells in all species studied were located in both white and grey matter, often associated with intraparenchymal blood vessels. Their distribution pattern exhibited interspecies differences, while their number varied considerably not only between species but also between individuals of each species. A distributional left-right asymmetry, with more cells present on the left side, was observed in all species studied but it was most prominent in the sheep brain. In the sheep, mast cells were abundantly distributed in forebrain areas, while in the hedgehog and the rat forebrain, mast cells were less widely distributed and were relatively or substantially fewer in number respectively. A limited number of brain mast cells, in all 3 species, but primarily in the rat, were found to react both immunocytochemically to 5-HT antibody and histochemically with Alcian blue/safranin staining. PMID:10634696

  7. Forebrain-independent generation of hyperthermic convulsions in infant rats.

    PubMed

    Pospelov, Alexey S; Yukin, Alexey Y; Blumberg, Mark S; Puskarjov, Martin; Kaila, Kai

    2016-01-01

    Febrile seizures are the most common type of convulsive events in children. It is generally assumed that the generalization of these seizures is a result of brainstem invasion by the initial limbic seizure activity. Using precollicular transection in 13-day-old rats to isolate the forebrain from the brainstem, we demonstrate that the forebrain is not required for generation of tonic-clonic convulsions induced by hyperthermia or kainate. Compared with sham-operated littermate controls, latency to onset of convulsions in both models was significantly shorter in pups that had undergone precollicular transection, indicating suppression of the brainstem seizure network by the forebrain in the intact animal. We have shown previously that febrile seizures are precipitated by hyperthermia-induced respiratory alkalosis. Here, we show that triggering of hyperthermia-induced hyperventilation and consequent convulsions in transected animals are blocked by diazepam. The present data suggest that the role of endogenous brainstem activity in triggering tonic-clonic seizures should be re-evaluated in standard experimental models of limbic seizures. Our work sheds new light on the mechanisms that generate febrile seizures in children and, therefore, on how they might be treated. PMID:26547277

  8. Visualization of growth factor receptor sites in rat forebrain

    SciTech Connect

    Quirion, R.; Araujo, D.; Nair, N.P.; Chabot, J.G.

    1988-01-01

    It is now known that various growth factors may also act in the central nervous system. Among them, it has recently been shown that epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) may possess trophic effects in the mammalian brain. We report here on the respective autoradiographic distribution of (/sup 125/I)EGF and (/sup 125/I)IGF-I receptor binding sites in the rat brain, both during ontogeny and in adulthood. It appears that (/sup 125/I)EGF sites are mostly found in the rat forebrain during brain development. On the other hand, (/sup 125/I)IGF-I sites are more widely distributed both during ontogeny and in adulthood. These results reveal the plasticity of the expression of EGF and IGF-I receptor sites in the mammalian brain. This could be relevant for the respective role of these two growth factors in the development and maintenance of neuronal function.

  9. Dopamine receptor gene expression by enkephalin neurons in rat forebrain

    SciTech Connect

    Le Moine, C.; Normand, E.; Guitteny, A.F.; Fouque, B.; Teoule, R.; Bloch, B. )

    1990-01-01

    In situ hybridization experiments were performed with brain sections from normal, control and haloperidol-treated rats to identify and map the cells expressing the D2 dopamine receptor gene. D2 receptor mRNA was detected with radioactive or biotinylated oligonucleotide probes. D2 receptor mRNA was present in glandular cells of the pituitary intermediate lobe and in neurons of the substantia nigra, ventral tegmental area, and forebrain, especially in caudate putamen, nucleus accumbens, olfactory tubercle, and piriform cortex. Hybridization with D2 and preproenkephalin A probes in adjacent sections, as well as combined hybridization with the two probes in the same sections, demonstrated that all detectable enkephalin neurons in the striatum contained the D2 receptor mRNA. Large neurons in caudate putamen, which were unlabeled with the preproenkephalin A probe and which may have been cholinergic, also expressed the D2 receptor gene. Haloperidol treatment (14 or 21 days) provoked an increase in mRNA content for D2 receptor and preproenkephalin A in the striatum. This suggests that the increase in D2 receptor number observed after haloperidol treatment is due to increased activity of the D2 gene. These results indicate that in the striatum, the enkephalin neurons are direct targets for dopamine liberated from mesostriatal neurons.

  10. Local Administration of AAV-BDNF to Subventricular Zone Induces Functional Recovery in Stroke Rats

    PubMed Central

    Yu, Seong-Jin; Tseng, Kuan-Yin; Shen, Hui; Harvey, Brandon K.; Airavaara, Mikko; Wang, Yun

    2013-01-01

    Migration of new neuroprogenitor cells (NPCs) from the subventricular zone (SVZ) plays an important role in neurorepair after injury. Previous studies have shown that brain derived neurotrophic factor (BDNF) enhances the migration of NPCs from SVZ explants in neonatal mice in vitro. The purpose of this study was to identify the role of BDNF in SVZ cells using AAV-BDNF in an animal model of stroke. BDNF protein production after AAV‐BDNF infection was verified in primary neuronal culture. AAV-BDNF or AAV-RFP was injected into the left SVZ region of adult rats at 14 days prior to right middle cerebral artery occlusion (MCAo). SVZ tissues were collected from the brain and placed in Metrigel cultures 1 day after MCAo. Treatment with AAV-BDNF significantly increased the migration of SVZ cells in the stroke brain in vitro. In another set of animals, AAV-GFP was co-injected with AAV-BDNF or AAV-RFP to label cells in left SVZ prior to right MCAo. Local administration of AAV-BDNF significantly enhanced recovery of locomotor function and migration of GFP-positive cells from the SVZ toward the lesioned hemisphere in stroke rats. Our data suggest that focal administration of AAV-BDNF to the SVZ increases behavioral recovery post stroke, possibly through the enhancement of migration of cells from SVZ in stroke animals. Regional manipulation of BDNF expression through AAV may be a novel approach for neurorepair in stroke brains. PMID:24312581

  11. Prenatal cocaine exposure alters progenitor cell markers in the subventricular zone of the adult rat brain

    PubMed Central

    Patel, Dhyanesh Arvind; Booze, Rosemarie M.; Mactutus, Charles F.

    2013-01-01

    Long-term consequences of early developmental exposure to drugs of abuse may have deleterious effects on the proliferative plasticity of the brain. The purpose of this study was to examine the long-term effects of prenatal exposure to cocaine, using the IV route of administration and doses that mimic the peak arterial levels of cocaine use in humans, on the proliferative cell types of the subventricular zones (SVZ) in the adult (180 days-old) rat brain. Employing immunocytochemistry, the expression of GFAP+ (type B cells) and nestin+(GFAP−) (Type C and A cells) staining was quantified in the subcallosal area of the SVZ. GFAP+ expression was significantly different between the prenatal cocaine treated group and the vehicle (saline) control group. The prenatal cocaine treated group possessed significantly lower GFAP+ expression relative to the vehicle control group, suggesting that prenatal cocaine exposure significantly reduced the expression of type B neural stem cells of the SVZ. In addition, there was a significant sex difference in nestin+ expression with females showing approximately 8–13% higher nestin+ expression compared to the males. More importantly, a significant prenatal treatment condition (prenatal cocaine, control) by sex interaction in nestin+ expression was confirmed, indicating different effects of cocaine based on sex of the animal. Specifically, prenatal cocaine exposure eliminated the basal difference between the sexes. Collectively, the present findings suggest that prenatal exposure to cocaine, when delivered via a protocol designed to capture prominent features of recreational usage, can selectively alter the major proliferative cell types in the subcallosal area of the SVZ in an adult rat brain, and does so differently for males and females. PMID:22119286

  12. Development of glucocorticoid receptor regulation in the rat forebrain: Implications for adverse effects of glucocorticoids in preterm infants

    EPA Science Inventory

    Glucocorticoids are the consensus treatment to avoid respiratory distress in preterm infants but there is accumulating evidence that these agents evoke long-term neurobehavioral deficits. Earlier, we showed that the developing rat forebrain is far more sensitive to glucocorticoi...

  13. Reduced forebrain serotonin transmission is causally involved in the development of compulsive cocaine seeking in rats.

    PubMed

    Pelloux, Yann; Dilleen, Ruth; Economidou, Daina; Theobald, David; Everitt, Barry J

    2012-10-01

    Whereas the majority of cocaine users quit as they experience the negative consequences of drug use, some lose control over their drug taking and compulsively seek drugs. We report that 20% of rats compulsively seek cocaine despite intermittent negative outcomes after escalating their cocaine self-administration. This compulsive subgroup showed marked reductions in forebrain serotonin utilization; increasing serotonin transmission reduced their compulsive cocaine seeking. Depleting forebrain serotonin induced compulsive cocaine seeking in rats with a limited cocaine taking history; this was reversed by systemic treatment with a 5-hydroxytryptamine (5-HT2C) receptor agonist and mimicked by systemic treatment with a 5-HT2C receptor antagonist in intact animals. These results indicate the causal involvement of reduced serotoninergic transmission in the emergence of compulsive drug seeking after a long cocaine-taking history. PMID:22763621

  14. Receptors for GRP/bombesin-like peptides in the rat forebrain

    SciTech Connect

    Wolf, S.S.; Moody, T.W.

    1985-01-01

    Binding sites in the rat forebrain were characterized using ( SVI-Tyr4)bombesin as a receptor probe. Pharmacology experiments indicate that gastrin releasing peptide (GRP) and the GRP fragments GRP as well as Ac-GRP inhibited radiolabeled (Tyr4)bombesin binding with high affinity. Biochemistry experiments indicated that heat, N-ethyl maleimide or trypsin greatly reduced radiolabeled (Tyr4)bombesin binding. Also, autoradiographic studies indicated that highest grain densities were present in the stria terminalis, periventricular and suprachiasmatic nucleus of the hypothalamus, dorsomedial and rhomboid thalamus, dentate gyrus, hippocampus and medial amygdaloid nucleus. The data suggest that CNS protein receptors, which are discretely distributed in the rat forebrain, may mediate the action of endogenous GRP/bombesin-like peptides.

  15. Relative and absolute quantification of postsynaptic density proteome isolated from rat forebrain and cerebellum.

    PubMed

    Cheng, Dongmei; Hoogenraad, Casper C; Rush, John; Ramm, Elizabeth; Schlager, Max A; Duong, Duc M; Xu, Ping; Wijayawardana, Sameera R; Hanfelt, John; Nakagawa, Terunaga; Sheng, Morgan; Peng, Junmin

    2006-06-01

    The postsynaptic density (PSD) of central excitatory synapses is essential for postsynaptic signaling, and its components are heterogeneous among different neuronal subtypes and brain structures. Here we report large scale relative and absolute quantification of proteins in PSDs purified from adult rat forebrain and cerebellum. PSD protein profiles were determined using the cleavable ICAT strategy and LC-MS/MS. A total of 296 proteins were identified and quantified with 43 proteins exhibiting statistically significant abundance change between forebrain and cerebellum, indicating marked molecular heterogeneity of PSDs between different brain regions. Moreover we utilized absolute quantification strategy, in which synthetic isotope-labeled peptides were used as internal standards, to measure the molar abundance of 32 key PSD proteins in forebrain and cerebellum. These data confirm the abundance of calcium/calmodulin-dependent protein kinase II and PSD-95 and reveal unexpected stoichiometric ratios between glutamate receptors, scaffold proteins, and signaling molecules in the PSD. Our data also demonstrate that the absolute quantification method is well suited for targeted quantitative proteomic analysis. Overall this study delineates a crucial molecular difference between forebrain and cerebellar PSDs and provides a quantitative framework for measuring the molecular stoichiometry of the PSD. PMID:16507876

  16. Probucol attenuates oxidative stress, energy starvation, and nitric acid production following transient forebrain ischemia in the rat hippocampus.

    PubMed

    Al-Majed, Abdulhakeem A

    2011-01-01

    Oxidative stress and energy depletion are believed to participate in hippocampal neuronal damage after forebrain ischemia. This study has been initiated to investigate the potential neuroprotective effects of probucol, a lipid-lowering drug with strong antioxidant properties, against transient forebrain ischemia-induced neuronal damage and biochemical abnormalities in rat hippocampal CA1 region. Adult male Wistar albino rats were subjected to forebrain ischemia and injected with probucol for the next 7 successive days, and compared to controls. Forebrain ischemia resulted in a significant decrease in the number of intact neurons (77%), glutathione (GSH), and adenosine triphosphate (ATP), and a significant increase in thiobarbituric acid reactive substances (TBARS) and total nitrate/nitrite, (NO(x)) production in hippocampal tissues. The administration of probucol attenuated forebrain ischemia-induced neuronal damage, manifested as a complete reversal of the decrease in the number of intact neurons, ATP and GSH and the increase in TBARS and NO(x) in hippocampal tissues. This study demonstrates that probucol treatment abates forebrain ischemia-induced hippocampal neuronal loss, energy depletion, and oxidative stress in hippocampal CA1 region. Thus, probucol could be a promising neuroprotective agent in the treatment of forebrain ischemia. PMID:21904644

  17. Developmental vitamin D deficiency alters dopamine turnover in neonatal rat forebrain.

    PubMed

    Kesby, James P; Cui, Xiaoying; Ko, Pauline; McGrath, John J; Burne, Thomas H J; Eyles, Darryl W

    2009-09-18

    There is growing evidence that low vitamin D impacts adversely on brain development. The current study investigated the impact of developmental vitamin D (DVD) deficiency on dopamine and serotonin metabolism in the neonatal rat brain. DVD-deficiency resulted in an altered dopaminergic metabolic profile in the forebrain, with a decrease in the conversion of dihydroxyphenylacetic acid (DOPAC) to homovanillic acid (HVA). Correspondingly, expression of the enzyme required for this conversion, catechol-O-methyl transferase (COMT), was decreased. These results suggest that DVD-deficiency influences dopamine turnover during development. PMID:19500655

  18. Agmatine protection against chlorpromazine-induced forebrain cortex injury in rats.

    PubMed

    Dejanovic, Bratislav; Stevanovic, Ivana; Ninkovic, Milica; Stojanovic, Ivana; Lavrnja, Irena; Radicevic, Tatjana; Pavlovic, Milos

    2016-03-01

    This study was conducted to investigate whether agmatine (AGM) provides protection against oxidative stress induced by treatment with chlorpromazine (CPZ) in Wistar rats. In addition, the role of reactive oxygen species and efficiency of antioxidant protection in the brain homogenates of forebrain cortexes prepared 48 h after treatment were investigated. Chlorpromazine was applied intraperitoneally (i.p.) in single dose of 38.7 mg/kg body weight (BW) The second group was treated with both CPZ and AGM (75 mg/kg BW). The control group was treated with 0.9% saline solution in the same manner. All tested compounds were administered i.p. in a single dose. Rats were sacrificed by decapitation 48 h after treatment Treatment with AGM significantly attenuated the oxidative stress parameters and restored antioxidant capacity in the forebrain cortex. The data indicated that i.p. administered AGM exerted antioxidant action in CPZ-treated animals. Moreover, reactive astrocytes and microglia may contribute to secondary nerve-cell damage and participate in the balance of destructive vs. protective actions involved in the pathogenesis after poisoning. PMID:27051340

  19. Agmatine protection against chlorpromazine-induced forebrain cortex injury in rats

    PubMed Central

    Stevanovic, Ivana; Ninkovic, Milica; Stojanovic, Ivana; Lavrnja, Irena; Radicevic, Tatjana; Pavlovic, Milos

    2016-01-01

    This study was conducted to investigate whether agmatine (AGM) provides protection against oxidative stress induced by treatment with chlorpromazine (CPZ) in Wistar rats. In addition, the role of reactive oxygen species and efficiency of antioxidant protection in the brain homogenates of forebrain cortexes prepared 48 h after treatment were investigated. Chlorpromazine was applied intraperitoneally (i.p.) in single dose of 38.7 mg/kg body weight (BW) The second group was treated with both CPZ and AGM (75 mg/kg BW). The control group was treated with 0.9% saline solution in the same manner. All tested compounds were administered i.p. in a single dose. Rats were sacrificed by decapitation 48 h after treatment Treatment with AGM significantly attenuated the oxidative stress parameters and restored antioxidant capacity in the forebrain cortex. The data indicated that i.p. administered AGM exerted antioxidant action in CPZ-treated animals. Moreover, reactive astrocytes and microglia may contribute to secondary nerve-cell damage and participate in the balance of destructive vs. protective actions involved in the pathogenesis after poisoning. PMID:27051340

  20. Gypenosides Protected the Neural Stem Cells in the Subventricular Zone of Neonatal Rats that Were Prenatally Exposed to Ethanol

    PubMed Central

    Dong, Lun; Yang, Kun-Qi; Fu, Wen-Yan; Shang, Zhen-Hua; Zhang, Qing-Yu; Jing, Fang-Miao; Li, Lin-Lin; Xin, Hua; Wang, Xiao-Jing

    2014-01-01

    Fetal alcohol spectrum disorder (FASD) can cause severe mental retardation in children who are prenatally exposed to ethanol. The effects of prenatal and early postnatal ethanol exposure on adult hippocampal neurogenesis have been investigated; however, the effects of prenatal ethanol exposure on the subventricular zone (SVZ) have not. Gypenosides (GPs) have been reported to have neuroprotective effects in addition to other bioactivities. The effects of GPs on neural stem cells (NSCs) in the FASD model are unknown. Here, we test the effect of prenatal ethanol exposure on the neonatal SVZ, and the protection potential of GPs on NSCs in FASD rats. Our results show that prenatal ethanol exposure can suppress the cell proliferation and differentiation of neural stem cells in the neonatal SVZ and that GPs (400 mg/kg/day) can significantly increase the cell proliferation and differentiation of neural stem cells inhibited by ethanol. Our data indicate that GPs have neuroprotective effects on the NSCs and can enhance the neurogenesis inhibited by ethanol within the SVZ of neonatal rats. These findings provide new evidence for a potential therapy involving GPs for the treatment of FASD. PMID:25464383

  1. Pharmacological modulation of Alzheimer's beta-amyloid precursor protein levels in the CSF of rats with forebrain cholinergic system lesions.

    PubMed

    Haroutunian, V; Greig, N; Pei, X F; Utsuki, T; Gluck, R; Acevedo, L D; Davis, K L; Wallace, W C

    1997-06-01

    Abnormal deposition and accumulation of Alzheimer's amyloid beta-protein (A beta) and degeneration of forebrain cholinergic neurons are among the principal features of Alzheimer's disease. Studies in rat model systems have shown that forebrain cholinergic deficits are accompanied by induction of cortical beta-amyloid precursor protein (beta-APP) mRNAs and increased levels of secreted beta-APP in the CSF. The studies reported here determined whether the CSF levels of secreted beta-APP could be altered pharmacologically. In different experiments, rats with lesions of the forebrain cholinergic system received injections of vehicle, a muscarinic receptor antagonist scopolamine, or one of two cholinesterase inhibitors - diisopropyl phosphorofluoridate (DFP) or phenserine. Scopolamine was administered to determine whether the levels of beta-APP in the CSF could be increased by anticholinergic agents. The cholinesterase inhibitors were administered to determine whether the forebrain cholinergic system lesion-induced increases in CSF beta-APP could be reduced by cholinergic augmentation. Scopolamine administration led to a significant increase in the CSF levels of secreted beta-APP in sham-lesioned rats. Phenserine, a novel, reversible acetyl-selective cholinesterase inhibitor, significantly decreased the levels of secreted beta-APP in the CSF of forebrain cholinergic system-lesioned rats whereas DFP, a relatively non-specific cholinesterase inhibitor, failed to affect CSF levels of secreted beta-APP. These results suggest that the levels of secreted beta-APP in the CSF can be pharmacologically modulated but that this modulation is dependent upon the status of the forebrain cholinergic system and the pharmacological properties of the drugs used to influence it. PMID:9191090

  2. Regional glucose utilization and blood flow following graded forebrain ischemia in the rat: correlation with neuropathology

    SciTech Connect

    Ginsberg, M.D.; Graham, D.I.; Busto, R.

    1985-10-01

    Regional patterns of cerebral glucose utilization (rCMRglc) and blood flow (rCBF) were examined in the early recovery period following transient forebrain ischemia in order to correlate early postischemic physiological events with regionally selective patterns of ischemic neuropathology. Wistar rats were subjected to 30 or 60 minutes of graded forebrain ischemia by a method combining unilateral occlusion of the common carotid artery with moderate elevation of intracranial pressure and mild hypotension; this procedure results in a high-grade ischemic deficit affecting chiefly the lateral neocortex, striatum, and hippocampus ipsilateral to the carotid occlusion. Simultaneous measurements of rCMRglc and rCBF made in regional tissue samples after 2 and 4 hours of postischemic recirculation using a double-tracer radioisotopic strategy revealed a disproportionately high level of glucose metabolism relative to blood flow in the early postischemic striatum, owing to the resumption of nearly normal rCMRglc in the face of depressed flow. In contrast, the neocortex, which had been equally ischemic, showed parallel depressions of both metabolism and blood flow during early recovery. Light microscopy at 4 and 8 hours after recovery revealed the striatum to be the predominant locus of ischemic neuronal alterations, whereas neocortical lesions were much less prominent in extent and severity at this time. The resumption of normal levels of metabolism in the setting of a disproportionate depression of rCBF in the early postischemic period may accentuate the process of neuronal injury initiated by ischemia and may contribute to the genesis of neuronal necrosis in selectively vulnerable areas of the forebrain.

  3. Alteration of Forebrain Neurogenesis after Cervical Spinal Cord Injury in the Adult Rat

    PubMed Central

    Felix, Marie-Solenne; Popa, Natalia; Djelloul, Mehdi; Boucraut, José; Gauthier, Patrick; Bauer, Sylvian; Matarazzo, Valery A.

    2012-01-01

    Spinal cord injury (SCI) triggers a complex cellular response at the injury site, leading to the formation of a dense scar tissue. Despite this local tissue remodeling, the consequences of SCI at the cellular level in distant rostral sites (i.e., brain), remain unknown. In this study, we asked whether cervical SCI could alter cell dynamics in neurogenic areas of the adult rat forebrain. To this aim, we quantified BrdU incorporation and determined the phenotypes of newly generated cells (neurons, astrocytes, or microglia) during the subchronic and chronic phases of injury. We find that subchronic SCI leads to a reduction of BrdU incorporation and neurogenesis in the olfactory bulb and in the hippocampal dentate gyrus. By contrast, subchronic SCI triggers an increased BrdU incorporation in the dorsal vagal complex of the hindbrain, where most of the newly generated cells are identified as microglia. In chronic condition 90 days after SCI, BrdU incorporation returns to control levels in all regions examined, except in the hippocampus, where SCI produces a long-term reduction of neurogenesis, indicating that this structure is particularly sensitive to SCI. Finally, we observe that SCI triggers an acute inflammatory response in all brain regions examined, as well as a hippocampal-specific decline in BDNF levels. This study provides the first demonstration that forebrain neurogenesis is vulnerable to a distal SCI. PMID:22509147

  4. Pattern of Forebrain Activation in High Novelty-Seeking Rats Following Aggressive Encounter

    PubMed Central

    Clinton, Sarah M.; Kerman, Ilan A.; Orr, Hailey R.; Bedrosian, Tracy A.; Abraham, Antony D.; Simpson, Danielle N.; Watson, Stanley J.; Akil, Huda

    2011-01-01

    We have previously demonstrated that selectively-bred High (bHR) and Low (bLR) novelty-seeking rats exhibit agonistic differences, with bHRs acting in a highly aggressive manner when facing homecage intrusion. In order to discover the specific neuronal pathways responsible for bHRs’ high levels of aggression, the present study compared c-fos mRNA expression in several forebrain regions of bHR/bLR males following this experience. bHR/bLR males were housed with female rats for two weeks, and then the females were replaced with a male intruder for 10 min. bHR/bLR residents were subsequently sacrificed by rapid decapitation, and their brains were removed and processed for c-fos in situ hybridization. Intrusion elicited robust c-fos mRNA expression in both phenotypes throughout the forebrain, including the septum, amygdala, hippocampus, cingulate cortex, and the hypothalamus. However, bHRs and bLRs exhibited distinct activation patterns in select areas. Compared to bHR rats, bLRs expressed greater c-fos in the lateral septum and within multiple hypothalamic nuclei, while bHRs showed greater activation in the arcuate hypothalamic nucleus and in the hippocampus. No bHR/bLR differences in c-fos expression were detected in the amygdala, cortical regions, and striatum. We also found divergent 5-HT1A receptor mRNA expression within some of these same areas, with bLRs having greater 5-HT1A, but not 5-HT1B, receptor mRNA levels in the septum, hippocampus and cingulate cortex. These findings, together with our earlier work, suggest that bHRs exhibit altered serotonergic functioning within select circuits during an aggressive encounter. PMID:21974861

  5. Increased novelty seeking and decreased harm avoidance in rats showing Type 2-like behaviour following basal forebrain neuronal loss.

    PubMed

    Johansson, A K; Hansen, S

    2001-01-01

    Previous research has shown that excitotoxic lesions of the septum, ventral striatum and adjacent areas increase alcohol intake and defensive aggression in the rat. This behavioural constellation resembles that observed in early-onset Type 2 alcoholism. Due to the fact that the prototypical Type 2 alcoholic scores high on novelty seeking and low on harm avoidance, we studied these temperamental traits in rats with basal forebrain lesions. In comparison with controls, such rats showed more exploration (nose-poking) of a hole-board (indicating increased novelty seeking) and less risk assessment behaviour (stretched attend posturing) in an unfamiliar arena (indicating reduced harm avoidance). In both tests the experimental rats showed signs of motor restlessness. The results obtained indicate that basal forebrain neuronal loss may be associated with an enhanced exploratory responsiveness to novel stimuli together with a relative freedom of anticipatory anxiety. PMID:11704616

  6. Neonatal Subventricular Zone Electroporation

    PubMed Central

    Feliciano, David M.; Lafourcade, Carlos A.; Bordey, Angélique

    2013-01-01

    Neural stem cells (NSCs) line the postnatal lateral ventricles and give rise to multiple cell types which include neurons, astrocytes, and ependymal cells1. Understanding the molecular pathways responsible for NSC self-renewal, commitment, and differentiation is critical for harnessing their unique potential to repair the brain and better understand central nervous system disorders. Previous methods for the manipulation of mammalian systems required the time consuming and expensive endeavor of genetic engineering at the whole animal level2. Thus, the vast majority of studies have explored the functions of NSC molecules in vitro or in invertebrates. Here, we demonstrate the simple and rapid technique to manipulate neonatal NPCs that is referred to as neonatal subventricular zone (SVZ) electroporation. Similar techniques were developed a decade ago to study embryonic NSCs and have aided studies on cortical development3,4 . More recently this was applied to study the postnatal rodent forebrain5-7. This technique results in robust labeling of SVZ NSCs and their progeny. Thus, postnatal SVZ electroporation provides a cost and time effective alternative for mammalian NSC genetic engineering. PMID:23426329

  7. Free mitochondria and synaptosomes from single rat forebrain. A comparison between two known subfractionation techniques.

    PubMed

    Dagani, F; Zanada, F; Marzatico, F; Benzi, G

    1985-08-01

    Two published subcellular subfractionation techniques employing Ficoll-sucrose or sucrose-density gradient centrifugation, respectively, are evaluated for their capacity to yield fractions containing free mitochondria and synaptosomes from a single rat forebrain. The enzymes lactate dehydrogenase, acetylcholinesterase, NAD(P)H-cytochrome c reductase, and citrate synthase, markers of different subcellular components, were used to assess the purity and integrity of the fractions. Judged by the distribution of these specific enzymatic markers, the free mitochondria obtained by the Ficoll-sucrose gradient technique were less contaminated by synaptosomes and had greater biochemical integrity than those obtained by the sucrose-gradient technique. By contrast, the synaptosomes obtained by the Ficoll-sucrose gradient technique resulted in more contamination by microsomes than those prepared in a sucrose gradient. PMID:3925087

  8. Severe instead of mild hyperglycemia inhibits neurogenesis in the subventricular zone of adult rats after transient focal cerebral ischemia.

    PubMed

    Tan, S; Zhi, P K; Luo, Z K; Shi, J

    2015-09-10

    Accumulated evidence suggests that enhanced neurogenesis stimulated by ischemic injury contributes to stroke outcome. However, it is unclear whether hyperglycemia, which is frequently tested positive in patients with acute ischemic stroke, influences stroke-induced neurogenesis. The aim of the present study is to examine the effect of hyperglycemia on stroke-induced neurogenesis in a rat model of transient focal cerebral ischemia. For this purpose, adult male Sprague-Dawley rats (220-250 g) were subjected to 90 min of middle cerebral artery occlusion (MCAO). Glucose was administered during ischemia to produce target blood levels ranging from 4.83 ± 0.94 mM (normoglycemia) to 20.76 ± 1.56 mM. To label proliferating cells in ischemic ipsilateral subventricular zone (SVZ) of lateral ventricles, 5'-bromo-2'-deoxyuridine (BrdU) was injected 24h after MCAO. Brains were harvested 2h post-BrdU to evaluate the effects of hyperglycemia on infarct volume and SVZ cell proliferation. Rats that were severely hyperglycemic (19.26 ± 1.48 mM to 20.76 ± 1.56 mM) during ischemia had 24.26% increase in infarct volume (P<0.05) and more serious neurological function deficits (P<0.05). The severe hyperglycemic rats also showed dramatically decreased proliferation of neural stem/progenitor cells (NSPCs) (P<0.05) and down-regulation of the phosphorylation of cyclic-AMP response element-binding protein (pCREB) (P<0.05)and brain-derived neurotrophic factor (BDNF) (P<0.05) in ipsilateral SVZ. But the above-mentioned detrimental effects were not observed in rats that were rendered with mild hyperglycemia (9.43 ± 1.39-10.13 ± 1.24 mM). Our findings indicate that severe instead of mild hyperglycemia exacerbates ischemic injury and inhibits stroke-induced SVZ neurogenesis by a mechanism involving suppression of CREB and BDNF signaling. PMID:26126927

  9. Galanin antagonizes acetylcholine on a memory task in basal forebrain-lesioned rats.

    PubMed Central

    Mastropaolo, J; Nadi, N S; Ostrowski, N L; Crawley, J N

    1988-01-01

    Galanin coexists with acetylcholine in medial septal neurons projecting to the ventral hippocampus, a projection thought to modulate memory functions. Neurochemical lesions of the nucleus basalis-medial septal area in rats impaired choice accuracy on a delayed alternation t-maze task. Acetylcholine (7.5 or 10 micrograms intraventricularly or 1 micrograms micro-injected into the ventral hippocampus) significantly improved performance in the lesioned rats. Atropine (5 mg/kg intraperitoneally or 10 micrograms intraventricularly), but not mecamylamine (3 mg/kg intraperitoneally or 20 micrograms intraventricularly), blocked this action of acetylcholine, suggesting involvement of a muscarinic receptor. Galanin (100-500 ng intraventricularly or 200 ng into the ventral hippocampus) attenuated the ability of acetylcholine to reverse the deficit in working memory in the lesioned rats. The antagonistic interaction between galanin and acetylcholine suggests that endogenous galanin may inhibit cholinergic function in memory processes, particularly in pathologies such as Alzheimer disease that involve degeneration of basal forebrain neurons. Images PMID:2462255

  10. Preischemic Administration of Sevoflurane Does not Exert Dose-dependent Effects on the Outcome of Severe Forebrain Ischemia in Rats.

    PubMed

    Miura, Yoshihide; Kanazawa, Kaoru; Nasu, Ikuko

    2015-07-01

    We previously showed that preischemic administration of high-dose isoflurane worsened the outcome from severe forebrain ischemia in rats. Conversely, high doses of sevoflurane have been reported to improve the outcome from forebrain ischemia when the insult is moderate. To clarify the dose-dependent effects of sevoflurane on severe forebrain ischemia, we performed an outcome study using an identical protocol to that in our previous study with isoflurane. Fasting male Sprague-Dawley rats underwent surgical preparation for forebrain ischemia under halothane anesthesia. Anesthesia was changed to fentanyl/nitrous oxide to eliminate the halothane, after which 30 minutes of 0.5, 1.0, 1.5, 2.0, or 2.5 minimum alveolar concentration sevoflurane was administered. Ten minutes of ischemia was induced by bilateral carotid occlusion plus systemic hypotension, in which cessation of electroencephalographic activity was confirmed. Sevoflurane was discontinued and anesthesia continued with fentanyl/nitrous oxide for an additional 100 minutes. Outcome evaluation at 5 days postischemia included seizure incidence, mortality rate, neuromotor score, and histologic injuries to the cerebral cortex and hippocampal CA1 and CA3. Different doses of sevoflurane did not statistically affect seizure incidence (10.0% to 18.2%), mortality rate (20.0% to 46.7%), cortical damage (mild to moderate degree), or hippocampal CA1 damage (93.7% to 96.7% neuronal necrosis) or CA3 damage (36.3% to 41.7%). Dose-dependent effects of sevoflurane were not observed for any of the outcome variables assessed in this rat model of severe forebrain ischemia. PMID:25390656

  11. Effects of Estrogen on Platelet Reactivity After Transient Forebrain Ischemia in Rats

    PubMed Central

    Littleton-Kearney, Marguerite T.; Gaines, Jessica M.; Callahan, Kevin P.; Murphy, Stephanie J.; Hurn, Patricia D.

    2009-01-01

    Estrogen’s prothrombotic effects are of increasing concern, particularly in stroke risk and recovery. Using an ischemic rodent model, the authors sought to determine (a) if estrogen replacement increases post-ischemic platelet reactivity, (b) if changes in estrogen status alter intraplatelet endothelial nitric oxide synthase (eNOS) synthesis, and (c) if estrogen-mediated effects on platelets alter cerebral blood flow during reperfusion. Intact (I), ovariectomized (OVX), and OVX + 17β-estradiol (E50) rats were subjected to 30 min of forebrain ischemia and 60 min of reperfusion. Using the platelet activation marker P-selectin, postischemic platelet reactivity was quantified by flow cytometry. In a separate cohort (I, OVX, E50), the authors quantified platelet eNOS by Western blot. Another cohort (OVX, E50) was subjected to ischemia/reperfusion, and cerebral blood flow was determined using the iodoantipyrine technique. Collagen-stimulated platelet P-selectin expression was increased in the OVX rats at 60 min of reperfusion, and this effect was reversed by estrogen treatment. No differences in platelet eNOS expression were detected among groups. Cerebral blood flow at 60 min reperfusion was comparable between the OVX and the E50 rats. The authors conclude that during reperfusion, estrogen deficiency increases postischemic platelet sensitivity to stimuli in estrogen-deficient rats. Estrogen treatment mitigates effects of estrogen loss on platelets, but this early effect is apparently not caused by intraplatelet eNOS depression. Neither estrogen deficiency nor estrogen treatment changes early postischemic regional brain blood flow. In this rodent global cerebral ischemic model, physiologic doses of estrogen are not deleterious to platelet reactivity and may initially reduce postischemic platelet reactivity. PMID:16267375

  12. Hypocretin/orexin antagonism enhances sleep-related adenosine and GABA neurotransmission in rat basal forebrain.

    PubMed

    Vazquez-DeRose, Jacqueline; Schwartz, Michael D; Nguyen, Alexander T; Warrier, Deepti R; Gulati, Srishti; Mathew, Thomas K; Neylan, Thomas C; Kilduff, Thomas S

    2016-03-01

    Hypocretin/orexin (HCRT) neurons provide excitatory input to wake-promoting brain regions including the basal forebrain (BF). The dual HCRT receptor antagonist almorexant (ALM) decreases waking and increases sleep. We hypothesized that HCRT antagonists induce sleep, in part, through disfacilitation of BF neurons; consequently, ALM should have reduced efficacy in BF-lesioned (BFx) animals. To test this hypothesis, rats were given bilateral IgG-192-saporin injections, which predominantly targets cholinergic BF neurons. BFx and intact rats were then given oral ALM, the benzodiazepine agonist zolpidem (ZOL) or vehicle (VEH) at lights-out. ALM was less effective than ZOL at inducing sleep in BFx rats compared to controls. BF adenosine (ADO), γ-amino-butyric acid (GABA), and glutamate levels were then determined via microdialysis from intact, freely behaving rats following oral ALM, ZOL or VEH. ALM increased BF ADO and GABA levels during waking and mixed vigilance states, and preserved sleep-associated increases in GABA under low and high sleep pressure conditions. ALM infusion into the BF also enhanced cortical ADO release, demonstrating that HCRT input is critical for ADO signaling in the BF. In contrast, oral ZOL and BF-infused ZOL had no effect on ADO levels in either BF or cortex. ALM increased BF ADO (an endogenous sleep-promoting substance) and GABA (which is increased during normal sleep), and required an intact BF for maximal efficacy, whereas ZOL blocked sleep-associated BF GABA release, and required no functional contribution from the BF to induce sleep. ALM thus induces sleep by facilitating the neural mechanisms underlying the normal transition to sleep. PMID:25431268

  13. Distribution of neurotensin/neuromedin N mRNA in rat forebrain: Unexpected abundance in hippocampus and subiculum

    SciTech Connect

    Alexander, M.J.; Miller, M.A.; Dorsa, D.M.; Bullock, B.P.; Helloni, R.H. Jr.; Dobner, P.R.; Leeman, S.E. )

    1989-07-01

    The authors have used in situ hybridization to determine the regional distribution of mRNA encoding the neurotensin/neuromedin N (NT/N) precursor in the forebrain of the adult male rat. Cells containing NT/N mRNA are widely distributed in the forebrain. These areas include the septum, bed nucleus of the stria terminalis, preoptic area, hypothalamus, amygdala, accumbens nucleus, caudate-putamen, and piriform and retrosplenial cortex. In general, the regional distribution of NT/N mRNA corresponds to the previously determined distribution of neurotensin-immunoreactive cell bodies; however, several notable exceptions were observed. The most striking difference occurs specifically in the CA1 region of the hippocampus, where intense labeling is associated with the pyramidal cell layer despite the reported absence of neurotensin-immunoreactive cells in this region. A second major discrepancy between NT/N mRNA abundance and neurotensin-immunoreactivity occurs in the intensely labeled subiculum, a region that contains only scattered neurotensin-immunoreactive cells in the adult. These results suggest that, in specific regions of the forebrain, NT/N precursor is processed to yield products other than neurotensin. In addition, these results provide an anatomical basis for studying the physiological regulation of NT/N mRNA levels in the forebrain.

  14. Low dose naltrexone administration in morphine dependent rats attenuates withdrawal-induced norepinephrine efflux in forebrain

    PubMed Central

    Van Bockstaele, Elisabeth J.; Qian, Yaping; Sterling, Robert C.; Page, Michelle E.

    2009-01-01

    The administration of low dose opioid antagonists has been explored as a potential means of detoxification in opiate dependence. Previous results from our laboratory have shown that concurrent administration of low dose naltrexone in the drinking water of rats implanted with subcutaneous morphine pellets attenuates behavioral and biochemical signs of withdrawal in brainstem noradrenergic nuclei. Noradrenergic projections originating from the nucleus tractus solitarius (NTS) and the locus coeruleus (LC) have previously been shown to be important neural substrates involved in the somatic expression of opiate withdrawal. The hypothesis that low dose naltrexone treatment attenuates noradrenergic hyperactivity typically associated with opiate withdrawal was examined in the present study by assessing norepinephrine tissue content and norepinephrine efflux using in vivo microdialysis coupled to high performance liquid chromatography (HPLC) with electrochemical detection (ED). The frontal cortex (FC), amygdala, bed nucleus of the stria terminalis (BNST) and cerebellum were analyzed for tissue content of norepinephrine following withdrawal in morphine dependent rats. Naltrexone precipitated withdrawal elicited a significant decrease in tissue content of norepinephrine in the BNST and amygdala. This decrease was significantly attenuated in the BNST of rats that received low dose naltrexone pretreatment compared to controls. No significant difference was observed in the other brain regions examined. In a separate group of rats, norepinephrine efflux was assessed with in vivo microdialysis in the BNST or the FC of morphine dependent rats or placebo treated rats subjected to naltrexone-precipitated withdrawal that received either naltrexone in their drinking water (5 mg/L) or unadulterated water. Following baseline dialysate collection, withdrawal was precipitated by injection of naltrexone and sample collection continued for an additional four hours. At the end of the

  15. Antagonist of the amylin receptor blocks beta-amyloid toxicity in rat cholinergic basal forebrain neurons.

    PubMed

    Jhamandas, Jack H; MacTavish, David

    2004-06-16

    Salvage of cholinergic neurons in the brain through a blockade of the neurotoxic effects of amyloidbeta protein (Abeta) is one of the major, but still elusive, therapeutic goals of current research in Alzheimer's disease (AD). To date, no receptor has been unequivocally identified for Abeta. Human amylin, which acts via a receptor composed of the calcitonin receptor-like receptor and a receptor-associated membrane protein, possesses amyloidogenic properties and has a profile of neurotoxicity that is strikingly similar to Abeta. In this study, using primary cultures of rat cholinergic basal forebrain neurons, we show that acetyl-[Asn30, Tyr32] sCT(8-37) (AC187), an amylin receptor antagonist, blocks Abeta-induced neurotoxicity. Treatment of cultures with AC187 before exposure to Abeta results in significantly improved neuronal survival as judged by MTT and live-dead cell assays. Quantitative measures of Abeta-evoked apoptotic cell death, using Hoechst and phosphotidylserine staining, confirm neuroprotective effects of AC187. We also demonstrate that AC187 attenuates the activation of initiator and effector caspases that mediate Abeta-induced apoptotic cell death. These data are the first to show that expression of Abeta toxicity may occur through the amylin receptor and suggest a novel therapeutic target for the treatment of AD. PMID:15201330

  16. Upregulation of metabotropic glutamate receptor 8 mRNA expression in the rat forebrain after repeated amphetamine administration

    PubMed Central

    Parelkar, Nikhil K; Wang, John Q.

    2008-01-01

    Metabotropic glutamate receptors (mGluRs) are G-protein-coupled receptors and are densely expressed in the forebrain of adult rats. Accumulative evidence suggests a critical role of mGluRs in the regulation of normal physiological activity of neurons and pathogenesis of mental illnesses such as schizophrenia, depression, and substance addiction. In this study, we investigated alterations in mGluR8 subtype mRNA expression in the rat forebrain in response to repeated intraperitoneal administration of amphetamine (twice daily for 12 days, 5 mg/kg per injection) using quantitative in situ hybridization. We found that mGluR8 mRNA levels were profoundly increased in the dorsal (caudate putamen) and ventral (nucleus accumbens) striatum 1 day after the discontinuation of amphetamine treatments. Such increases were sustained up to 21 days of withdrawal. Increases in mGluR8 mRNAs were also found in the cerebral cortex, including the cingulate and sensory cortex but not the piriform cortex, at 1 and 21 days. These data demonstrate a positive response of mGluR8 in mRNA abundance in most forebrain regions to repeated stimulant exposure. PMID:18255232

  17. Loss of neurons in the rat basal forebrain cholinergic projection system after prolonged intake of ethanol.

    PubMed

    Arendt, T; Henning, D; Gray, J A; Marchbanks, R

    1988-10-01

    A reduction in the number of acetylcholinesterase (AChE)-positive neurons in the basal nucleus of Meynert complex (NbM, Ch 1 to Ch4) to 83% of control values was observed in rat after ethanol intake (20% v/v) for 12 weeks. Activity of choline acetyltransferase (ChAT) and AChE in the basal forebrain was simultaneously reduced to 74% and 81% and content of acetylcholine (ACh) to 56% of control values respectively. Neuronal loss showed a gradient over the rostro-caudal extension of the cholinergic projection system being most pronounced in the septal-diagonal band area and reaching 27% in the medial septum (Ch1). Number of AChE-positive neurons was insignificantly reduced in the pedunculopontine nucleus (Ch5) and unchanged in the laterodorsal tegmental gray of the periventricular area (Ch6). ACh content and activity of AChE was significantly reduced in target areas of the NbM such as cortex, hippocampus and amygdala, but changes were less pronounced than in the basal nucleus. The results indicate a neurotoxic effect of prolonged intake of ethanol on cholinergic neurons in the NbM leading to a partial cholinergic denervation of cortex, hippocampus and amygdala. Chronic intake of ethanol in rat is suggested to represent an animal model suitable to test the cholinergic hypothesis of geriatric memory dysfunction and to develop strategies for an amelioration of the impairment in memory and cognitive function in dementing disorders associated with a degeneration in the NbM such as postalcoholic dementia and Alzheimer's disease. PMID:2850095

  18. Astaxanthin limits fish oil-related oxidative insult in the anterior forebrain of Wistar rats: putative anxiolytic effects?

    PubMed

    Mattei, Rita; Polotow, Tatiana G; Vardaris, Cristina V; Guerra, Beatriz A; Leite, José Roberto; Otton, Rosemari; Barros, Marcelo P

    2011-09-01

    The habitual consumption of marine fish is largely associated to human mental health. Fish oil is particularly rich in n-3 polyunsaturated fatty acids that are known to play a role in several neuronal and cognitive functions. In parallel, the orange-pinkish carotenoid astaxanthin (ASTA) is found in salmon and displays important antioxidant and anti-inflammatory properties. Many neuronal dysfunctions and anomalous psychotic behavior (such as anxiety, depression, etc.) have been strongly related to the higher sensitivity of cathecolaminergic brain regions to oxidative stress. Thus, the aim of this work was to study the combined effect of ASTA and fish oil on the redox status in plasma and in the monoaminergic-rich anterior forebrain region of Wistar rats with possible correlations with the anxiolytic behavior. Upon fish oil supplementation, the downregulation of superoxide dismutase and catalase activities combined to increased "free" iron content resulted in higher levels of lipid and protein oxidation in the anterior forebrain of animals. Such harmful oxidative modifications were hindered by concomitant supplementation with ASTA despite ASTA-related antioxidant protection was mainly observed in plasma. Although it is clear that ASTA properly crosses the brain-blood barrier, our data also address a possible indirect role of ASTA in restoring basal oxidative conditions in anterior forebrain of animals: by improving GSH-based antioxidant capacity of plasma. Preliminary anxiolytic tests performed in the elevated plus maze are in alignment with our biochemical observations. PMID:21619892

  19. Protracted Maturation of Forebrain Afferent Connections of the Ventral Tegmental Area in the Rat

    PubMed Central

    Yetnikoff, Leora; Reichard, Rhett A.; Schwartz, Zachary M.; Parsely, Kenneth P.; Zahm, Daniel S.

    2014-01-01

    The mesocorticolimbic dopamine system has long attracted the interest of researchers concerned with the unique gamut of behavioral and mental health vulnerabilities associated with adolescence. Accordingly, the development of the mesocorticolimbic system has been studied extensively, but almost exclusively with regard to dopaminergic output, particularly in the nucleus accumbens and medial prefrontal cortex. To the contrary, the ontogeny of inputs to the ventral tegmental area (VTA), the source of mesocorticolimbic dopamine, has been neglected. This is not a trivial oversight, as the activity of VTA neurons, which reflects their capacity to transmit information about salient events, is sensitively modulated by inputs. Here, we assessed the development of VTA afferent connections using the β subunit of cholera toxin (Ctβ) as a retrograde axonal tracer in adolescent (postnatal day 39) and early adult (8–9-week-old) rats. After intra-VTA injections of Ctβ, adolescent and early adult animals exhibited qualitatively similar distributions of retrogradely labeled neurons in the sense that VTA-projecting neurons were present at all of the same rostrocaudal levels in all of the same structures in both age groups. However, quantitation of retrogradely labeled neurons revealed that adolescent brains, compared with early adult brains, had significantly fewer VTA-projecting neurons preferentially within an interconnected network of cortical and striatopallidal forebrain structures. These findings provide a novel perspective on the development of the mesocorticolimbic dopamine system and may have important implications for age-dependent specificity in the function of this system, particularly with regard to adolescent impulsivity and mental health vulnerabilities. PMID:23983069

  20. Mitochondria accumulate Ca2+ following intense glutamate stimulation of cultured rat forebrain neurones.

    PubMed Central

    White, R J; Reynolds, I J

    1997-01-01

    1. In cultures of rat forebrain neurones, mitochondria buffer glutamate-induced, NMDA receptor-mediated Ca2+ influx. Here, we have used the fluorescent calcium indicator, indo-1 AM to record [Ca2+]i from single cells. We varied either the glutamate concentration or the duration of exposure to investigate the cellular mechanisms recruited to buffer [Ca2+]i within different stimulation protocols. 2. For a 15 s stimulus, the recovery time doubled as the glutamate concentration was raised from 3 to 300 microM. Changing the duration of exposure from 15 s to 5 min increased the recovery time tenfold even when the glutamate concentration was held at 3 microM. 3. We used a selective inhibitor of the mitochondrial Na(+)-Ca2+ exchange, CGP-37157. When applied immediately after a 15 s, 100 microM glutamate challenge, CGP-37157 consistently caused a rapid fall in [Ca2+]i followed by a slow rise after the drug was washed out. A similar pattern was seen with the 5 min, 3 microM glutamate stimulus. The effects of CGP-37157 are consistent with the release of substantial mitochondrial Ca2+ stores during recovery from an intense glutamate stimulus. 4. These studies suggest that mitochondria become progressively more important for buffering glutamate-induced Ca2+ loads as the stimulus intensity increases. The recovery of [Ca2+]i to baseline following glutamate removal is critically regulated by the release of Ca2+ from mitochondrial stores via mitochondrial Na(+)-Ca2+ exchange. The data highlight a previously under-appreciated role for [Na+]i in the regulation of [Ca2+]i in central neurones. PMID:9023766

  1. Topographic organization of the basal forebrain projections to the perirhinal, postrhinal, and entorhinal cortex in rats.

    PubMed

    Kondo, Hideki; Zaborszky, Laszlo

    2016-08-15

    Previous studies have shown that the basal forebrain (BF) modulates cortical activation via its projections to the entire cortical mantle. However, the organization of these projections is only partially understood or, for certain areas, unknown. In this study, we examined the topographic organization of cholinergic and noncholinergic projections from the BF to the perirhinal, postrhinal, and entorhinal cortex by using retrograde tracing combined with choline acetyltransferase (ChAT) immunohistochemistry in rats. The perirhinal and postrhinal cortex receives major cholinergic and noncholinergic input from the caudal BF, including the caudal globus pallidus and substantia innominata and moderate input from the horizontal limb of the diagonal band, whereas the entorhinal cortex receives major input from the rostral BF, including the medial septum and the vertical and horizontal limbs of the diagonal band. In the perirhinal cases, cholinergic projection neurons are distributed more caudally in the caudal globus pallidus than noncholinergic projection neurons. Compared with the perirhinal cases, the distribution of cholinergic and noncholinergic neurons projecting to the postrhinal cortex shifts slightly caudally in the caudal globus pallidus. The distribution of cholinergic and noncholinergic neurons projecting to the lateral entorhinal cortex extends more caudally in the BF than to the medial entorhinal cortex. The ratio of ChAT-positive projection neurons to total projection neurons is higher in the perirhinal/postrhinal cases (26-48%) than in the entorhinal cases (13-30%). These results indicate that the organization of cholinergic and noncholinergic projections from the BF to the parahippocampal cortex is more complex than previously described. J. Comp. Neurol. 524:2503-2515, 2016. © 2016 Wiley Periodicals, Inc. PMID:26780730

  2. Pain sensitivity following loss of cholinergic basal forebrain (CBF) neurons in the rat.

    PubMed

    Vierck, C J; Yezierski, R P; Wiley, R G

    2016-04-01

    Flexion/withdrawal reflexes are attenuated by spinal, intracerebroventricular (ICV) and systemic delivery of cholinergic agonists. In contrast, some affective reactions to pain are suppressed by systemic cholinergic antagonism. Attention to aversive stimulation can be impaired, as is classical conditioning of fear and anxiety to aversive stimuli and psychological activation of stress reactions that exacerbate pain. Thus, in contrast to the suppressive effects of cholinergic agonism on reflexes, pain sensitivity and affective reactions to pain could be attenuated by reduced cerebral cholinergic activation. This possibility was evaluated in the present study, using an operant test of escape from nociceptive thermal stimulation (10 °C and 44.5 °C) before and after destruction of basal forebrain cholinergic neurons. ICV injection of 192 IgG-saporin produced widespread loss of basal forebrain cholinergic innervation of the cerebral cortex and hippocampus. Post-injection, escape from thermal stimulation was decreased with no indication of recovery for upto 19 weeks. Also, the normal hyperalgesic effect of sound stress was absent after ICV 192-sap. Effects of cerebral cholinergic denervation or stress on nociceptive licking and guarding reflexes were not consistent with the effects on operant escape, highlighting the importance of evaluating pain sensitivity of laboratory animals with an operant behavioral test. These results reveal that basal forebrain cholinergic transmission participates in the cerebral processing of pain, which may be relevant to the pain sensitivity of patients with Alzheimer's disease who have prominent degeneration of basal forebrain cholinergic neurons. PMID:26812034

  3. Alterations in nitric oxide synthase-expressing neurons in the forebrain regions of rats after developmental exposure to organophosphates.

    PubMed

    Naseh, Maryam; Vatanparast, Jafar; Baniasadi, Mansoureh; Hamidi, Gholam Ali

    2013-01-01

    Several mechanisms have been addressed as contributors to the long lasting behavioral deficits after developmental exposure to organophosphate (OP) compounds. Here, the effects of developmental exposure to two common OP insecticides, chlorpyrifos (CPF) and diazinon (DZN), on nitric oxide synthase (NOS)-expressing neurons in the rat forebrain are reported. A daily dose of 1mg/kg of either CPF or DZN was administered to rats during gestational days 15-18 or postnatal days (PND) 1-4. We then assessed NADPH-diaphorase and neuronal NOS (nNOS) immunohistochemistry in forebrain sections on different postnatal days. Prenatal exposure to CPF and DZN induced a transient reduction of NADPH-d(+)/nNOS-immunoreactive (IR) neurons in most cortical regions on PND 4 but exceptionally increased them in the entorhinal/piriform cortex. On PND 15, NADPH-d(+)/nNOS-IR neurons showed morphological abnormalities within entorhinal/piriform cortex of the rats that gestationally exposed to CPF. Postnatal exposure to CPF and DZN did not induce widespread effects on the number of NADPH-d(+)/nNOS-IR neurons on PNDs 7 and 15 but significantly reduced them in most cortical regions and hippocampal subfields on PND 60. The OPs affected NADPH-d(+)/nNOS-IR neurons in a sex independent manner and apparently spared them in the striatum. While the NADPH-d reactivity of microvessels was normally diminished by age, OP treated rats evidently preserved the NADPH-d reactivity of microvessels in the cerebral cortex and hippocampus. The effects of OPs on NADPH-d(+)/nNOS-IR neurons may contribute to the long-lasting behavioral outcomes and expand the neurotransmitter system that need to be considered in OP neurotoxicity evaluations. PMID:23416429

  4. Transplantation of subventricular zone neural precursors induces an endogenous precursor cell response in a rat model of Parkinson’s disease

    PubMed Central

    Madhavan, Lalitha; Daley, Brian F; Paumier, Katrina L; Collier, Timothy J

    2009-01-01

    Realistically, future stem cell therapies for neurological conditions including Parkinson’s disease (PD) will most probably entail combination treatment strategies, involving both the stimulation of endogenous cells and transplantation. Therefore, this study investigates these two modes of neural precursor cell (NPC) therapy in concert in order to determine their interrelationships in a rat PD model. Human placental alkaline phosphatase (hPAP) labeled NPCs were transplanted unilaterally into host rats which were subsequently infused ipsilaterally with 6-hydroxydopamine (6-OHDA). The reaction of host NPCs to the transplantation and 6-OHDA was tracked by bromodeoxyuridine labeling. Two weeks after transplantation, in animals transplanted with NPCs, we found evidence of elevated host subventricular zone NPC proliferation, neurogenesis, and migration to the graft site. In these animals, we also observed a significant preservation of striatal tyrosine hydroxylase (TH) expression and substantia nigra TH cell number. We have seen no evidence that neuroprotection is a product of DA neuron replacement by NPC-derived cells. Rather, the NPCs expressed glial cell line-derived neurotrophic factor (GDNF), sonic hedgehog (Shh) and stromal cell derived factor 1 alpha (SDF1α) providing a molecular basis for the observed neuroprotection and endogenous NPC response to transplantation. In summary, our data suggests plausible synergy between exogenous and endogenous NPC actions, and that NPC implantation before the 6-OHDA insult can create a host microenvironment conducive to stimulation of endogenous NPCs, and protection of mature nigral neurons. PMID:19399899

  5. A Novel Biopsy Method for Isolating Neural Stem Cells from the Subventricular Zone of the Adult Rat Brain for Autologous Transplantation in CNS Injuries.

    PubMed

    Aligholi, Hadi; Hassanzadeh, Gholamreza; Gorji, Ali; Azari, Hassan

    2016-01-01

    Despite all attempts the problem of regeneration in damaged central nervous system (CNS) has remained challenging due to its cellular complexity and highly organized and sophisticated connections. In this regard, stem cell therapy might serve as a viable therapeutic approach aiming either to support the damaged tissue and hence to reduce the subsequent neurological dysfunctions and impairments or to replace the lost cells and re-establish damaged circuitries. Adult neural stem/progenitor cells (NS/PCs) are one of the outstanding cell sources that can be isolated from the subventricular zone (SVZ) of the lateral ventricles. These cells can differentiate into neurons, astrocytes, and oligodendrocytes. Implanting autologous NS/PCs will greatly benefit the patients by avoiding immune rejection after implantation, better survival, and integration with the host tissue. Developing safe and efficient methods in small animal models will provide us with the opportunity to optimize procedures required to achieve successful human autologous NS/PC transplantation in near future. In this chapter, a highly controlled and safe biopsy method for harvesting stem cell containing tissue from the SVZ of adult rat brain is introduced. Then, isolation and expansion of NS/PCs from harvested specimen as well as the techniques to verify proliferation and differentiation capacity of the resulting NS/PCs are discussed. Finally, a method for assessing the biopsy lesion volume in the brain is described. This safe biopsy method in rat provides a unique tool to study autologous NS/PC transplantation in different CNS injury models. PMID:27604747

  6. Attenuation of the blood flow response to physostigmine in the rat cortex deafferented from the basal forebrain.

    PubMed

    Peruzzi, Philippe; Von Euw, Dominique; Corrèze, Jean-Loup; Lacombe, Pierre

    2007-04-01

    Previous functional investigations in rats failed to demonstrate that the classical cholinesterase inhibitor, physostigmine, can compensate for cortical cholinergic deficit induced by deafferentation from the nucleus basalis magnocellularis (NBM). As these studies were carried out shortly after NBM lesion (1-2 weeks), we sought to determine whether compensatory effects of physostigmine would appear at a longer postlesion time (3-5 weeks). Cerebral blood flow was used as a quantitative measure of brain function. At 3-5 weeks after unilateral NBM lesion, interhemispheric comparisons in resting conditions showed that the cortical cholinergic deficit was still present and that blood flow was lower in cortical areas on the lesion side, similarly to what was observed after 1-2 weeks, while basal blood flow in intact hemispheres remained unchanged. In contrast, under physostigmine, blood flow became significantly lower in deafferented cortical areas at 3-5 weeks postlesion time, whereas there were no significant interhemispheric differences in the short term. Comparisons with saline-infused rats showed reduced blood flow responses to physostigmine in forebrain regions, e.g. in the parietal cortex from 83% to 25% at 1-2 and 3-5 weeks postlesion, respectively. These changes cannot be ascribed to a global loss of reactivity, since responses in brainstem regions (medulla, cerebellum) remained unchanged statistically. The results demonstrate a reduced responsiveness to physostigmine at the longer postlesion time, and support the existence of a cholinosensitive mechanism antagonizing NBM influence. This mechanism may limit the activating effects of cholinergic agonists in the forebrain after NBM deafferentation. PMID:17303509

  7. Neuroprotective effects of selective β-1 adrenoceptor antagonists, landiolol and esmolol, on transient forebrain ischemia in rats; a dose-response study.

    PubMed

    Goyagi, Toru; Horiguchi, Takashi; Nishikawa, Toshiaki; Tobe, Yoshitsugu; Masaki, Yoko

    2012-06-21

    Although selective beta-1 adrenoceptor antagonists are known to provide neuroprotective effects after brain ischemia, dose-response relationships of their neuroprotective effects have not been examined. The present study was conducted to evaluate whether the degree of brain protection against transient forebrain ischemia would be influenced by different doses of selective beta-1 adrenoceptor antagonists, esmolol and landiolol, in rats. Adult male S.D. rats received intravenous infusion of saline 0.5 ml/h, esmolol 20, 200, 2,000 μg/kg/min, or landiolol 5, 50, 500 μg/kg/min. Infusion was initiated 30 min prior to ischemia and continued for 24h. Ten-minute forebrain ischemia was induced by hemorrhagic hypotension and occlusion of the bilateral carotid arteries. Neurological and histological examinations were performed. Neurological deficit scores at 1, 4 and 7 days were lower, and the number of intact neurons in CA1 hippocampal region was larger in the rats treated with esmolol and landiolol after ischemia, compared with saline-treated rats (P<0.05), whereas no difference was found among different doses of esmolol and landiolol. These results suggested that selective beta-1 adrenoceptor antagonists improved neurological and histological outcomes following forebrain ischemia in rats, irrespective of their doses. PMID:22583856

  8. Castration reversibly alters levels of cholecystokinin immunoreactivity within cells of three interconnected sexually dimorphic forebrain nuclei in the rat.

    PubMed Central

    Simerly, R B; Swanson, L W

    1987-01-01

    Three sexually dimorphic cell groups in the forebrain of the rat--the central part of the medial preoptic nucleus, the encapsulated part of the bed nucleus of the stria terminalis, and the posterodorsal part of the medial nucleus of the amygdala--are larger in males, contain a high density of gonadal-steroid-concentrating cells, and are thought to play important roles in the control of reproductive behavior and physiology. Since each of these regions contains a large number of cholecystokinin-immunoreactive cells, we used an indirect immunohistochemical method to examine the possibility that levels of this peptide are modulated by circulating gonadal steroids in adult male rats. Rats were castrated at 60 days of age, and one group each was pretreated with colchicine and then killed 3, 7, and 14 days after gonadectomy. Castration clearly decreased CCK immunoreactivity within cells of each region, with the most dramatic effects occurring 7 and 14 days after gonadectomy, and these effects were reversed by treatment with testosterone over a 14-day period. The results suggest that CCK levels within individual cells in each of the interconnected sexually dimorphic nuclei examined here are regulated by circulating gonadal steroids and may be related to the hormonal modulation of reproductive functions thought to be mediated by these cell groups. Images PMID:3550806

  9. Postnatal subventricular zone progenitors give rise not only to granular and periglomerular interneurons but also to interneurons in the external plexiform layer of the rat olfactory bulb.

    PubMed

    Yang, Zhengang

    2008-01-10

    Interneurons in the granule cell layer (GCL) and glomerular layer (GL) of the olfactory bulb (OB) are generated from progenitors in the subventricular zone (SVZ) of the lateral ventricle. However, little is known about the origin of interneurons in the external plexiform layer (EPL) of the OB. On the basis of the concept of corticogenesis, I hypothesized that interneurons in the EPL of the rodent OB also originate in the SVZ. In the present study, replication-incompetent retroviruses encoding a marker gene, human placental alkaline phosphatase (AP), were injected into the lateral ventricles of postnatal day 4 Wistar rats to label dividing cells in the SVZ. Two days after injection, some of the AP-labeled cells had migrated into the OB. Five weeks after injection, AP/NeuN double-labeled cells were found not only in the GCL and GL but also in the EPL of the OB. In the EPL, most AP-labeled cells were calcium-binding protein parvalbumin (PV)-immunoreactive (+) interneurons. A subset of these cells was made up of calcium-binding protein calretinin (CR)(+) interneurons. According to their structural features, AP-labeled cells in the EPL were Van Gehuchten cells, multipolar cells, and superficial short-axon cells. Thus, postnatal SVZ progenitors give rise not only to granular and periglomerular interneurons but also to interneurons in the EPL of the OB. Furthermore, these results suggest that SVZ progenitors give rise to virtually all subpopulations of interneurons in the OB. PMID:18022946

  10. Dose-related gene expression changes in forebrain following acute, low-level chlorpyrifos exposure in neonatal rats

    SciTech Connect

    Ray, Anamika; Liu Jing; Ayoubi, Patricia; Pope, Carey

    2010-10-15

    Chlorpyrifos (CPF) is a widely used organophosphorus insecticide (OP) and putative developmental neurotoxicant in humans. The acute toxicity of CPF is elicited by acetylcholinesterase (AChE) inhibition. We characterized dose-related (0.1, 0.5, 1 and 2 mg/kg) gene expression profiles and changes in cell signaling pathways 24 h following acute CPF exposure in 7-day-old rats. Microarray experiments indicated that approximately 9% of the 44,000 genes were differentially expressed following either one of the four CPF dosages studied (546, 505, 522, and 3,066 genes with 0.1, 0.5, 1.0 and 2.0 mg/kg CPF). Genes were grouped according to dose-related expression patterns using K-means clustering while gene networks and canonical pathways were evaluated using Ingenuity Pathway Analysis (registered) . Twenty clusters were identified and differential expression of selected genes was verified by RT-PCR. The four largest clusters (each containing from 276 to 905 genes) constituted over 50% of all differentially expressed genes and exhibited up-regulation following exposure to the highest dosage (2 mg/kg CPF). The total number of gene networks affected by CPF also rose sharply with the highest dosage of CPF (18, 16, 18 and 50 with 0.1, 0.5, 1 and 2 mg/kg CPF). Forebrain cholinesterase (ChE) activity was significantly reduced (26%) only in the highest dosage group. Based on magnitude of dose-related changes in differentially expressed genes, relative numbers of gene clusters and signaling networks affected, and forebrain ChE inhibition only at 2 mg/kg CPF, we focused subsequent analyses on this treatment group. Six canonical pathways were identified that were significantly affected by 2 mg/kg CPF (MAPK, oxidative stress, NF{Kappa}B, mitochondrial dysfunction, arylhydrocarbon receptor and adrenergic receptor signaling). Evaluation of different cellular functions of the differentially expressed genes suggested changes related to olfactory receptors, cell adhesion/migration, synapse

  11. Roles of forebrain GABA receptors in controlling vasopressin secretion and related phenomena under basal and hyperosmotic circumstances in conscious rats.

    PubMed

    Yamaguchi, Ken'ichi; Yamada, Takaho

    2008-09-01

    Although the anteroventral third ventricular region (AV3V), a forebrain area essential for homeostatic responses, includes receptors for gamma-aminobutyric acid (GABA), the roles of these receptors in controlling vasopressin (AVP) secretion and related phenomena have not been clarified as yet. This study aimed to pursue this problem in conscious rats implanted with indwelling catheters. Cerebral injection sites were determined histologically. Applications of bicuculline, a GABA(A) receptor antagonist, to the AV3V induced prompt and marked augmentations in plasma AVP, osmolality, glucose, arterial pressure and heart rate, without affecting plasma electrolytes. Such phenomena did not occur when phaclofen, a GABA(B) receptor antagonist, was applied to the AV3V. All of the effects of AV3V-administered bicuculline were abolished by preadministration of the GABA(A) receptor agonist muscimol. Preadministration of either MK-801 or NBQX, ionotropic glutamatergic receptor antagonists, was also potent to abolish the AVP response to AV3V bicuculline. When hypertonic saline was infused intravenously, plasma AVP increased progressively, in parallel with rises in plasma osmolality, sodium and arterial pressure. AV3V application of muscimol or baclofen, a GABA(B) receptor agonist, was found to abolish the response of plasma AVP, without inhibiting that of the osmolality or sodium. The response of arterial pressure was also blocked by muscimol treatment, but not by baclofen treatment. Based on these results, we concluded that, under basal conditions, GABA receptors in the AV3V or vicinity may tonically operate to attenuate AVP secretion and cardiovascular functions through mechanisms associated with glutamatergic activity, and that plasma hyperosmolality may cause facilitation of AVP release by decreasing forebrain GABAergic activity. PMID:18639747

  12. Novel AAV-Based Rat Model of Forebrain Synucleinopathy Shows Extensive Pathologies and Progressive Loss of Cholinergic Interneurons

    PubMed Central

    Aldrin-Kirk, Patrick; Davidsson, Marcus; Holmqvist, Staffan; Li, Jia-Yi; Björklund, Tomas

    2014-01-01

    Synucleinopathies, characterized by intracellular aggregation of α-synuclein protein, share a number of features in pathology and disease progression. However, the vulnerable cell population differs significantly between the disorders, despite being caused by the same protein. While the vulnerability of dopamine cells in the substantia nigra to α-synuclein over-expression, and its link to Parkinson's disease, is well studied, animal models recapitulating the cortical degeneration in dementia with Lewy-bodies (DLB) are much less mature. The aim of this study was to develop a first rat model of widespread progressive synucleinopathy throughout the forebrain using adeno-associated viral (AAV) vector mediated gene delivery. Through bilateral injection of an AAV6 vector expressing human wild-type α-synuclein into the forebrain of neonatal rats, we were able to achieve widespread, robust α-synuclein expression with preferential expression in the frontal cortex. These animals displayed a progressive emergence of hyper-locomotion and dysregulated response to the dopaminergic agonist apomorphine. The animals receiving the α-synuclein vector displayed significant α-synuclein pathology including intra-cellular inclusion bodies, axonal pathology and elevated levels of phosphorylated α-synuclein, accompanied by significant loss of cortical neurons and a progressive reduction in both cortical and striatal ChAT positive interneurons. Furthermore, we found evidence of α-synuclein sequestered by IBA-1 positive microglia, which was coupled with a distinct change in morphology. In areas of most prominent pathology, the total α-synuclein levels were increased to, on average, two-fold, which is similar to the levels observed in patients with SNCA gene triplication, associated with cortical Lewy body pathology. This study provides a novel rat model of progressive cortical synucleinopathy, showing for the first time that cholinergic interneurons are vulnerable to

  13. Nonspecific association of 2',3'-cyclic nucleotide 3'-phosphodiesterase with the rat forebrain postsynaptic density fraction.

    PubMed

    Cho, Sun-Jung; Jung, Jae Seob; Shin, Seung Chul; Jin, IngNyol; Ko, Bok Hyun; Kim Kwon, Yunhee; Suh-Kim, Haeyoung; Moon, Il Soo

    2003-12-31

    The 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP), a protein of unknown function in vivo, is abundantly expressed in myelinating glia in two isoforms, CNP1 and CNP2. In this study, immunoblot analysis showed that CNP1 is the major isoform in adult forebrain, and that both isoforms are included in the postsynaptic density (PSD) fraction and tyrosine-phosphorylated at the basal level. However, subcellular distribution and detergent extraction data showed that CNP is nonspecifically associated with the PSD fraction. Immunocytochemistry revealed that CNP is detected, in a weak but punctate pattern, in dissociated rat hippocampal neurons of 3 days to 2 weeks in vitro. The CNP-positive punctae were distributed throughout soma and dendrites, and distinct from PSD95-positive ones. Immunoblot analysis indicated that CNP is also expressed in neuronal stem cell lines, HiB5 and F11. Interestingly, in addition to the known two isoforms, a new CNP isoform of MW 45 kDa was expressed in these cell lines and was the major type of isoform in F11 cells. Taken together, our data suggest that CNP is expressed in the early stage of in vitro development and nonspecifically included in the adult rat PSD fraction. PMID:14749525

  14. Maternal separation produces alterations of forebrain brain-derived neurotrophic factor expression in differently aged rats

    PubMed Central

    Wang, Qiong; Shao, Feng; Wang, Weiwen

    2015-01-01

    Early life adversity, such as postnatal maternal separation (MS), play a central role in the development of psychopathologies during individual ontogeny. In this study, we investigated the effects of repeated MS (4 h per day from postnatal day (PND) 1–21) on the brain-derived neurotrophic factor (BDNF) expression in the medial prefrontal cortex (mPFC), the nucleus accumbens (NAc) and the hippocampus of male and female juvenile (PND 21), adolescent (PND 35) and young adult (PND 56) Wistar rats. The results indicated that MS increased BDNF in the CA1 and the dentate gyrus (DG) of adolescent rats as well as in the DG of young adult rats. However, the expression of BDNF in the mPFC in the young adult rats was decreased by MS. Additionally, in the hippocampus, there was decreased BDNF expression with age in both the MS and non separated rats. However, in the mPFC, the BDNF expression was increased with age in the non separated rats; nevertheless, the BDNF expression was significantly decreased in the MS young adult rats. In the NAc, the BDNF expression was increased with age in the male non-maternal separation (NMS) rats, and the young adult female MS rats had less BDNF expression than the adolescent female MS rats. The present study shows unique age-differently changes on a molecular level induced by MS and advances the use of MS as a valid animal model to detect the underlying neurobiological mechanisms of mental disorders. PMID:26388728

  15. Forebrain gene expression predicts deficits in sensorimotor gating after isolation rearing in male rats

    PubMed Central

    Swerdlow, Neal R.; Light, Gregory A.; Trim, Ryan S.; Breier, Michelle R.; Hines, Samantha R.; Powell, Susan B.

    2013-01-01

    Compared to socially housed (SH) rats, adult isolation-reared (IR) rats exhibit phenotypes relevant to schizophrenia (SZ), including reduced prepulse inhibition (PPI) of startle. PPI is normally regulated by the medial prefrontal cortex (mPFC) and nucleus accumbens (NAC). We assessed PPI, auditory-evoked local field potentials (LFPs) and expression of 7 PPI- and SZ-related genes in the mPFC and NAC, in IR and SH rats. Buffalo (BUF) rats were raised in same-sex groups of 2–3 (SH) or in isolation (IR). PPI was measured early (d53) and later in adulthood (d74); LFPs were measured approximately on d66. Brains were processed for RT-PCR measures of mPFC and NAC expression of Comt, Erbb4, Grid2, Ncam1, Slc1a2, Nrg1 and Reln. Male IR rats exhibited PPI deficits, most pronounced at d53; male and female IR rats had significantly elevated startle magnitude on both test days. Gene expression levels were not significantly altered by IR. PPI levels (d53) were positively correlated with mPFC expression of several genes, and negatively correlated with NAC expression of several genes, in male IR but not SH rats. Late (P90) LFP amplitudes correlated significantly with expression levels of 6/7 mPFC genes in male rats, independent of rearing. After IR that disrupts early adult PPI in male BUF rats, expression levels of PPI- and SZ-associated genes in the mPFC correlate positively with PPI, and levels in the NAC correlate negatively with PPI. These results support the model that specific gene-behavior relationships moderate the impact of early-life experience on SZ-linked behavioral and neurophysiological markers. PMID:24076151

  16. Treatment with Actovegin improves spatial learning and memory in rats following transient forebrain ischaemia.

    PubMed

    Meilin, Sigal; Machicao, Fausto; Elmlinger, Martin

    2014-08-01

    This study aimed to investigate whether Actovegin, which is a deproteinized ultrafiltrate derived from calf blood, demonstrates neuroprotective effects in a rat model of transient global cerebral ischaemia. Forty Sprague Dawley rats were subjected to four-vessel occlusion to induce transient global cerebral ischaemia followed by either saline or Actovegin treatment. Sham operations were performed on 15 rats. Actovegin (200 mg/kg) or saline was administered 6 hrs after carotid artery occlusion and then daily until Day 40. Learning and memory were evaluated using the Morris water maze test over two different 5-day periods, and grip strength testing was also performed to control for potential motor impairments. Rat brains were harvested for histological analysis on Day 68. In comparison to controls, Actovegin-treated rats exhibited a decreased latency to reach the hidden platform on the second learning trial of water maze testing (46.82 ± 6.18 versus 27.64 ± 4.53 sec., P < 0.05; 38.3 ± 8.23 versus 13.37 ± 2.73 sec., P < 0.01 for the first and second 5-day testing periods, respectively). In addition, Actovegin-treated rats spent more time in the platform quadrant than saline-treated rats during memory trials (P < 0.05). No differences in grip strength were detected. Histological analyses demonstrated increased cell survival in the CA1 region of the hippocampus following Actovegin treatment (left hemisphere, 166 ± 50 versus 332 ± 27 cells, P < 0.05; right hemisphere, 170 ± 45 versus 307 ± 28 cells, P < 0.05, in saline- versus Actovegin-treated rats, respectively). In rats, Actovegin treatment improves spatial learning and memory following cerebral ischaemia, which may be related to hippocampal CA1 neuroprotection. PMID:24797227

  17. Treatment with Actovegin improves spatial learning and memory in rats following transient forebrain ischaemia

    PubMed Central

    Meilin, Sigal; Machicao, Fausto; Elmlinger, Martin

    2014-01-01

    This study aimed to investigate whether Actovegin, which is a deproteinized ultrafiltrate derived from calf blood, demonstrates neuroprotective effects in a rat model of transient global cerebral ischaemia. Forty Sprague Dawley rats were subjected to four-vessel occlusion to induce transient global cerebral ischaemia followed by either saline or Actovegin treatment. Sham operations were performed on 15 rats. Actovegin (200 mg/kg) or saline was administered 6 hrs after carotid artery occlusion and then daily until Day 40. Learning and memory were evaluated using the Morris water maze test over two different 5-day periods, and grip strength testing was also performed to control for potential motor impairments. Rat brains were harvested for histological analysis on Day 68. In comparison to controls, Actovegin-treated rats exhibited a decreased latency to reach the hidden platform on the second learning trial of water maze testing (46.82 ± 6.18 versus 27.64 ± 4.53 sec., P < 0.05; 38.3 ± 8.23 versus 13.37 ± 2.73 sec., P < 0.01 for the first and second 5-day testing periods, respectively). In addition, Actovegin-treated rats spent more time in the platform quadrant than saline-treated rats during memory trials (P < 0.05). No differences in grip strength were detected. Histological analyses demonstrated increased cell survival in the CA1 region of the hippocampus following Actovegin treatment (left hemisphere, 166 ± 50 versus 332 ± 27 cells, P < 0.05; right hemisphere, 170 ± 45 versus 307 ± 28 cells, P < 0.05, in saline- versus Actovegin-treated rats, respectively). In rats, Actovegin treatment improves spatial learning and memory following cerebral ischaemia, which may be related to hippocampal CA1 neuroprotection. PMID:24797227

  18. Interstitial concentrations of amino acids in the rat striatum during global forebrain ischemia and potassium-evoked spreading depression.

    PubMed

    Molchanova, Svetlana; Kööbi, Peeter; Oja, Simo S; Saransaari, Pirjo

    2004-08-01

    The early detection and appropriate treatment of brain ischemia is of paramount importance. The interstitial concentrations of neurotransmitter amino acids are often used as an index of neuronal injury. However, monitoring of non-neurotransmitter amino acids may be equally important. We have studied the behavior of 10 amino acids during K(+)-induced spreading depression (application of 70 mM KCl during 40 min) and global forebrain ischemia (two-vessel occlusion with hypotension during 20 min). The concentrations of glutamate, aspartate, taurine, GABA, glycine, and alanine, measured in the rat striatum by microdialysis, increased during both ischemia and spreading depression, whereas glutamine concentrations decreased in both cases. Only ischemia, but not spreading depression, led to enhanced release of serine, threonine, and asparagine. We thus conclude that an elevation in the interstitial concentrations of non-neurotransmitter amino acids is specific to deep ischemic injury to nervous tissue. We propose the monitoring of serine, asparagine, and threonine, together with excitatory amino acids, as an index of the degree of ischemic brain injury. PMID:15260129

  19. Postnatal development of nestin positive neurons in rat basal forebrain: different onset and topography with choline acetyltransferase and parvalbumin expression.

    PubMed

    Guo, Kai-Hua; Li, Dong-Pei; Gu, Huai-Yu; Jie-Xu; Yao, Zhi-Bin

    2014-06-01

    Our previous studies identified a sub-population of cholinergic neurons which express nestin in the rostral part of the basal forebrain (BF) in normal adult rats. In the present study, the postnatal developmental patterns of nestin, choline acetyl transferase (ChAT) and parvalbumin (PV) positive neurons were explored by means of immunohistochemistry combined with immunofluorescence double label methods. Compared with early onset of ChAT expression (from P1) and delayed onset of PV expression (from P16), nestin positive activity was detected in the BF from P9 and co-expressed by parts of the ChAT positive neurons within the same region during the whole postnatal development process. However, ChAT and PV were not coexpressed by the neurons within the medial septum-diagonal band of Broca (MS-DBB) of BF. These results might imply a composite of separate development patterns displayed by different subpopulations of cholinergic neurons (nestin positive cholinergic neurons and nestin negative cholinergic neurons) within this region. Moreover, the topographic distribution of nestin, ChAT and PV positive neurons also showed different characteristics. In summary, our present study revealed a remarkable timing and topographic difference on the postnatal development of the nestin expression within the MS-DBB of BF compared with ChAT and PV expression. It is further suggested that nestin is re-expressed by cholinergic neurons in the BF after differentiation but not persisted from neuronal precursor cells. PMID:24657285

  20. [In vitro evaluation of metabolic change in forebrain ischemia model of rat using proton magnetic resonance spectroscopy].

    PubMed

    Tanaka, N

    1997-05-01

    Metabolic disruption resulted from cerebral ischemia and post-ischemia reperfusion injury was studied using proton magnetic resonance spectroscopy (1H MRS). We also analyzed the effect of 3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186) which can scavenge free radicals induced in the brain tissue due to ischemic-reperfusion in this experiment. The ischemic model was produced using rat forebrain ischemic model (Pulsinelli's 4 vessels occlusion model). Post-ischemic reperfusion was also induced by the re-opening of the occluded common carotid arteries. The occluded time was 30 min and reperfusion time 0, 10, 30, 60 min. We obtained the specimens in the cortex under microwave fixation. Choline and acetate increased during ischemia and gradually decreased during reperfusion period. These two signals seen in 1H MRS are supposed to represent cell membrane components (products) and the increase of these signals after reperfusion seems to be related to the post ischemic reperfusion injury due to the explosive increase of free radicals. Lactate, which is induced by anaerobic glycolysis, increased during ischemia and promptly disappeared after reperfusion. The treatment of pre-ischemic administration of MCI-186 significantly suppressed increases of choline and acetate. As far as lactate is concerned, post-ischemic administration of this drug significantly reduced its increase at the point of reperfusion. Our results suggest that MCI-186 alternates changes induced by ischemic-reperfusion injury in membranous metabolism, probably due to its free radical scavenging action. PMID:9226472

  1. Inhibition of mTOR Pathway by Rapamycin Reduces Brain Damage in Rats Subjected to Transient Forebrain Ischemia

    PubMed Central

    Yang, Xiao; Hei, Changhun; Liu, Ping; Song, Yaozu; Thomas, Taylor; Tshimanga, Sylvie; Wang, Feng; Niu, Jianguo; Sun, Tao; Li, P. Andy

    2015-01-01

    The aims of this study are to clarify the role of mTOR in mediating cerebral ischemic brain damage and the effects of rapamycin on ischemic outcomes. Ten minutes of forebrain ischemia was induced in rats, and their brains were sampled after 3 h, 16 h, and 7 days reperfusion for histology, immunohistochemistry and biochemical analysis. Our data demonstrated that cerebral ischemia resulted in both apoptotic and necrotic neuronal death; cerebral ischemia and reperfusion led to significant increases of mRNA and protein levels of p-mTOR and its downstream p-P70S6K and p-S6; elevation of LC3-II, and release of cytochrome c into the cytoplasm in both the cortex and hippocampus. Inhibition of mTOR by rapamycin markedly reduced ischemia-induced damage; suppressed p-Akt, p-mTOR, p-P70S6K and p-S6 protein levels; decreased LC3-II and Beclin-1; and prevented cytochrome c release in the two structures. All together, these data provide evidence that cerebral ischemia activates mTOR and autophagy pathways. Inhibition of mTOR deactivates the mTOR pathway, suppresses autophagy, prevents cytochrome c release and reduces ischemic brain damage. PMID:26681922

  2. The effect of prefrontal stimulation on the firing of basal forebrain neurons in urethane anesthetized rat

    PubMed Central

    Gyengési, Erika; Zaborszky, Laszlo; Détári, László

    2008-01-01

    The basal forebrain (BF) contains a heterogeneous population of cholinergic and non-cholinergic corticopetal neurons and interneurons. Neurons firing at a higher rate during fast cortical EEG activity (f > 16Hz) were called F-cells, while neurons that increase their firing rate during high-amplitude slow-cortical waves (f < 4Hz) were categorized as S-cells. The prefrontal cortex (PFC) projects heavily to the BF, although little is know how it affects the firing of BF units. In this study, we investigated the effect of stimulation of the medial PFC on the firing rate of BF neurons (n=57) that were subsequently labeled by biocytin using juxtacellular filling (n=22). BF units were categorized in relation to tail-pinch induced and spontaneous EEG changes. Electrical stimulation of the medial PFC led to responses in 28 out of 41 F cells and in 8 out of 9 S cells. Within the sample of responsive F cells, 57% showed excitation (n=8) or excitation followed by inhibitory period (n=8). The remaining F cells expressed a short (n=6) or long inhibitory (n=6) response. In contrast, 75% of the recorded S cells (n=9) reduced their firing after prefrontal stimulation. Among the F-cells, we recovered one cholinergic neuron and one parvalbumin-containing neuron using juxtacellular filling and subsequent immunocytochemistry. While the PV cell displayed short latency facilitation, the cholinergic cell showed significant inhibition with much longer latency in response to the prefrontal stimulus. This is in agreement with previous anatomical data showing that prefrontal projections directly target mostly non-cholinergic cells, including GABAergic neurons. PMID:18355633

  3. Modulation of schizophrenia-related genes in the forebrain of adolescent and adult rats exposed to maternal immune activation.

    PubMed

    Hemmerle, Ann M; Ahlbrand, Rebecca; Bronson, Stefanie L; Lundgren, Kerstin H; Richtand, Neil M; Seroogy, Kim B

    2015-10-01

    Maternal immune activation (MIA) is an environmental risk factor for schizophrenia, and may contribute to other developmental disorders including autism and epilepsy. Activation of pro-inflammatory cytokine systems by injection of the synthetic double-stranded RNA polyriboinosinic-polyribocytidilic acid (Poly I:C) mediates important neurochemical and behavioral corollaries of MIA, which have relevance to deficits observed in schizophrenia. We examined the consequences of MIA on forebrain expression of neuregulin-1 (NRG-1), brain-derived neurotrophic factor (BDNF) and their receptors, ErbB4 and trkB, respectively, genes associated with schizophrenia. On gestational day 14, pregnant rats were injected with Poly I:C or vehicle. Utilizing in situ hybridization, expression of NRG-1, ErbB4, BDNF, and trkB was examined in male rat offspring at postnatal day (P) 14, P30 and P60. ErbB4 mRNA expression was significantly increased at P30 in the anterior cingulate (AC Ctx), frontal, and parietal cortices, with increases in AC Ctx expression continuing through P60. ErbB4 expression was also elevated in the prefrontal cortex (PFC) at P14. In contrast, NRG-1 mRNA was decreased in the PFC at P60. Expression of BDNF mRNA was significantly upregulated in the PFC at P60 and decreased in the AC Ctx at P14. Expression of trkB was increased in two regions, the piriform cortex at P14 and the striatum at P60. These findings demonstrate developmentally and regionally selective alterations in the expression of schizophrenia-related genes as a consequence of MIA. Further study is needed to determine contributions of these effects to the development of alterations of relevance to neuropsychiatric diseases. PMID:26206493

  4. Patterns of Toxoplasma gondii cyst distribution in the forebrain associate with individual variation in predator odor avoidance and anxiety-related behavior in male Long-Evans rats

    PubMed Central

    Evans, Andrew K.; Strassmann, Patrick S.; Lee, I-Ping; Sapolsky, Robert M.

    2014-01-01

    Toxoplasma gondii (T. gondii) is one of the world’s most successful brain parasites. T. gondii engages in parasite manipulation of host behavior and infection has been epidemiologically linked to numerous psychiatric disorders. Mechanisms by which T. gondii alters host behavior are not well understood, but neuroanatomical cyst presence and the localized host immune response to cysts are potential candidates. The aim of these studies was to test the hypothesis that T. gondii manipulation of specific host behaviors is dependent on neuroanatomical location of cysts in a time-dependent function post-infection. We examined neuroanatomical cyst distribution (53 forebrain regions) in infected rats after predator odor aversion behavior and anxiety-related behavior in the elevated plus maze and open field arena, across a 6-week time course. In addition, we examined evidence for microglial response to the parasite across the time course. Our findings demonstrate that while cysts are randomly distributed throughout the forebrain, individual variation in cyst localization, beginning 3 weeks post-infection, can explain individual variation in the effects of T. gondii on behavior. Additionally, not all infected rats develop cysts in the forebrain, and attenuation of predator odor aversion and changes in anxiety-related behavior are linked with cyst presence in specific forebrain areas. Finally, the immune response to cysts is striking. These data provide the foundation for testing hypotheses about proximate mechanisms by which T. gondii alters behavior in specific brain regions, including consequences of establishment of a homeostasis between T. gondii and the host immune response. PMID:24269877

  5. Stimulation of 5-HT7 receptor during adolescence determines its persistent upregulation in adult rat forebrain areas.

    PubMed

    Nativio, Paola; Zoratto, Francesca; Romano, Emilia; Lacivita, Enza; Leopoldo, Marcello; Pascale, Esterina; Passarelli, Francesca; Laviola, Giovanni; Adriani, Walter

    2015-11-01

    Brain serotonin 7 (5-HT7) receptors play an important functional role in learning and memory, in regulation of mood and motivation, and for circadian rhythms. Recently, we have studied the modulatory effects of a developmental exposure (under subchronic regimen) in rats with LP-211, a brain-penetrant and selective 5-HT7 receptor agonist. We aimed at further deciphering long-term sequelae into adulthood. LP-211 (0.250 mg/kg i.p., once/day) was administered for 5 days during the adolescent phase (postnatal days 43-45 to 47-49). When adult (postnatal days >70), forebrain areas were obtained for ex vivo immunohistochemistry, whose results prompted us to reconsider the brain connectivity maps presented in our previous study (Canese et al., Psycho-Pharmacol 2015;232:75-89.) Significant elevation in levels of 5-HT7 receptors were evidenced due to adolescent LP-211 exposure, in dorsal striatum (which also shows an increase of dopaminergic D2 auto-receptors) and-unexpectedly-in piriform cortex, with no changes in ventral striatum. We observed that functional connectivity from a seed on the right hippocampus was more extended than reported, also including the piriform cortex. As a whole, the cortical loop rearranged by adolescent LP-211 exposure consisted in a hippocampus receiving connections from piriform cortex and dorsal striatum, the latter both directly and through functional control over the 'extended amygdala'. Such results represent a starting point to explore neurophysiology of 5-HT7 receptors. Further investigation is warranted to develop therapies for sleep disorders, for impaired emotional and motivational regulation, for attentive and executive deficit. The 5-HT7 agonist LP-211 (0.250 mg/kg i.p., once/day) was administered for 5 days during adolescence (postnatal days 43-45 to 47-49) in rats. When adult (postnatal days >70), a significant elevation in levels of 5-HT7 receptors were evidenced in dorsal striatum and-unexpectedly-in piriform cortex. PMID:26364910

  6. Over-expression of the GluN2B subunit in the forebrain facilitates the acquisition of morphine-related positive and aversive memory in rats.

    PubMed

    Li, Yijing; Ping, Xingjie; Yu, Peng; Liang, Jing; Shen, Fang; Han, Jisheng; Cui, Cailian

    2016-09-15

    GluN2B-containing N-methyl-d-aspartate (NMDA) receptors in the brain are known to have an important role in drug-associated learning and memory. Selective blockage of GluN2B-containing NMDA receptors (GluN2B-NMDARs) has been shown to impair morphine-induced conditioned place preference (CPP) without affecting natural reward-induced CPP. In the present study, GluN2B transgenic rats with over-expressed GluN2B-subunits in the forebrain were used to assess the susceptibility to CPP induced by morphine and natural rewards as well as to naloxone-induced conditioned place aversion (CPA). The results showed that GluN2B transgenic rats exhibited a relatively higher susceptibility to morphine-induced CPP and naloxone-induced CPA than their wild-type littermates did, while they retained the similar sensitivity as wild-type rats to CPP induced by natural reinforcers (food and sucrose). These findings suggest that increased level of GluN2B-NMDARs in forebrain facilitates formation of drug-related memory, but not that associated with natural rewards. GluN2B-NMDARs might be a potential target for the treatment of drug abuse. PMID:27217103

  7. Increases in mature brain-derived neurotrophic factor protein in the frontal cortex and basal forebrain during chronic sleep restriction in rats: possible role in initiating allostatic adaptation.

    PubMed

    Wallingford, J K; Deurveilher, S; Currie, R W; Fawcett, J P; Semba, K

    2014-09-26

    Chronic sleep restriction (CSR) has various negative consequences on cognitive performance and health. Using a rat model of CSR that uses alternating cycles of 3h of sleep deprivation (using slowly rotating activity wheels) and 1h of sleep opportunity continuously for 4 days ('3/1' protocol), we previously observed not only homeostatic but also allostatic (adaptive) sleep responses to CSR. In particular, non-rapid eye movement sleep (NREMS) electroencephalogram (EEG) delta power, an index of sleep intensity, increased initially and then declined gradually during CSR, with no rebound during a 2-day recovery period. To study underlying mechanisms of these allostatic responses, we examined the levels of brain-derived neurotrophic factor (BDNF), which is known to regulate NREMS EEG delta activity, during the same CSR protocol. Mature BDNF protein levels were measured in the frontal cortex and basal forebrain, two brain regions involved in sleep and EEG regulation, and the hippocampus, using Western blot analysis. Adult male Wistar rats were housed in motorized activity wheels, and underwent the 3/1 CSR protocol for 27 h, for 99 h, or for 99 h followed by 24h of recovery. Additional rats were housed in either locked wheels (locked wheel controls [LWCs]) or unlocked wheels that rats could rotate freely (wheel-running controls [WRCs]). BDNF levels did not differ between WRC and LWC groups. BDNF levels were increased, compared to the control levels, in all three brain regions after 27 h, and were increased less strongly after 99 h, of CSR. After 24h of recovery, BDNF levels were at the control levels. This time course of BDNF levels parallels the previously reported changes in NREMS delta power during the same CSR protocol. Changes in BDNF protein levels in the cortex and basal forebrain may be part of the molecular mechanisms underlying allostatic sleep responses to CSR. PMID:25010399

  8. Continuous estrone treatment impairs spatial memory and does not impact number of basal forebrain cholinergic neurons in the surgically menopausal middle-aged rat

    PubMed Central

    Engler-Chiurazzi, Elizabeth B.; Talboom, Joshua S.; Braden, B. Blair; Tsang, Candy W.S.; Mennenga, Sarah; Andrews, Madeline; Demers, Laurence M.; Bimonte-Nelson, Heather A.

    2012-01-01

    Premarin (conjugated equine estrogens) is the most widely prescribed estrogen-only menopausal hormone therapy in the United States, and is comprised of over 50% estrone (E1) sulfate. Following CEE administration, E1 is the principal circulating estrogen. However, the cognitive and neurobiological effects of E1 in a middle-aged rodent model have not yet been evaluated. We assessed cognitive effects of continuous E1 treatment in middle-aged surgically menopausal rats using a maze battery. We also quantified number of choline acetyltransferase-immunoreactive (ChAT-IR) neurons in distinct basal forebrain regions known in earlier studies in to be impacted by the most potent naturally-circulating estrogen in rodents and women, 17β-estradiol (17β-E2), as well as CEE. On the spatial working memory delayed-match-to-sample water maze, the highest E1 dose impaired memory performance during acquisition and after delay challenge. E1 did not impact ChAT-IR neuron number in the medial septum (MS) or horizontal/vertical diagonal bands. In a comparison study, 17β-E2 increased MS ChAT-IR neuron number. Findings indicate that E1 negatively impacts spatial working memory and memory retention, but does not increase ChAT-IR neuron number in basal forebrain, as does 17β-E2. Thus, data from prior studies suggest that 17β-E2 and CEE can enhance cognition and increase number of ChAT-IR basal forebrain neurons, while here we show that E1 does not induce these effects. Findings from preclinical basic science studies can inform the design of specific combinations of estrogens that could be beneficial to the brain and cognition. Accumulating data suggest that E1 is not likely to be among these key beneficial estrogens. PMID:22522079

  9. The mRNA expression and histological integrity in rat forebrain motor and sensory regions are minimally affected by acrylamide exposure through drinking water

    SciTech Connect

    Bowyer, John F.; Latendresse, John R.; Delongchamp, Robert R.; Warbritton, Alan R.; Thomas, Monzy; Divine, Becky; Doerge, Daniel R.

    2009-11-01

    A study was undertaken to determine whether alterations in the gene expression or overt histological signs of neurotoxicity in selected regions of the forebrain might occur from acrylamide exposure via drinking water. Gene expression at the mRNA level was evaluated by cDNA array and/or RT-PCR analysis in the striatum, substantia nigra and parietal cortex of rat after a 2-week acrylamide exposure. The highest dose tested (maximally tolerated) of approximately 44 mg/kg/day resulted in a significant decreased body weight, sluggishness, and locomotor activity reduction. These physiological effects were not accompanied by prominent changes in gene expression in the forebrain. All the expression changes seen in the 1200 genes that were evaluated in the three brain regions were <= 1.5-fold, and most not significant. Very few, if any, statistically significant changes were seen in mRNA levels of the more than 50 genes directly related to the cholinergic, noradrenergic, GABAergic or glutamatergic neurotransmitter systems in the striatum, substantia nigra or parietal cortex. All the expression changes observed in genes related to dopaminergic function were less than 1.5-fold and not statistically significant and the 5HT1b receptor was the only serotonin-related gene affected. Therefore, gene expression changes were few and modest in basal ganglia and sensory cortex at a time when the behavioral manifestations of acrylamide toxicity had become prominent. No histological evidence of axonal, dendritic or neuronal cell body damage was found in the forebrain due to the acrylamide exposure. As well, microglial activation was not present. These findings are consistent with the absence of expression changes in genes related to changes in neuroinflammation or neurotoxicity. Over all, these data suggest that oral ingestion of acrylamide in drinking water or food, even at maximally tolerable levels, induced neither marked changes in gene expression nor neurotoxicity in the motor and

  10. Dopamine systems in the forebrain

    PubMed Central

    Cave, John W.; Baker, Harriet

    2009-01-01

    The brain contains a number of distinct regions that share expression of dopamine (DA) and its requisite biosynthetic machinery, but otherwise encompass a diverse array of features and functions. Across the vertebrate family, the olfactory bulb (OB) contains the major DA system in the forebrain. OB DA cells are primarily periglomerular interneurons that define the glomerular structures in which they receive innervation from olfactory receptor neurons as well as mitral and tufted cells, the primary OB output neurons. The OB DA cells are necessary for both discrimination and the dynamic range over which odorant sensory information can be detected. In the embryo, OB DA neurons are derived from the ventricular area of the evaginating telencephalon, the dorsal lateral ganglionic eminence, and the septum. However, most OB DA interneurons are generated post-natally and continue to be produced throughout adult life from neural stem cells in the subventricular zone of the lateral ventricle and rostral migratory stream. Adult born OB DA neurons are capable of integrating into existing circuits and do not appear to degenerate in Parkinson’s disease. Several genes have been identified that regulate the differentiation of OB DA interneurons from neural stem cells. These include transcription factors that modify the expression of tyrosine hydroxylase, the first enzyme in the DA biosynthetic pathway and a reliable marker of the DA phenotype. Elucidation of the molecular genetic pathways of OB DA differentiation may advance the development of strategies to treat neurological disease. PMID:19731547

  11. Proliferation and Glia-Directed Differentiation of Neural Stem Cells in the Subventricular Zone of the Lateral Ventricle and the Migratory Pathway to the Lesions after Cortical Devascularization of Adult Rats

    PubMed Central

    Wan, Feng; Bai, Hua-Jing; Liu, Jun-Qi; Tian, Mo; Wang, Yong-Xue; Niu, Xin; Si, Yin-Chu

    2016-01-01

    We investigated the effects of cortical devascularization on the proliferation, differentiation, and migration of neural stem cells (NSCs) in the subventricular zone (SVZ) of the lateral ventricle of adult rats. 60 adult male Wistar rats were randomly divided into control group and devascularized group. At 15 and 30 days after cerebral cortices were devascularized, rats were euthanized and immunohistochemical analysis was performed. The number of PCNA-, Vimentin-, and GFAP-positive cells in the bilateral SVZ of the lateral wall and the superior wall of the lateral ventricles of 15- and 30-day devascularized groups increased significantly compared with the control group (P < 0.05 and P < 0.01). The area density of PCNA-, Vimentin-, and GFAP-positive cells in cortical lesions of 15- and 30-day devascularized groups increased significantly compared with the control group (P < 0.05 and P < 0.01). PCNA-, GFAP-, and Vimentin-positive cells in the SVZ migrated through the rostral migratory stream (RMS), and PCNA-, GFAP-, and Vimentin-positive cells from both the ipsilateral and contralateral dorsolateral SVZ (dl-SVZ) migrated into the corpus callosum (CC) and accumulated, forming a migratory pathway within the CC to the lesioned site. Our study suggested that cortical devascularization induced proliferation, glia-directed differentiation, and migration of NSCs from the SVZ through the RMS or directly to the corpus callosum and finally migrating radially to cortical lesions. This may play a significant role in neural repair. PMID:27294116

  12. Projections from the nociceptive area of the central nucleus of the amygdala to the forebrain: a PHA-L study in the rat.

    PubMed

    Bourgeais, L; Gauriau, C; Bernard, J F

    2001-07-01

    The lateral capsular division (CeLC) of the central nucleus (Ce) of the amygdala, in the rat, has been shown to be the main terminal area of a spino(trigemino)-parabrachio-amygdaloid nociceptive pathway [Bernard & Besson (1990) J. Neurophysiol. 63, 473-490; Bernard et al. (1992) J. Neurophysiol. 68, 551-569; Bernard et al. (1993) J. Comp. Neurol. 329, 201-229]. The projections to the forebrain from the CeLC and adjacent regions were studied in the rat by using microinjections of Phaseolus vulgaris leucoagglutinin (PHA-L) restricted in subdivisions of the Ce and the basolateral amygdaloid nucleus anterior (BLA). Our data showed that the entire CeLC projects primarily and extensively to the substantia innominata dorsalis (SId). The terminal labelling is especially dense in the caudal aspect of the SId. The other projections of the CeLC in the forebrain were dramatically less dense. They terminate in the bed nucleus of the stria terminalis (BST) and the posterior hypothalamus (pLH). No (or only scarce) other projections were found in the remaining forebrain areas. The Ce lateral division (CeL) and the Ce medial division (CeM), adjacent to the CeLC, also project to the SId with slightly lower density labelling. However, contrary to the case of the CeLC, both the CeL and the CeM extensively project to the ventrolateral subnucleus of the BST (BSTvl) with a few additional terminals found in other regions of the lateral BST. Only the CeM projects densely to both the interstitial nucleus of the posterior limb of the anterior commissure and the caudal most portion of the pLH. The projections of the BLA are totally different from those of the Ce as they terminate in the dorsal striatum, the accumbens nucleus, the olfactory tubercle, the nucleus of olfactory tract and the rostral pole of the cingulate/frontal cortex. This study demonstrates that the major output of the nociceptive spino(trigemino)-parabrachio-CeLC pathway is to the SId. It is suggested that the Ce

  13. Serotonin 5-HT1B receptor-mediated calcium influx-independent presynaptic inhibition of GABA release onto rat basal forebrain cholinergic neurons.

    PubMed

    Nishijo, Takuma; Momiyama, Toshihiko

    2016-07-01

    Modulatory roles of serotonin (5-HT) in GABAergic transmission onto basal forebrain cholinergic neurons were investigated, using whole-cell patch-clamp technique in the rat brain slices. GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) were evoked by focal stimulation. Bath application of 5-HT (0.1-300 μm) reversibly suppressed the amplitude of evoked IPSCs in a concentration-dependent manner. Application of a 5-HT1B receptor agonist, CP93129, also suppressed the evoked IPSCs, whereas a 5-HT1A receptor agonist, 8-OH-DPAT had little effect on the evoked IPSCs amplitude. In the presence of NAS-181, a 5-HT1B receptor antagonist, 5-HT-induced suppression of evoked IPSCs was antagonised, whereas NAN-190, a 5-HT1A receptor antagonist did not antagonise the 5-HT-induced suppression of evoked IPSCs. Bath application of 5-HT reduced the frequency of spontaneous miniature IPSCs without changing their amplitude distribution. The effect of 5-HT on miniature IPSCs remained unchanged when extracellular Ca(2+) was replaced by Mg(2+) . The paired-pulse ratio was increased by CP93129. In the presence of ω-CgTX, the N-type Ca(2+) channel blocker, ω-Aga-TK, the P/Q-type Ca(2+) channel blocker, or SNX-482, the R-type Ca(2+) channel blocker, 5-HT could still inhibit the evoked IPSCs. 4-AP, a K(+) channel blocker, enhanced the evoked IPSCs, and CP93129 had no longer inhibitory effect in the presence of 4-AP. CP93129 increased the number of action potentials elicited by depolarising current pulses. These results suggest that activation of presynaptic 5-HT1B receptors on the terminals of GABAergic afferents to basal forebrain cholinergic neurons inhibits GABA release in Ca(2+) influx-independent manner by modulation of K(+) channels, leading to enhancement of neuronal activities. PMID:27177433

  14. 2-Deoxy-D-glucose-induced hypothermia in anesthetized rats: Lack of forebrain contribution and critical involvement of the rostral raphe/parapyramidal regions of the medulla oblongata.

    PubMed

    Osaka, Toshimasa

    2015-07-01

    Systemic or central administration of 2-deoxy-d-glucose (2DG), a competitive inhibitor of glucose utilization, induces hypothermia in awake animals and humans. This response is mediated by the central nervous system, though the neural mechanism involved is largely unknown. In this study, I examined possible involvement of the forebrain, which contains the hypothalamic thermoregulatory center, and the medullary rostral raphe/parapyramidal regions (rRPa/PPy), which mediate hypoxia-induced heat-loss responses, in 2DG-induced hypothermia in urethane-chloralose-anesthetized, neuromuscularly blocked, artificially ventilated rats. The intravenous injection of 2DG (250mgkg(-1)) elicited an increase in tail skin temperature and decreases in body core temperature and the respiratory exchange ratio, though it did not induce any significant change in the metabolic rate. These results indicate that the hypothermic response was caused by an increase in heat loss, but not by a decrease in heat production and that it was accompanied by a decrease in carbohydrate utilization and/or an increase in lipid utilization as energy substrates. Complete surgical transection of the brainstem between the hypothalamus and the midbrain had no effect on the 2DG-induced hypothermic responses, suggesting that the hindbrain, but not the forebrain, was sufficient for the responses. However, pretreatment of the rRPa/PPy with the GABAA receptor blocker bicuculline methiodide, but not with vehicle saline, greatly attenuated the 2DG-induced responses, suggesting that the 2DG-induced hypothermia was mediated, at least in part, by GABAergic neurons in the hindbrain and activation of GABAA receptors on cutaneous sympathetic premotor neurons in the rRPa/PPy. PMID:26146232

  15. Retinoic Acid and Environmental Enrichment Alter Subventricular Zone and Striatal Neurogenesis after Stroke

    PubMed Central

    Plane, Jennifer M.; Whitney, Justin T.; Schallert, Tim; Parent, Jack M.

    2010-01-01

    Neurogenesis increases in the adult rodent forebrain subventricular zone (SVZ) after experimental stroke. Newborn neurons migrate to the injured striatum, but few survive long-term and little evidence exists to suggest that they integrate or contribute to functional recovery. One potential strategy to improve stroke recovery is to stimulate neurogenesis and integration of adult-born neurons by using treatments that enhance neurogenesis. We examined the influence of retinoic acid (RA), which stimulates neonatal SVZ and adult hippocampal neurogenesis, and environmental enrichment (EE), which enhances survival of adult-born hippocampal neurons. We hypothesized that the combination of RA and EE would promote survival of adult-generated SVZ-derived neurons and improve functional recovery after stroke. Adult rats underwent middle cerebral artery occlusion, received BrdU on days 5–11 after stroke and were treated with RA/EE, RA alone, EE/vehicle or vehicle alone and were killed 61 days after stroke. Rats underwent repeated MRI and behavioral testing. We found that RA/EE treatment preserved striatal and hemisphere tissue and increased SVZ neurogenesis as demonstrated by Ki67 and doublecortin (DCx) immunolabeling. All treatments influenced the location of BrdU- and DCx-positive cells in the post-stroke striatum. RA/EE increased the number of BrdU/NeuN-positive cells in the injured striatum but did not lead to improvements in behavioral function. These results demonstrate that combined pharmacotherapy and behavioral manipulation enhances post-stroke striatal neurogenesis and decreases infarct volume without promoting detectable functional recovery. Further study of the integration of adult-born neurons in the ischemic striatum is necessary to determine their restorative potential. PMID:18778705

  16. In Vivo Electrochemical Evidence for Simultaneous 5-HT and Histamine Release in the Rat Substantia Nigra pars Reticulata Following Medial Forebrain Bundle Stimulation

    PubMed Central

    Hashemi, Parastoo; Dankoski, Elyse C.; Wood, Kevin M.; Ambrose, R. Ellen; Wightman, R. Mark

    2011-01-01

    Exploring the mechanisms of serotonin (5-hydoxytryptophan (5-HT)) in the brain requires an in vivo method that combines fast temporal resolution with chemical selectivity. Fast-scan cyclic voltammetry (FSCV) is a technique with sufficient temporal and chemical resolution for probing dynamic 5-HT neurotransmission events; however, traditionally it has not been possible to probe in vivo 5-HT mechanisms. Recently, we optimized FSCV for measuring 5-HT release and uptake in vivo in the substantia nigra pars reticulata (SNR) with electrical stimulation of the dorsal raphe nucleus (DRN) in the rat brain. Here, we address technical challenges associated with rat DRN surgery by electrically stimulating 5-HT projections in the medial forebrain bundle (MFB), a more accessible anatomical location. MFB stimulation elicits 5-HT in the SNR; furthermore, we find simultaneous release of an additional species. We use electrochemical and pharmacological methods and describe physiological, anatomical and independent chemical analyses to identify this species as histamine. We also show pharmacologically that increasing the lifetime of extracellular histamine significantly decreases 5-HT release, most likely due to increased activation of histamine H-3 receptors that inhibit 5-HT release. Despite this, under physiological conditions, we find by kinetic comparisons of DRN and MFB stimulations that the simultaneous release of histamine does not interfere with the quantitative 5-HT concentration profile. We therefore present a novel and robust electrical stimulation of the MFB that is technically less challenging than DRN stimulation to study 5-HT and histamine release in the SNR. PMID:21682723

  17. Combined damage to entorhinal cortex and cholinergic basal forebrain neurons, two early neurodegenerative features accompanying Alzheimer's disease: effects on locomotor activity and memory functions in rats.

    PubMed

    Traissard, Natalia; Herbeaux, Karine; Cosquer, Brigitte; Jeltsch, Hélène; Ferry, Barbara; Galani, Rodrigue; Pernon, Anne; Majchrzak, Monique; Cassel, Jean-Christophe

    2007-04-01

    In Alzheimer's disease (AD), cognitive decline is linked to cholinergic dysfunctions in the basal forebrain (BF), although the earliest neuronal damage is described in the entorhinal cortex (EC). In rats, selective cholinergic BF lesions or fiber-sparing EC lesions may induce memory deficits, but most often of weak magnitude. This study investigated, in adult rats, the effects on activity and memory of both lesions, alone or in combination, using 192 IgG-saporin (OX7-saporin as a control) and L-N-methyl-D-aspartate to destroy BF and EC neurons, respectively. Rats were tested for locomotor activity in their home cage and for working- and/or reference-memory in various tasks (water maze, Hebb-Williams maze, radial maze). Only rats with combined lesions showed diurnal and nocturnal hyperactivity. EC lesions impaired working memory and induced anterograde memory deficits in almost all tasks. Lesions of BF cholinergic neurons induced more limited deficits: reference memory was impaired in the probe trial of the water-maze task and in the radial maze. When both lesions were combined, performance never improved in the water maze and the number of errors in the Hebb-Williams and the radial mazes was always larger than in any other group. These results (i) indicate synergistic implications of BF and EC in memory function, (ii) suggest that combined BF cholinergic and fiber-sparing EC lesions may model aspects of anterograde memory deficits and restlessness as seen in AD, (iii) challenge the cholinergic hypothesis of cognitive dysfunctions in AD, and (iv) contribute to open theoretical views on AD-related memory dysfunctions going beyond the latter hypothesis. PMID:16760925

  18. Developmental changes in the composition of polyadenylated RNA isolated from free and membrane-bound polyribosomes of the rat forebrain, analysed by translation in vitro.

    PubMed Central

    Hall, C; Lim, L

    1981-01-01

    Free and membrane-bound polyribosomes were isolated from the rat forebrain during its development. Polyadenylated RNA [poly(A)+ RNA] was isolated from both fractions, by using oligo(dT)-cellulose chromatography, and its composition studied by translating the poly(A)+ RNA in vitro in reticulocyte lysates. Electrophoretic analysis of the translation products showed that both free and membrane-bound polyribosomal poly(A)+ RNA gave many common components, but that there were also distinct differences in the protein composition of the products of the two fractions. Several proteins, of mol.wts. 39 000, 37 000, 31 000, 27 000 and 17 000, appeared to be products predominantly of free polyribosomal poly(A)+ RNA, whereas others, of mol.wt. 47 000, 33 000, 24 000 and 21 000 were specific to the membrane-bound polyribosomal poly(A)+ RNA fraction. More developmental changes were observed in the translational products of the membrane-bound poly(A)+ RNA fraction. Proteins of mol.wts. 33 000 and 21 000, which were predominant components of the translational products of this fraction when isolated from 10-day and older rats, were not present in translational products derived from preparations isolated from 3-day-old rats. The developmental appearance of these proteins as translational products of the membrane-bound poly(A)+ RNA suggests the appearance of new mRNA species. These transcriptional changes are discussed in relation to processes involved in brain differentiation, including myelination. Images Fig. 2. Fig. 4. Fig. 5. Fig. 6. PMID:6171267

  19. Longitudinal 1H MR spectroscopy of rat forebrain from infancy to adulthood reveals adolescence as a distinctive phase of neurometabolite development

    PubMed Central

    Morgan, Jonathan J.; Kleven, Gale A.; Tulbert, Christina D.; Olson, John; Horita, David A.; Ronca, April E.

    2013-01-01

    The present study represents the first longitudinal, within-subject 1H MRS investigation of the developing rat brain spanning infancy, adolescence, and early adulthood. We obtained neurometabolite profiles from a voxel located in a central location of the forebrain, centered on the striatum, with smaller contributions for cortex, thalamus, and hypothalamus, on postnatal days 7, 35, and 60. Water-scaled metabolite signals were corrected for T1 effects and quantified using the automated processing software LCModel, yielding molal concentrations. Our findings indicate age-related concentration changes in N-acetylaspartate + N-acetylaspartylglutamate, myo-inositol, glutamate + glutamine, taurine, creatine + phosphocreatine, and glycerophosphocholine + phosphocholine. Using a repeated measures design and analysis, we identified significant neurodevelopment change across all three developmental ages and identified adolescence as a distinctive phase in normative neurometabolic brain development. Between postnatal days 35 and 60, changes were observed in concentrations of N-acetylaspartate + N-acetylaspartylglutamate, glutamate + glutamine, and glycerophosphocholine + phosphocholine observed between postnatal days 35 and 60. Our data replicate past studies of early neurometabolite development and, for the first time, link maturational profiles in the same subjects across infancy, adolescence, and adulthood. PMID:23322706

  20. Induction of Apg-1, a member of the heat shock protein 110 family, following transient forebrain ischemia in the rat brain.

    PubMed

    Xue, J H; Fukuyama, H; Nonoguchi, K; Kaneko, Y; Kido, T; Fukumoto, M; Fujibayashi, Y; Itoh, K; Fujita, J

    1998-06-29

    Apg-1 (Osp94) and apg-2 belong to the heat shock protein (hsp) 110 family. In mouse somatic cells the apg-1 and hsp105/110 transcripts are inducible by a 32 degrees C to 39 degrees C heat shock, while apg-2 is not heat-inducible. Since ischemia is known to induce expression of hsp70, its effect on expression of apg-1 was assessed by using the 20-min forebrain ischemia model of the rat. In the cerebral cortex, Northern blot analysis and in situ hybridization histochemistry demonstrated an increased expression in neuronal cells of apg-1 transcripts 3 h after the onset of reperfusion, with a peak at 12 h, followed by a decline. In the hippocampus, the level was increased at 3 h, remained constant until 24 h, and then declined. Transcript levels of apg-2 as well as hsp 105 were also increased under the present conditions, indicating that the expression of apg-2 was differentially regulated in response to heat and ischemic stresses. The induction kinetics of hsp 105, but neither apg-2 nor hsp 70, were identical to those of apg-1. These results demonstrated that brain ischemia/reperfusion induced expression of each member of the hsp 110 family, although the regulatory mechanisms may not be the same. They also suggest a significant role of apg-1 in both the ischemic- and heat-stress responses and in the normal functioning of the non-stressed neuronal cells. PMID:9647773

  1. Feasibility and Safety of Continuous and Chronic Bilateral Deep Brain Stimulation of the Medial Forebrain Bundle in the Naïve Sprague-Dawley Rat

    PubMed Central

    Furlanetti, Luciano L.; Döbrössy, Máté D.; Aranda, Iñigo A.; Coenen, Volker A.

    2015-01-01

    Objective. Deep brain stimulation (DBS) of the superolateral branch of the medial forebrain bundle (MFB) has provided rapid and dramatic reduction of depressive symptoms in a clinical trial. Early intracranial self-stimulation experiments of the MFB suggested detrimental side effects on the animals' health; therefore, the current study looked at the viability of chronic and continuous MFB-DBS in rodents, with particular attention given to welfare issues and identification of stimulated pathways. Methods. Sprague-Dawley female rats were submitted to stereotactic microelectrode implantation into the MFB. Chronic continuous DBS was applied for 3–6 weeks. Welfare monitoring and behavior changes were assessed. Postmortem histological analysis of c-fos protein expression was carried out. Results. MFB-DBS resulted in mild and temporary weight loss in the animals, which was regained even with continuing stimulation. MFB-DBS led to increased and long-lasting c-fos expression in target regions of the mesolimbic/mesocortical system. Conclusions. Bilateral continuous chronic MFB-DBS is feasible, safe, and without impact on the rodent's health. MFB-DBS results in temporary increase in exploration, which could explain the initial weight loss, and does not produce any apparent behavioral abnormalities. This platform represents a powerful tool for further preclinical investigation of the MFB stimulation in the treatment of depression. PMID:25960609

  2. Spatiotemporal Progression of Microcalcification in the Hippocampal CA1 Region following Transient Forebrain Ischemia in Rats: An Ultrastructural Study.

    PubMed

    Riew, Tae-Ryong; Shin, Yoo-Jin; Kim, Hong Lim; Cho, Jeong Min; Pak, Ha-Jin; Lee, Mun-Yong

    2016-01-01

    Calcification in areas of neuronal degeneration is a common finding in several neuropathological disorders including ischemic insults. Here, we performed a detailed examination of the onset and spatiotemporal profile of calcification in the CA1 region of the hippocampus, where neuronal death has been observed after transient forebrain ischemia. Histopathological examinations showed very little alizarin red staining in the CA1 pyramidal cell layer until day 28 after reperfusion, while prominent alizarin red staining was detected in CA1 dendritic subfields, particularly in the stratum radiatum, by 14 days after reperfusion. Electron microscopy using the osmium/potassium dichromate method and electron probe microanalysis revealed selective calcium deposits within the mitochondria of degenerating dendrites at as early as 7 days after reperfusion, with subsequent complete mineralization occurring throughout the dendrites, which then coalesced to form larger mineral conglomerates with the adjacent calcifying neurites by 14 days after reperfusion. Large calcifying deposits were frequently observed at 28 days after reperfusion, when they were closely associated with or completely engulfed by astrocytes. In contrast, no prominent calcification was observed in the somata of CA1 pyramidal neurons showing the characteristic features of necrotic cell death after ischemia, although what appeared to be calcified mitochondria were noted in some degenerated neurons that became dark and condensed. Thus, our data indicate that intrahippocampal calcification after ischemic insults initially occurs within the mitochondria of degenerating dendrites, which leads to the extensive calcification that is associated with ischemic injuries. These findings suggest that in degenerating neurons, the calcified mitochondria in the dendrites, rather than in the somata, may serve as the nidus for further calcium precipitation in the ischemic hippocampus. PMID:27414398

  3. Spatiotemporal Progression of Microcalcification in the Hippocampal CA1 Region following Transient Forebrain Ischemia in Rats: An Ultrastructural Study

    PubMed Central

    Kim, Hong Lim; Cho, Jeong Min; Pak, Ha-Jin; Lee, Mun-Yong

    2016-01-01

    Calcification in areas of neuronal degeneration is a common finding in several neuropathological disorders including ischemic insults. Here, we performed a detailed examination of the onset and spatiotemporal profile of calcification in the CA1 region of the hippocampus, where neuronal death has been observed after transient forebrain ischemia. Histopathological examinations showed very little alizarin red staining in the CA1 pyramidal cell layer until day 28 after reperfusion, while prominent alizarin red staining was detected in CA1 dendritic subfields, particularly in the stratum radiatum, by 14 days after reperfusion. Electron microscopy using the osmium/potassium dichromate method and electron probe microanalysis revealed selective calcium deposits within the mitochondria of degenerating dendrites at as early as 7 days after reperfusion, with subsequent complete mineralization occurring throughout the dendrites, which then coalesced to form larger mineral conglomerates with the adjacent calcifying neurites by 14 days after reperfusion. Large calcifying deposits were frequently observed at 28 days after reperfusion, when they were closely associated with or completely engulfed by astrocytes. In contrast, no prominent calcification was observed in the somata of CA1 pyramidal neurons showing the characteristic features of necrotic cell death after ischemia, although what appeared to be calcified mitochondria were noted in some degenerated neurons that became dark and condensed. Thus, our data indicate that intrahippocampal calcification after ischemic insults initially occurs within the mitochondria of degenerating dendrites, which leads to the extensive calcification that is associated with ischemic injuries. These findings suggest that in degenerating neurons, the calcified mitochondria in the dendrites, rather than in the somata, may serve as the nidus for further calcium precipitation in the ischemic hippocampus. PMID:27414398

  4. Experiment K-7-18: Effects of Spaceflight in the Muscle Adductor Longus of Rats Flown in the Soviet Biosatellite Cosmos 2044. Part 2; Quantitative Autoradiographic Analysis of Gaba (Benzodiazepine) and Muscarinic (Cholinergic) Receptors in the Forebrain of Rats Flown on Cosmos 2044

    NASA Technical Reports Server (NTRS)

    Wu, L.; Daunton, N. G.; Krasnov, I. B.; DAmelio, F.; Hyde, T. M.; Sigworth, S. K.

    1994-01-01

    Quantitative autoradiographic analysis of receptors for GABA and acetylcholine in the forebrain of rats flown on COSMOS 2044 was undertaken as part of a joint US-Soviet study to determine the effects of microgravity on the central nervous system, and in particular on the sensory and motor portions of the forebrain. Changes in binding of these receptors in tissue from animals exposed to microgravity would provide evidence for possible changes in neural processing as a result of exposure to microgravity. Tritium-labelled diazepam and Quinuclidinyl-benzilate (QNB) were used to visualize GABA (benzodiazepine) and muscarinic (cholinergic) receptors, respectively. The density of tritium-labelled radioligands bound to various regions in the forebrain of both flight and control animals were measured from autoradiograms. Data from rats flown in space and from ground-based control animals that were not exposed to microgravity were compared.

  5. [REACTIVE CHANGES IN THE ASTROCYTES OF FOREBRAIN NUCLEUS ACCUMBENS AFTER RESTRICTION OF BLOOD FLOW IN THE BASIN OF BOTH COMMON CAROTID ARTERIES IN RATS].

    PubMed

    Naumov, N G

    2016-01-01

    Reactive changes of astrocytes were studied in forebrain nucleus accumbens in rats (n = 12) after global cerebral ischemia induced by bilateral occlusion of both common carotid arteries, which is a frequently used model to assess the effectiveness of pharmacological agents that have anti-ischemic and neuroprotective properties. Under these conditions, the nucleus accumbens was in the area of partial ischemia. Morphometric study of nucleus accumbens was performed in three groups of rats (4 animals in each group) after ligation of both common carotid arteries, after a sham operation and in healthy animals. Astrocytes were demonstrated in serial sections using the reaction to glial fibrillary acidic protein counterstained with hematoxylin. 7 days after the surgery, in each animal the number of astrocytes was counted in the sections in 7 successiive squares of 0.01 mm2 each, the distance between their bodies and the capillary wall was measured within the circle of 20 μm radius, the cell body area and the length of their main processes were determined. It is found that astrocytes in the nucleus accumbens in the model of bilateral occlusion of the common carotid arteries for 7 days experienced a partial state of ischemia. Their reactive changes were manifested by the signs of the cytotoxic edema, damaging intermediate filament proteins in their bodies, processes and in the perivascular glial membranes. The concentration of the astrocyte cell bodies near blood capillaries is the adaptation mechanism and is a condition for the survival of cells under the restriction of blood flow in the brain. PMID:27487658

  6. Tongxinluo Enhances Neurogenesis and Angiogenesis in Peri-Infarct Area and Subventricular Zone and Promotes Functional Recovery after Focal Cerebral Ischemic Infarction in Hypertensive Rats

    PubMed Central

    Chen, Li; Wang, Xiaoting; Zhang, Jian; Dang, Chao; Liu, Gang; Liang, Zhijian; Huang, Gelun; Zhao, Weijia; Zeng, Jinsheng

    2016-01-01

    Background. Tongxinluo is a traditional Chinese medicine compound with the potential to promote the neuronal functional recovery in cerebral ischemic infarction. Objective. This study aimed to disclose whether tongxinluo promotes neurological functional recovery and neurogenesis and angiogenesis in the infarcted area and SVZ after cerebral ischemic infarction in hypertensive rats. Methods. The ischemic model was prepared by distal middle cerebral artery occlusion (MCAO) in hypertensive rats. Tongxinluo was administrated 24 h after MCAO and lasted for 3, 7, or 14 days. Behavioral tests were performed to evaluate the protection of tongxinluo. Immunochemical staining was applied on brain tissue to evaluate the effects of tongxinluo on neurogenesis and vascularization in the MCAO model rats. Results. Postinjury administration of tongxinluo ameliorated the neuronal function deficit in the MCAO model rats. As evidenced by the immunochemical staining, BrdU+/DCX+, BrdU+/nestin+, and BrdU+ vascular endothelial cells were promoted to proliferate in SVZ after tongxinluo administration. The matured neurons stained by NeuN and vascularization by laminin staining were observed after tongxinluo administration in the peri-infarct area. Conclusion. Tongxinluo postischemia administration could ameliorate the neurological function deficit in the model rats. Possible mechanisms are related to neurogenesis and angiogenesis in the peri-infarct area and SVZ. PMID:27069496

  7. Blockade of the cerebral aqueduct in rats provides evidence of antagonistic leptin responses in the forebrain and hindbrain

    PubMed Central

    Vaill, Michael I.; Desai, Bhavna N.

    2013-01-01

    Previously, we reported that low-dose leptin infusions into the fourth ventricle produced a small but significant increase in body fat. These data contrast with reports that injections of higher doses of leptin into the fourth ventricle inhibit food intake and weight gain. In this study, we tested whether exogenous leptin in the fourth ventricle opposed or contributed to weight loss caused by third ventricle leptin infusion by blocking diffusion of CSF from the third to the fourth ventricle. Male Sprague-Dawley rats received third ventricle infusions of PBS or 0.3 μg leptin/24 h from miniosmotic pumps. After 4 days, rats received a 3-μl cerebral aqueduct injection of saline or of thermogelling nanoparticles (hydrogel) that solidified at body temperature. Third ventricle leptin infusion inhibited food intake and caused weight loss. Blocking the aqueduct exaggerated the effect of leptin on food intake and weight loss but had no effect on the weight of PBS-infused rats. Leptin reduced both body fat and lean body mass but did not change energy expenditure. Blocking the aqueduct decreased expenditure of rats infused with PBS or leptin. Infusion of leptin into the third ventricle increased phosphorylated STAT3 in the VMHDM of the hypothalamus and the medial NTS in the hindbrain. Blocking the aqueduct did not change hypothalamic p-STAT3 but decreased p-STAT3 in the medial NTS. These results support previous observations that low-level activation of hindbrain leptin receptors has the potential to blunt the catabolic effects of leptin in the third ventricle. PMID:24347057

  8. Blockade of the cerebral aqueduct in rats provides evidence of antagonistic leptin responses in the forebrain and hindbrain.

    PubMed

    Vaill, Michael I; Desai, Bhavna N; Harris, Ruth B S

    2014-02-15

    Previously, we reported that low-dose leptin infusions into the fourth ventricle produced a small but significant increase in body fat. These data contrast with reports that injections of higher doses of leptin into the fourth ventricle inhibit food intake and weight gain. In this study, we tested whether exogenous leptin in the fourth ventricle opposed or contributed to weight loss caused by third ventricle leptin infusion by blocking diffusion of CSF from the third to the fourth ventricle. Male Sprague-Dawley rats received third ventricle infusions of PBS or 0.3 μg leptin/24 h from miniosmotic pumps. After 4 days, rats received a 3-μl cerebral aqueduct injection of saline or of thermogelling nanoparticles (hydrogel) that solidified at body temperature. Third ventricle leptin infusion inhibited food intake and caused weight loss. Blocking the aqueduct exaggerated the effect of leptin on food intake and weight loss but had no effect on the weight of PBS-infused rats. Leptin reduced both body fat and lean body mass but did not change energy expenditure. Blocking the aqueduct decreased expenditure of rats infused with PBS or leptin. Infusion of leptin into the third ventricle increased phosphorylated STAT3 in the VMHDM of the hypothalamus and the medial NTS in the hindbrain. Blocking the aqueduct did not change hypothalamic p-STAT3 but decreased p-STAT3 in the medial NTS. These results support previous observations that low-level activation of hindbrain leptin receptors has the potential to blunt the catabolic effects of leptin in the third ventricle. PMID:24347057

  9. Aging, aluminium and basal forebrain lesions modify substrate kinetics of erythrocyte membrane Na,K-ATPase in the rat.

    PubMed

    Jovicić, Milena Erić; Popović, Miroljub; Nesić, Katica Jovanova; Popović, Natalija; Pavlović, Svetlana Jovicić; Rakić, Ljubisav

    2008-05-01

    Several studies suggested that the activity of erythrocyte Na,K-ATPase declines with aging. Here, it is postulated that alterations in the substrate kinetics of the erythrocyte membrane Na,K-ATPase could be more aggravated in conditions of brain cholinergic dysfunction seen in Alzheimer's disease than in normal aging. To test this hypothesis, we compared the Na,K-ATPase activity (Vmax/Km parameters) in aged rats with those in young rats with brain cholinergic dysfunction induced by electrolytic-, kainic acid-lesioned nucleus basalis magnocellularis (NBM) or by intracerebroventricular AlCl_{3} administration. In the above mentioned groups, Vmax values were significantly lower in comparison to the control animals. Furthermore, Km values were significantly higher in animals with electrolytic-induced NBM lesions, AlCl_{3} treated rats and aged animals. However, Km was significantly lower in kainic acid-induced NBM lesions compared to the control group. The Na,K-ATPase catalytic efficiency, estimated by the ratio Vm/Km, decreased as followed: young animals > aged animals > kainic acid lesion > electrolityc lesion > AlCl_{3}. Our data suggest that neurodegenerative processes similar to those seen in Alzheimer's disease affect the sodium/potassium pump functionality which might be detected in peripheral blood erythrocyte membranes. PMID:18525130

  10. Mitochondria buffer non-toxic calcium loads and release calcium through the mitochondrial permeability transition pore and sodium/calcium exchanger in rat basal forebrain neurons.

    PubMed

    Murchison, D; Griffith, W H

    2000-01-31

    Mitochondria participate in intracellular Ca2+ buffering and signalling. They are also major mediators of cell death. Toxic Ca2+ accumulation in mitochondria is widely believed to initiate cell death in many cell types by opening the permeability transition pore (PTP). In non-neuronal cells, the PTP has been implicated as a Ca2+ release mechanism in physiological Ca2+ signalling. In neurons, Ca2+ release from mitochondria has been attributed primarily to mitochondrial Na+/Ca2+ exchange. Using fura-2 ratiometric microfluorimetry in acutely dissociated rat basal forebrain neurons, we show that mitochondria are able to buffer non-toxic Ca2+ loads arising from caffeine-sensitive internal stores or from extracellular influx through voltage gated channels. We also show that these non-toxic Ca2+ loads are reversibly released from mitochondria through the PTP and the Na+/Ca2+ exchanger. Evoked Ca2+ transients have characteristic peak and shoulder features mediated by mitochondrial buffering and release. Depolarizing mitochondria with carbonyl cyanide m-chlorophenylhydrazone (CCCP, 5 microM) causes release of mitochondrial Ca2+ and prevents Ca2+ uptake. In CCCP, the magnitudes of evoked Ca2+ transients are increased, and the peak and shoulder features are eliminated. The PTP antagonist, cyclosporin A, (CSA, 2 microM) and the Na+/Ca2+ exchange blocker, clonazepam, (CLO, 20 microM) reversibly inhibited both the shoulder features of evoked Ca2+ transients and Ca2+ transients associated with CCCP application. We suggest that central neuronal mitochondria buffer and release Ca2+ through the PTP and Na+/Ca2+ exchanger during physiological Ca2+ signalling. We also suggest that CLO blocks both the PTP and the mitochondrial Na+/Ca2+ exchanger. PMID:10784115

  11. Effects of amyloid-beta on cholinergic and acetylcholinesterase-positive cells in cultured basal forebrain neurons of embryonic rat brain.

    PubMed

    Kasa, Peter; Papp, Henrietta; Kasa, Peter; Pakaski, Magdolna; Balaspiri, Lajos

    2004-02-13

    The neurotoxic effects of amyloid-beta(1-42) and amyloid-beta(25-35) (A beta) on cholinergic and acetylcholinesterase-positive neurons were investigated in primary cultures derived from embryonic 18-day-old rat basal forebrain. After various time intervals, the cultures were treated with 1, 5, 10 or 20 microM A beta for different time periods. The cholinergic neurons and their axon terminals were revealed by vesicular acetylcholine transporter immunohistochemistry and the cholinoceptive cells by acetylcholinesterase histochemical staining. To assess the toxic effects of these A beta peptides on the cholinergic neurons, image analysis was applied for quantitative determination of the numbers of axon varicosities/terminals and cells. The results demonstrate that, following treatment with 1 or 5 microM A beta for 5, 10, 30, 60 or 120 min, no changes in vesicular acetylcholine transporter immunohistochemical staining were observed. However, after treatment for 30 min with 10 or 20 microM A beta, the number of stained axon varicosities was reduced, and treatment for 2 h they had disappeared. In contrast, vesicular acetylcholine transporter-positivity could be seen in some of the neuronal perikarya even after 3 days after treatment. The acetylcholinesterase staining was homogeneously distributed in the control neurons. After A beta treatment, the histochemical reaction end-product was detected in some of the neuronal perikarya or in the dendritic processes near to the soma. It is concluded that the neurotoxic effects of A beta appear more rapidly in the cholinergic axon terminals than in the cholinergic and acetylcholinesterase-positive neuronal perikarya. PMID:14725970

  12. Detergent-dependent separation of postsynaptic density, membrane rafts and other subsynaptic structures from the synaptic plasma membrane of rat forebrain.

    PubMed

    Zhao, LiYing; Sakagami, Hiroyuki; Suzuki, Tatsuo

    2014-10-01

    We systematically investigated the purification process of post-synaptic density (PSD) and post-synaptic membrane rafts (PSRs) from the rat forebrain synaptic plasma membranes by examining the components and the structures of the materials obtained after the treatment of synaptic plasma membranes with TX-100, n-octyl β-d-glucoside (OG) or 3-([3-cholamidopropyl]dimethylammonio)-2-hydroxy-1-propanesulfonate (CHAPSO). These three detergents exhibited distinct separation profiles for the synaptic subdomains. Type I and type II PSD proteins displayed mutually exclusive distribution. After TX-100 treatment, type I PSD was recovered in two fractions: a pellet and an insoluble fraction 8, which contained partially broken PSD-PSR complexes. Conventional PSD was suggested to be a mixture of these two PSD pools and did not contain type II PSD. An association of type I PSD with PSRs was identified in the TX-100 treatment, and those with type II PSD in the OG and CHAPSO treatments. An association of GABA receptors with gephyrin was easily dissociated. OG at a high concentration solubilized the type I PSD proteins. CHAPSO treatment resulted in a variety of distinct fractions, which contained certain novel structures. Two different pools of GluA, either PSD or possibly raft-associated, were identified in the OG and CHAPSO treatments. These results are useful in advancing our understanding of the structural organization of synapses at the molecular level. We systematically investigated the purification process of post-synaptic density (PSD) and synaptic membrane rafts by examining the structures obtained after treatment of the SPMs with TX-100, n-octyl β-d-glucoside or CHAPSO. Differential distribution of type I and type II PSD, synaptic membrane rafts, and other novel subdomains in the SPM give clues to understand the structural organization of synapses at the molecular level. PMID:24985044

  13. Comparison of somatostatin and corticotrophin releasing hormone immunoreactivity in forebrain neurons projecting to taste responsive and non responsive regions of the parabrachial nucleus in rat

    PubMed Central

    Panguluri, Siva; Saggu, Shalini; Lundy, Robert

    2009-01-01

    Several forebrain areas have been shown to project to the parabrachial nucleus (PBN) and exert inhibitory and excitatory influences on taste processing. The neurochemicals by which descending forebrain inputs modulate neural taste-evoked responses remain to be established. This study investigated the existence of somatostatin (SS) and corticotrophin releasing factor (CRF) in forebrain neurons that project to caudal regions of the PBN responsive to chemical stimulation of the anterior tongue as well as more rostral unresponsive regions. Retrograde tracer was iontophoretically or pressure ejected from glass micropipettes, and seven days later the animals were euthanized for subsequent immunohistochemical processing for co-localization of tracer with SS and CRF in tissue sections containing the lateral hypothalamus (LH), central nucleus of the amygdala (CeA), bed nucleus of the stria terminalis (BNST), and insular cortex (IC). In each forebrain site, robust labeling of cells with distinguishable nuclei and short processes was observed for SS and CRF. The results indicate that CRF neurons in each forebrain site send projections throughout the rostral caudal extent of the PBN with a greater percentage terminating in regions rostral to the anterior tongue responsive area. For SS, the percentage of double-labeled neurons was more forebrain site specific in that only BNST and CeA exhibited significant numbers of double labeled neurons. Few retrogradely labeled cells in LH co-expressed SS, while no double labeled cells were observed in IC. Again, tracer injections into rostral PBN resulted in a greater percentage of double labeled neurons in BNST and CeA compared to caudal injections. The present results suggest that some sources of descending forebrain input might utilize somatostatin and/or CRF to exert a broad influence on sensory information processing in the PBN. PMID:19699720

  14. Dynamics of c-fos and ICER mRNA expression in rat forebrain following lithium chloride injection.

    PubMed

    Spencer, C M; Houpt, T A

    2001-09-30

    Lithium is commonly used as a treatment for affective disorders in humans and as a toxin to produce conditioned taste aversions in rats. LiCl administration in rats has been correlated with activation of c-fos and cAMP-mediated gene transcription in many brain regions; however, little is known about the timing or duration of gene activation. We hypothesized that c-fos gene transcription is rapidly stimulated by LiCl, followed later by the expression of the inducible cAMP early repressor (ICER) transcription factor, a negative modulator of cAMP-mediated gene transcription. By in situ hybridization, we analyzed the timecourse of c-fos and ICER mRNA expression in the central nucleus of the amygdala (CeA), the paraventricular nucleus of the hypothalamus (PVN) and the supraoptic nucleus (SON) at seven time points (0, 0.3, 1, 3, 6, 9 and 12 h) after intraperitoneal LiCl injection (0.15 M, 12 ml/kg, 76 mg/kg). Expression of c-fos mRNA peaked between 20 min and 1 h and returned to baseline by 3 h in the CeA, PVN and SON. ICER mRNA was detected in these regions at 20 min, peaked at 1-3 h and returned to nearly baseline 9 h following LiCl injection. The time lag between c-fos mRNA expression and ICER mRNA expression within the same regions is consistent with ICER terminating c-fos gene transcription. However, no refractory period was detected for restimulation of c-fos transcription by a second injection of LiCl during the period of peak ICER mRNA expression, suggesting the involvement of other transcriptional modulators. PMID:11589989

  15. Melanocortin receptor agonist ACTH 1-39 protects rat forebrain neurons from apoptotic, excitotoxic and inflammation-related damage.

    PubMed

    Lisak, Robert P; Nedelkoska, Liljana; Bealmear, Beverly; Benjamins, Joyce A

    2015-11-01

    Patients with relapsing-remitting multiple sclerosis (RRMS) are commonly treated with high doses of intravenous corticosteroids (CS). ACTH 1-39, a member of the melanocortin family, stimulates production of CS by the adrenals, but melanocortin receptors are also found in the central nervous system (CNS) and on immune cells. ACTH is produced within the CNS and may have direct protective effects on glia and neurons independent of CS. We previously reported that ACTH 1-39 protected oligodendroglia (OL) and their progenitors (OPC) from a panel of excitotoxic and inflammation-related agents. Neurons are the most vulnerable cells in the CNS. They are terminally differentiated, and sensitive to inflammatory and excitotoxic insults. For potential therapeutic protection of gray matter, it is important to investigate the direct effects of ACTH on neurons. Cultures highly enriched in neurons were isolated from 2-3 day old rat brain. After 4-7 days in culture, the neurons were treated for 24h with selected toxic agents with or without ACTH 1-39. ACTH 1-39 protected neurons from death induced by staurosporine, glutamate, NMDA, AMPA, kainate, quinolinic acid, reactive oxygen species and, to a modest extent, from rapidly released NO, but did not protect against kynurenic acid or slowly released nitric oxide. Our results show that ACTH 1-39 protects neurons in vitro from several apoptotic, excitotoxic and inflammation-related insults. PMID:26300474

  16. Evaluation for roles of neurosteroids in modulating forebrain mechanisms controlling vasopressin secretion and related phenomena in conscious rats.

    PubMed

    Yamaguchi, Ken'ichi

    2015-06-01

    Anteroventral third ventricular region (AV3V) that regulates autonomic functions through a GABAergic mechanism possesses neuroactive steroid (NS)-synthesizing ability. Although NS can exert effects by acting on a certain type of GABAA-receptor (R), it is not clear whether NS may operate to modulate AV3V GABAergic activity for controlling autonomic functions. This study aimed to investigate the issue. AV3V infusion with a GABAA antagonist bicuculline increased plasma vasopressin (AVP), glucose, blood pressure (BP), and heart rate in rats. These events were abolished by preinjecting its agonist muscimol, whereas the infusion with allopregnanolone, a NS capable of potentiating GABAA-R function, affected none of the variables in the absence or presence of such bicuculline actions. Similarly, AV3V infusion with pregnanolone sulfate, a NS capable of antagonizing GABAA-R, produced no effect on those variables. AV3V infusion with muscimol was effective in inhibiting the responses of plasma AVP or glucose, or BP to an osmotic loading or bleeding. However, AV3V infusion with aminoglutethimide, a NS synthesis inhibitor, did not affect any of the variables in the absence or presence of those stimuli. These results suggest that NS may not cause acute effects on the AV3V GABAergic mechanism involved in regulating AVP release and other autonomic function. PMID:25598212

  17. D1-like dopamine receptors selectively block P/Q-type calcium channels to reduce glutamate release onto cholinergic basal forebrain neurones of immature rats

    PubMed Central

    Momiyama, Toshihiko; Fukazawa, Yugo

    2007-01-01

    Whole-cell patch-clamp recordings of non-NMDA glutamatergic EPSCs were made from identified cholinergic neurones in slices of basal forebrain (BF) of young rats (P13–P18), to investigate the subtypes of calcium channels involved in dopamine D1-like receptor-mediated presynaptic inhibition of the EPSCs. The BF cholinergic neurones were pre-labelled by intracerebroventricular injection of a fluorescent marker, Cy3-192IgG. A D1-like receptor agonist, SKF 81297 (30 μm) suppressed the EPSCs reversibly by about 30%, and this inhibition was reproducible. Calcium channel subtypes involved in the glutamatergic transmission were elucidated using selective Ca2+ channel blockers. The N-type Ca2+ channel blocker ω-conotoxin (ω-CgTX, 3 μm) suppressed the EPSCs by 57.5%, whereas the P/Q-type channel selective blocker ω-agatoxin-TK (ω-Aga-TK, 200 nm) suppressed the EPSCs by 68.9%. Simultaneous application of both blockers suppressed the EPSCs by 96.1%. The R-type Ca2+ channel blocker SNX-482 (300 nm) suppressed the EPSCs by 18.4%, whereas nifedipine, the L-type Ca2+ channel blocker (10 μm), had little effect. In the presence of ω-Aga-TK, SKF 81297, a dopamine D1-like receptor agonist, had no effect on the EPSCs. On the other hand, SKF 81297 could still inhibit the EPSCs in the presence of either ω-CgTX, SNX-482 or nifedipine. SKF 81297 had no further effect on the EPSCs when external Ca2+ concentration was raised to 7.2 mm in the presence of ω-Aga-TK, but could still inhibit the EPSCs in high Ca2+ solution after ω-CgTX application. Forskolin (FK, 10 μm), an activator of adenylyl cyclase pathway, suppressed the EPSCs, and the FK-induced effect was mostly blocked in the presence of ω-Aga-TK but not that of ω-CgTX. These results suggest that D1-like receptor activation selectively blocks P/Q-type calcium channels to reduce glutamate release onto BF cholinergic neurones. PMID:17234695

  18. Molecular Diversity Subdivides the Adult Forebrain Neural Stem Cell Population

    PubMed Central

    Giachino, Claudio; Basak, Onur; Lugert, Sebastian; Knuckles, Philip; Obernier, Kirsten; Fiorelli, Roberto; Frank, Stephan; Raineteau, Olivier; Alvarez–Buylla, Arturo; Taylor, Verdon

    2014-01-01

    Neural stem cells (NSCs) in the ventricular domain of the subventricular zone (V-SVZ) of rodents produce neurons throughout life while those in humans become largely inactive or may be lost during infancy. Most adult NSCs are quiescent, express glial markers, and depend on Notch signaling for their self-renewal and the generation of neurons. Using genetic markers and lineage tracing, we identified subpopulations of adult V-SVZ NSCs (type 1, 2, and 3) indicating a striking heterogeneity including activated, brain lipid binding protein (BLBP, FABP7) expressing stem cells. BLBP+ NSCs are mitotically active components of pinwheel structures in the lateral ventricle walls and persistently generate neurons in adulthood. BLBP+ NSCs express epidermal growth factor (EGF) receptor, proliferate in response to EGF, and are a major clonogenic population in the SVZ. We also find BLBP expressed by proliferative ventricular and sub-ventricular progenitors in the fetal and postnatal human brain. Loss of BLBP+ stem/progenitor cells correlates with reduced neurogenesis in aging rodents and postnatal humans. These findings of molecular heterogeneity and proliferative differences subdivide the NSC population and have implications for neurogenesis in the forebrain of mammals during aging. PMID:23964022

  19. Developmental expression of vascular endothelial growth factor receptor 3 and vascular endothelial growth factor C in forebrain.

    PubMed

    Ward, M C; Cunningham, A M

    2015-09-10

    Increased understanding of the neurovascular niche suggests that development of the central nervous system (CNS) and its vasculature is coordinated through shared regulatory factors. These include the vascular endothelial growth factor (VEGF) family, reported to promote neuroproliferation and neuroprotection in addition to angiogenesis via its receptors VEGFR1-3. VEGFR3, a mediator of lymphangiogenesis, is expressed in murine and rat brain from early gestation, has been associated with neural progenitors and neurons (Choi et al., 2010) and oligodendroglia (Le Bras et al., 2006) in the developing cortex and is reported to mediate adult neurogenesis in the subventricular zone (SVZ) (Calvo et al., 2011). The early expression pattern of VEGFR3 protein and its cellular associations has not as yet been comprehensively reported. We describe the temporal expression of VEGFR3 protein at a cellular level and its close association with its VEGFC ligand, determined by double-labeling immunohistochemistry in the developing rat brain from embryonic day (E) 13 to postnatal day (P) 23. We found high expression of VEGFR3 in the ventricular zone and along radial glia in early gestation in association with neural stem cells and neuroblasts. Similar expression patterns were seen in the immature olfactory bulb and optic cup. In later development we found less expression by neural progenitors in proliferative regions including the SVZ and dentate gyrus of the hippocampus. In contrast, VEGFR3 expression increased with development in the cortex in neurons and astrocytes, and appeared in the emerging population of oligodendroglial progenitors. High expression in ventricular ependyma, choroid plexus and pigmented retinal epithelium was noted from E18. VEGFC ligand was found in association with VEGFR3 throughout development, with highest expression in embryonic stages. Our findings suggest an important role for VEGFC/VEGFR3 signaling in neuronal proliferation in early forebrain development

  20. A tyrosine hydroxylase-neurofilament chimeric promoter enhances long-term expression in rat forebrain neurons from helper virus-free HSV-1 vectors.

    PubMed

    Zhang, G R; Wang, X; Yang, T; Sun, M; Zhang, W; Wang, Y; Geller, A I

    2000-12-01

    Helper virus-free herpes simplex virus (HSV-1) plasmid vectors are attractive for neural gene transfer, but a promoter that supports neuronal-specific, long-term expression is required. Although expression from many promoters is unstable, a 6.8-kb, but not a 766-bp, fragment of the tyrosine hydroxylase (TH) promoter supports long-term expression. Thus, 5' upstream sequences in this promoter may enhance expression. In this study, we evaluated expression from vectors that contain 5' upstream sequences from this promoter (-0.5 to -6.8 kb) inserted at the 5' end of either a neurofilament heavy subunit (NF-H) promoter or the cytomegalovirus (CMV) immediate early promoter. The TH-NFH promoter supported expression for 6 months in the striatum, 2 months in the hippocampus, and for 1 month in both perirhinal and postrhinal cortex (the longest time points examined). Expression was targeted to neurons. The enhanced expression may require specific sequences in the TH promoter fragment because replacing this fragment with a similar sized fragment of bacteriophage lambda DNA did not enhance expression. The reverse orientation of the TH promoter fragment also enhanced expression. Insertion of insulators from the chicken beta-globin locus between the TH-NFHlac transcription unit and the vector backbone may support a modest additional enhancement in expression. Other eucaryotic sequences may also enhance expression; a S. cerevisiae (40-kb fragment)-NFH promoter enhanced expression. In contrast, the TH-CMV promoter did not enhance expression. Thus, the TH-NFH promoter may support some physiological studies that require long-term expression in forebrain neurons. PMID:11113528

  1. The association of thirst, sodium appetite and vasopressin release with c-fos expression in the forebrain of the rat after intracerebroventricular injection of angiotensin II, angiotensin-(1-7) or carbachol.

    PubMed

    Mahon, J M; Allen, M; Herbert, J; Fitzsimons, J T

    1995-11-01

    The effect intracerebroventricular injections of angiotensin II (0.1 nm), angiotensin-(1-7) (1 or 100 nm) and carbachol (500 ng) on c-fos expression was examined in the forebrain of Lister hooded rats. Intense staining of the c-Fos protein was found in the median preoptic nucleus, organum vasculosum of the lamina terminalis, subfornical organ, paraventricular nucleus and supraoptic nucleus after angiotensin II and carbachol Angiotensin II caused significantly more c-fos expression in the ventral median preoptic nucleus and organum vasculosum of the lamina terminalis than carbachol, whereas in the paraventricular and supraoptic nuclei this was reversed, with carbachol having a greater effect on c-fos expression in these areas. Angiotensin-(1-7), however, only induced c-Fos protein in the organum vasculosum of the lamina terminalis and median preoptic nucleus with the number and the intensity of staining of the nuclei significantly less in both areas than after angiotensin II or carbachol. Separate groups of Lister rats were given i.c.v. injections of the same substances at the same doses, but excluding the lower dose of angiotensin-(1-7), and the intakes of water and 1.8% NaCl over 60 min were measured. Angiotensin II stimulated intakes of both water and NaCl. The effect on water intake was almost immediate (<1 min), whereas NaCl intake did not usually start until at least 5 min after injection. Over 60 min, water (12.4 +/- 1.0 ml) and NaCl (4.2 +/- 0.9 ml) intakes were significantly greater than water (1.1 +/- 0.2 ml) and NaCl (0.6 +/- 0.5 ml) intakes of the controls. Carbachol caused less drinking than angiotensin II, the water intake over 60 min being significantly less (4.8 +/- 0.7 ml) and the latency of response greater (>5 min). Carbachol, unlike angiotensin II, had little effect on NaCl intake (0.7 +/- 0.4 ml). Angiotensin-(1-7) had no effect on water (1.1 +/- 0.3 ml) or NaCl (0.3 +/- 0.3 ml) intakes. The plasma levels of vasopressin were measured after i

  2. Effects of footshocks on anxiety-like behavior and mRNA levels of precursor peptides for corticotropin releasing factor and opioids in the forebrain of the rat.

    PubMed

    Wang, Huiying; Li, Sa; Kirouac, Gilbert J

    2015-12-01

    Corticotropin releasing factor (CRF) and dynorphin are neuropeptides that are associated with the negative emotional states. Experimental evidence indicates that dynorphin neurons located in the nucleus accumbens and CRF neurons in the bed nucleus of the stria terminalis (BST) and the central nucleus of the amygdala (CeA) mediate anxiety-like behaviors immediately after the stressful experience (24-48h). The present study was done to evaluate if changes in the levels of the mRNA for these peptides in the striatum, BST, and CeA were associated with the long-lasting avoidance of novelty, a measure of an anxiety-like state, in a subset of rats exposed to unpredictable and moderately intense footshocks (5×2s of 1.5mA). Shocked rats with enhanced fear to a novel tone 24h after the footshocks (high responders; HR) displayed long-lasting avoidance in the elevated T-maze whereas shocked rats with low levels of acute fear (low responders; LR) had low levels of avoidance similar to nonshocked rats. An increase in the level of proCRF mRNA was detected in the CeA of the HR compared to LR and nonshocked rats but not in other areas of the brain sampled. In contrast, prodynorphin and proenkephalin mRNA levels in the striatum, BST and CeA were not different between HR, LR and nonshocked rats. This study provides evidence that CRF neurons in the CeA may play a role in the anxiety-like state produced in a subset of rats exposed to footshocks. PMID:26363852

  3. Effects of hypocretin (orexin) neuronal loss on sleep and extracellular adenosine levels in the basal forebrain

    PubMed Central

    Murillo-Rodriguez, Eric; Liu, Meng; Blanco-Centurion, Carlos; Shiromani, Priyattam J.

    2009-01-01

    Neurons containing the neuropeptide hypocretin (orexin) are localized only in the lateral hypothalamus from where they innervate multiple regions implicated in arousal, including the basal forebrain. HCRT activation of downstream arousal neurons is likely to stimulate release of endogenous factors. One such factor is adenosine (AD), which in the basal forebrain increases with waking and decreases with sleep, and is hypothesized to regulate the waxing and waning of sleep drive. Does loss of HCRT neurons affect AD levels in the basal forebrain? Is the increased sleep that accompanies HCRT loss a consequence of higher AD levels in the basal forebrain? In the present study, we investigate these questions by lesioning the HCRT neurons (hypocretin-2-saporin) and measuring sleep and extracellular levels of AD in the basal forebrain. In separate groups of rats, the neurotoxin HCRT2-SAP or saline were administered locally to the lateral hypothalamus and 80 days later AD and sleep were assessed. Rats given the neurotoxin had a 94% loss of the HCRT neurons. These rats awake less at night, and had more REM sleep, which is consistent with a HCRT hypofunction. These rats also had more sleep after brief periods of sleep deprivation. However, in the lesioned rats, AD levels did not increase with 6h sleep deprivation, whereas such an increase in AD occurred in rats without lesion of the HCRT neurons. These findings indicate that AD levels do not increase with waking in rats with a HCRT lesion, and that the increased sleep in these rats occurs independently of AD levels in the basal forebrain. PMID:18783368

  4. Reproducible expansion and characterization of mouse neural stem/progenitor cells in adherent cultures derived from the adult subventricular zone

    PubMed Central

    Theus, Michelle H.; Ricard, Jerome; Liebl, Daniel J.

    2012-01-01

    Endogenous neural stem/progenitor cells (NSPCs) residing in the subventricular zone (SVZ) of the adult mouse forebrain have been shown to enhance their neurogenic potential in response to CNS injury. Mechanisms involved in regulating adult neurogenesis under naïve or stressed conditions can be studied using a monolayer cell-culture system of the nestin-expressing NSPC lineage to analyze proliferation, survival and differentiation. Here, we describe a protocol for the expansion of NSPCs for studies aimed at understanding the functional role of NSPCs in maintaining adult neurogenic processes. In this unit, we outline in detail the procedures for: (1) isolation, maintenance and culture of the NSPC component of the SVZ niche from the lateral wall of the lateral ventricle; (2) characterization of NSPC functions by examining proliferation, survival and differentiation; and (3) efficient siRNA transfection methods in 96-well format. PMID:22415840

  5. Forebrain Mechanisms of Nociception and Pain: Analysis through Imaging

    NASA Astrophysics Data System (ADS)

    Casey, Kenneth L.

    1999-07-01

    Pain is a unified experience composed of interacting discriminative, affective-motivational, and cognitive components, each of which is mediated and modulated through forebrain mechanisms acting at spinal, brainstem, and cerebral levels. The size of the human forebrain in relation to the spinal cord gives anatomical emphasis to forebrain control over nociceptive processing. Human forebrain pathology can cause pain without the activation of nociceptors. Functional imaging of the normal human brain with positron emission tomography (PET) shows synaptically induced increases in regional cerebral blood flow (rCBF) in several regions specifically during pain. We have examined the variables of gender, type of noxious stimulus, and the origin of nociceptive input as potential determinants of the pattern and intensity of rCBF responses. The structures most consistently activated across genders and during contact heat pain, cold pain, cutaneous laser pain or intramuscular pain were the contralateral insula and anterior cingulate cortex, the bilateral thalamus and premotor cortex, and the cerebellar vermis. These regions are commonly activated in PET studies of pain conducted by other investigators, and the intensity of the brain rCBF response correlates parametrically with perceived pain intensity. To complement the human studies, we developed an animal model for investigating stimulus-induced rCBF responses in the rat. In accord with behavioral measures and the results of human PET, there is a progressive and selective activation of somatosensory and limbic system structures in the brain and brainstem following the subcutaneous injection of formalin. The animal model and human PET studies should be mutually reinforcing and thus facilitate progress in understanding forebrain mechanisms of normal and pathological pain.

  6. The effect of clonidine on cell survival, glutamate, and aspartate release in normo- and hyperglycemic rats after near complete forebrain ischemia.

    PubMed

    Jellish, W Scott; Murdoch, John; Kindel, Gisela; Zhang, Xin; White, Fletcher A

    2005-12-01

    The present study was undertaken to investigate the effects of the alpha2 adrenergic agonist, clonidine, on the near complete cerebral ischemia (NCFI) evoked release of glutamate and aspartate from normo- and hyperglycemic rodent brain tissue using microdialysis tissue techniques. Hemodynamic variables, blood lactate, and glucose levels were monitored throughout the 40 min NCFI occlusion period. After 48 h, rats were killed and the extent of neuronal injury was determined in the cortex, striatum, and hippocampus. Hemodynamic variables recorded during ischemia improved with clonidine treatment in both normo- and hyperglycemic groups. Glutamate and aspartate levels were greatly increased over control values during normo- and hyperglycemic NCFI treatment. Clonidine pretreatment suppressed the release of both glutamate and aspartate during NCFI in normo- and hyperglycemic rodents when compared with NCFI-treated normo- and hyperglycemic rats without the drug. Significant neuroprotection of cells in the cortex, striatum, and hippocampus was also observed in drug-treated animals 48 h postischemia. The combined effects of diminished glutamate release after NCFI and reduced neuronal injury in both normo- and hyperglycemic states suggests that clonidine treatment during NCFI is neuroprotective. The neuroprotective effect of clonidine during ischemia may be ascribed to both a sensitization of central sympathetic activity and a reduced release of glutamate thereby reducing NMDA receptor activation and neuronal damage. PMID:16044300

  7. A mathematical model of adult subventricular neurogenesis

    PubMed Central

    Ashbourn, J. M. A.; Miller, J. J.; Reumers, V.; Baekelandt, V.; Geris, L.

    2012-01-01

    Neurogenesis has been the subject of active research in recent years and many authors have explored the phenomenology of the process, its regulation and its purported purpose. Recent developments in bioluminescent imaging (BLI) allow direct in vivo imaging of neurogenesis, and in order to interpret the experimental results, mathematical models are necessary. This study proposes such a mathematical model that describes adult mammalian neurogenesis occurring in the subventricular zone and the subsequent migration of cells through the rostral migratory stream to the olfactory bulb (OB). This model assumes that a single chemoattractant is responsible for cell migration, secreted both by the OB and in an endocrine fashion by the cells involved in neurogenesis. The solutions to the system of partial differential equations are compared with the physiological rodent process, as previously documented in the literature and quantified through the use of BLI, and a parameter space is described, the corresponding solution to which matches that of the rodent model. A sensitivity analysis shows that this parameter space is stable to perturbation and furthermore that the system as a whole is sloppy. A large number of parameter sets are stochastically generated, and it is found that parameter spaces corresponding to physiologically plausible solutions generally obey constraints similar to the conditions reported in vivo. This further corroborates the model and its underlying assumptions based on the current understanding of the investigated phenomenon. Concomitantly, this leaves room for further quantitative predictions pertinent to the design of future proposed experiments. PMID:22572029

  8. Effects of intracerebroventricular dizocilpine (MK801) on dehydration-induced dipsogenic responses, plasma vasopressin and c-fos expression in the rat forebrain.

    PubMed

    Xu, Z; Herbert, J

    1998-02-16

    This study determines the interaction between glutamate receptors and dehydration-induced drinking, vasopressin (AVP) release, plasma osmolality and c-fos expression in the brain of conscious rats. The NMDA receptor antagonist dizocilpine (100 nmol infused into the cerebral ventricles) suppressed drinking following either 22 h water deprivation or intragastric injection of hypertonic saline (1.5 M), attenuated the increased plasma vasopressin induced by dehydration, but had no effects on peripheral hyperosmolality caused by either water deprivation or injections of hypertonic saline. Dizocilpine had no inhibitory effects on feeding after 24 h food deprivation. Dizocilpine also suppressed c-fos expression induced by dehydration in the median preoptic nucleus (MPN), the supraoptic and paraventricular nuclei (SON and PVN), but did not influence c-fos expression in the subfornical organ (SFO). The non-NMDA receptor antagonists CNQX (400 nmol) or DNQX (60 nmol) affected neither the animals' drinking nor c-fos expression induced by dehydration. Double staining showed that suppression of c-fos expression following dizocilpine occurred in the NMDA R1 receptor containing neurons in the hypothalamus. These results suggest that the NMDA-type glutamate receptors may be involved in dehydration induced dipsogenic and neuroendocrinological responses. They complement our earlier findings that dizocilpine also attenuates drinking and c-fos expression following intraventricular infusions of angiotensin II. PMID:9518565

  9. Amphetamine elevates phosphorylation of eukaryotic initiation factor 2α (eIF2α) in the rat forebrain via activating dopamine D1 and D2 receptors.

    PubMed

    Xue, Bing; Fitzgerald, Cole A; Jin, Dao-Zhong; Mao, Li-Min; Wang, John Q

    2016-09-01

    Psychostimulants have an impact on protein synthesis, although underlying molecular mechanisms are unclear. Eukaryotic initiation factor 2α-subunit (eIF2α) is a key player in initiation of protein translation and is regulated by phosphorylation. While this factor is sensitive to changing synaptic input and is critical for synaptic plasticity, its sensitivity to stimulants is poorly understood. Here we systematically characterized responses of eIF2α to a systemic administration of the stimulant amphetamine (AMPH) in dopamine responsive regions of adult rat brains. Intraperitoneal injection of AMPH at 5mg/kg increased eIF2α phosphorylation at serine 51 in the striatum. This increase was transient. In the medial prefrontal cortex (mPFC), AMPH induced a relatively delayed phosphorylation of the factor. Pretreatment with a dopamine D1 receptor antagonist SCH23390 blocked the AMPH-stimulated eIF2α phosphorylation in both the striatum and mPFC. Similarly, a dopamine D2 receptor antagonist eticlopride reduced the effect of AMPH in the two regions. Two antagonists alone did not alter basal eIF2α phosphorylation. AMPH and two antagonists did not change the amount of total eIF2α proteins in both regions. These results demonstrate the sensitivity of eIF2α to stimulant exposure. AMPH possesses the ability to stimulate eIF2α phosphorylation in striatal and mPFC neurons in vivo in a D1 and D2 receptor-dependent manner. PMID:27338925

  10. Subventricular zone cytoarchitecture changes in autism.

    PubMed

    Kotagiri, Prasanti; Chance, Steven A; Szele, Francis G; Esiri, Margaret M

    2014-01-01

    Autism is thought to be a neurodevelopmental disorder with symptoms developing during neonatal neurogenesis in the subventricular zone (SVZ). Autism associated genes alter SVZ proliferation and cytoarchitecture, yet the response of the human SVZ in autism is unknown. Epilepsy drives neurogenesis in rodents, but it is unclear how epilepsy interacts with autism in SVZ responses. The striatal and septal SVZ derive from separate lineages in rodents and generate different interneuron types. Yet it is unclear if autism unevenly regulates the striatal and septal SVZ. The human SVZ was immunohistochemically examined post-mortem from individuals with autism (n = 11) and controls (n = 11). Autism showed a lower cell density in the septal, but not striatal, SVZ hypocellular gap only in the absence of epilepsy. There was a decline in septal hypocellular gap cells with age in autism, but no correlation with age in controls. In contrast, PCNA+ cell numbers increased only in autism with epilepsy both in the hypocellular gap and in the ependymal layer on the septal but not striatal side. Ependymal cells also became GFAP immunoreactive in autism irrespective of epilepsy co-morbidity; however, this only occurred on the striatal side. In examining these questions we also discovered a subset of ependymal, astrocyte ribbon and RMS cells which express PCNA and Ki67, PLP, and α-tubulin. These results are the first example of a neuropsychiatric disease differentially affecting the septal and striatal SVZ. Altered cell density in the hypocellular gap and proliferation marker expression suggest individuals with autism may follow a different growth-trajectory. PMID:24002902

  11. STEREOLOGICAL ESTIMATES OF THE BASAL FOREBRAIN CELL POPULATION IN THE RAT, INCLUDING NEURONS CONTAINING CHOLINE ACETYLTRANSFERASE (ChAT), GLUTAMIC ACID DECARBOXYLASE (GAD) OR PHOSPHATE-ACTIVATED GLUTAMINASE (PAG) AND COLOCALIZING VESICULAR GLUTAMATE TRANSPORTERS (VGluTs)

    PubMed Central

    GRITTI, I.; HENNY, P.; GALLONI, F.; MAINVILLE, L.; MARIOTTI, M.; JONES, B. E.

    2006-01-01

    The basal forebrain (BF) plays an important role in modulating cortical activity and influencing attention, learning and memory. These activities are fulfilled importantly yet not entirely by cholinergic neurons. Noncholinergic neurons also contribute and are comprised by GABAergic neurons and other possibly glutamatergic neurons. The aim of the present study was to estimate the total number of cells in the BF of the rat and the proportions of that total represented by cholinergic, GABAergic and glutamatergic neurons. For this purpose, cells were counted using unbiased stereological methods within the medial septum, diagonal band, magnocellular preoptic nucleus, substantia innominata and globus pallidus in sections stained for Nissl substance and/or the neurotransmitter enzymes, choline acetyltransferase (ChAT), glutamic acid decarboxylase (GAD) or phosphate-activated glutaminase (PAG). In Nissl-stained sections, the total number of neurons in the BF was estimated as ~355,000 and the numbers of ChAT-immuno-positive (+) as ~22,000, GAD+ ~119,000 and PAG+ ~316,000, corresponding to ~5%, ~35% and ~90% of the total. Thus, of the large population of BF neurons, only a small proportion has the capacity to synthesize acetylcholine (ACh), one third to synthesize GABA and the vast majority to synthesize glutamate (Glu). Moreover, through the presence of PAG, a proportion of ACh- and GABA-synthesizing neurons also have the capacity to synthesize Glu. In sections dual fluorescent immunostained for vesicular transporters, VGluT3 and not VGluT2 was present in the cell bodies of most PAG+ and ChAT+ and half the GAD+ cells. Given previous results showing that VGluT2 and not VGluT3 was present in BF axon terminals and not colocalized with VAChT or VGAT, we conclude that the BF cell population influences cortical and subcortical regions through neurons which release ACh, GABA or Glu from their terminals but which in part can also synthesize and release Glu from their soma or

  12. Extensive Lesions of Cholinergic Basal Forebrain Neurons Do Not Impair Spatial Working Memory

    ERIC Educational Resources Information Center

    Vuckovich, Joseph A.; Semel, Mara E.; Baxter, Mark G.

    2004-01-01

    A recent study suggests that lesions to all major areas of the cholinergic basal forebrain in the rat (medial septum, horizontal limb of the diagonal band of Broca, and nucleus basalis magnocellularis) impair a spatial working memory task. However, this experiment used a surgical technique that may have damaged cerebellar Purkinje cells. The…

  13. CONDITIONAL ABLATION AND RECOVERY OF FOREBRAIN NEUROGENESIS IN THE MOUSE

    PubMed Central

    Singer, Benjamin H.; Jutkiewicz, Emily M.; Fuller, Cynthia L.; Lichtenwalner, Robin J.; Zhang, Helen; Velander, Alan J.; Li, Xiangquan; Gnegy, Margaret E.; Burant, Charles F.; Parent, Jack M.

    2009-01-01

    Forebrain neurogenesis persists throughout life in the rodent subventricular zone (SVZ) and hippocampal dentate gyrus (DG). Several strategies have been employed to eliminate adult neurogenesis and thereby determine whether depleting adult-born neurons disrupts specific brain functions, but some approaches do not specifically target neural progenitors. We have developed a transgenic mouse line to reversibly ablate adult neural stem cells and suppress neurogenesis. The nestin-tk mouse expresses herpes simplex virus thymidine kinase (tk) under the control of the nestin 2nd intronic enhancer, which drives expression in neural progenitors. Administration of ganciclovir (GCV) kills actively dividing cells expressing this transgene. We found that peripheral GCV administration suppressed SVZ-olfactory bulb and DG neurogenesis within two weeks but caused systemic toxicity. Intracerebroventricular GCV infusion for 28 days nearly completely depleted proliferating cells and immature neurons in both the SVZ and DG without systemic toxicity. Reversibility of the effects after prolonged GCV infusion was slow and partial. Neurogenesis did not recover 2 weeks after cessation of GCV administration, but showed limited recovery 6 weeks after GCV that differed between the SVZ and DG. Suppression of neurogenesis did not inhibit antidepressant responsiveness of mice in the tail suspension test. These findings indicate that SVZ and DG neural stem cells differ in their capacity for repopulation, and that adult-born neurons are not required for antidepressant responses in a common behavioral test of antidepressant efficacy. The nestin-tk mouse should be useful for studying how reversible depletion of adult neurogenesis influences neurophysiology, other behaviors, and neural progenitor dynamics. PMID:19363795

  14. Learning and the motivation to eat: Forebrain circuitry

    PubMed Central

    Petrovich, Gorica D.

    2011-01-01

    Appetite and eating are not only controlled by energy needs, but also by extrinsic factors that are not directly related to energy balance. Environmental signals that acquire motivational properties through associative learning—learned cues—can override homeostatic signals and stimulate eating in sated states, or inhibit eating in states of hunger. Such influences are important, as environmental factors are believed to contribute to the increased susceptibility to overeating and the rise in obesity in the developed world. Similarly, environmental and social factors contribute to the onset and maintenance of anorexia nervosa and other eating disorders through interactions with the individual genetic background. Nevertheless, how learning enables environmental signals to control feeding, and the underlying brain mechanisms are poorly understood. We developed two rodent models to study how learned cues are integrated with homeostatic signals within functional forebrain networks, and how these networks are modulated by experience. In one model, a cue previously paired with food when an animal was hungry induces eating in sated rats. In the other model, food-deprived rats inhibit feeding when presented with a cue that signals danger, a tone previously paired with footshocks. Here evidence will be reviewed that the forebrain network formed by the amygdala, lateral hypothalamus and medial prefrontal cortex mediates cue-driven feeding, while a parallel amygdalar circuitry mediates suppression of eating by the fear cue. Findings from the animal models may be relevant for understanding aspects of human appetite and eating, and maladaptive mechanisms that could lead to overeating and anorexia. PMID:21549730

  15. Primary cilia and forebrain development.

    PubMed

    Willaredt, Marc August; Tasouri, Evangelia; Tucker, Kerry L

    2013-01-01

    With a microtubule-based axoneme supporting its plasma membrane-ensheathed projection from the basal body of almost all cell types in the human body, and present in only one copy per cell, the primary cilium can be considered an organelle sui generis. Although it was first observed and recorded in histological studies from the late 19th century, the tiny structure was essentially forgotten for many decades. In the past ten years, however, scientists have turned their eyes once again upon primary cilia and realized that they are very important for the development of almost all organs in the mammalian body, especially those dependent upon the signaling from members Hedgehog family, such as Indian and Sonic hedgehog. In this review, we outline the roles that primary cilia play in forebrain development, not just in the crucial transduction of Sonic hedgehog signaling, but also new results showing that cilia are important for cell cycle progression in proliferating neural precursors. We will focus upon cerebral cortex development but will also discuss the importance of cilia for the embryonic hippocampus, olfactory bulb, and diencephalon. PMID:23085524

  16. Evolutionary origin of Tbr2-expressing precursor cells and the subventricular zone in the developing cortex.

    PubMed

    Martínez-Cerdeño, Verónica; Cunningham, Christopher L; Camacho, Jasmin; Keiter, Janet A; Ariza, Jeanelle; Lovern, Matthew; Noctor, Stephen C

    2016-02-15

    The subventricular zone (SVZ) is greatly expanded in primates with gyrencephalic cortices and is thought to be absent from vertebrates with three-layered, lissencephalic cortices, such as the turtle. Recent work in rodents has shown that Tbr2-expressing neural precursor cells in the SVZ produce excitatory neurons for each cortical layer in the neocortex. Many excitatory neurons are generated through a two-step process in which Pax6-expressing radial glial cells divide in the VZ to produce Tbr2-expressing intermediate progenitor cells, which divide in the SVZ to produce cortical neurons. We investigated the evolutionary origin of SVZ neural precursor cells in the prenatal cerebral cortex by testing for the presence and distribution of Tbr2-expressing cells in the prenatal cortex of reptilian and avian species. We found that mitotic Tbr2(+) cells are present in the prenatal cortex of lizard, turtle, chicken, and dove. Furthermore, Tbr2(+) cells are organized into a distinct SVZ in the dorsal ventricular ridge (DVR) of turtle forebrain and in the cortices of chicken and dove. Our results are consistent with the concept that Tbr2(+) neural precursor cells were present in the common ancestor of mammals and reptiles. Our data also suggest that the organizing principle guiding the assembly of Tbr2(+) cells into an anatomically distinct SVZ, both developmentally and evolutionarily, may be shared across vertebrates. Finally, our results indicate that Tbr2 expression can be used to test for the presence of a distinct SVZ and to define the boundaries of the SVZ in developing cortices. PMID:26267763

  17. Age-related changes in rostral basal forebrain cholinergic and GABAergic projection neurons: Relationship with spatial impairment

    PubMed Central

    Bañuelos, C.; LaSarge, C. L.; McQuail, J. A.; Hartman, J. J.; Gilbert, R. J.; Ormerod, B. K.; Bizon, J. L.

    2013-01-01

    Both cholinergic and GABAergic projections from the rostral basal forebrain have been implicated in hippocampal function and mnemonic abilities. While dysfunction of cholinergic neurons has been heavily implicated in age-related memory decline, significantly less is known regarding how age-related changes in co-distributed GABAergic projection neurons contribute to a decline in hippocampal-dependent spatial learning. In the current study, confocal stereology was used to quantify cholinergic (choline acetyltransferase (ChAT) immunopositive) neurons, GABAergic projection (glutamic decarboxylase 67 (GAD67) immunopositive) neurons, and total (NeuN immunopositive) neurons in the rostral basal forebrain of young and aged rats that were first characterized on a spatial learning task. ChAT immunopositive neurons were significantly but modestly reduced in aged rats. Although ChAT immunopositive neuron number was strongly correlated with spatial learning abilities among young rats, the reduction of ChAT immunopositive neurons was not associated with impaired spatial learning in aged rats. In contrast, the number of GAD67 immunopositive neurons was robustly and selectively elevated in aged rats that exhibited impaired spatial learning. Interestingly, the total number of rostral basal forebrain neurons was comparable in young and aged rats, regardless of their cognitive status. These data demonstrate differential effects of age on phenotypically distinct rostral basal forebrain projection neurons, and implicate dysregulated cholinergic and GABAergic septohippocampal circuitry in age-related mnemonic decline. PMID:22817834

  18. HSPC280, a winged helix protein expressed in the subventricular zone of the developing ganglionic eminences, inhibits neuronal differentiation.

    PubMed

    Stylianopoulou, Electra; Kalamakis, Georgios; Pitsiani, Margarita; Fysekis, Ioannis; Ypsilantis, Petros; Simopoulos, Constantinos; Skavdis, George; Grigoriou, Maria E

    2016-02-01

    Winged helix proteins have critical roles in a variety of developmental processes. During a screening for genes expressed in the developing forebrain, we identified HSPC280, a non-typical winged helix protein, which shares similarity with a protein-protein interaction domain found in the proteins of the actin-binding Rho-activating protein family. In this work, we analyzed HSPC280 expression during mouse development as well as during neuronal differentiation of mouse Neuro2a cells. HSPC280 expression is tightly regulated; during mouse development, it was detected predominantly in the ganglionic eminences of the ventral telencephalon, from their appearance at E11.5 to P0, with the highest levels between E13.5 and E15.5, a period that correlates with the peak of neurogenesis in these structures. Comparative expression analysis of HSPC280 with Dlx2, cyclinD2 and Lhx6 revealed that, within the ganglionic eminences, HSPC280 was restricted in the proliferating cell population of the subventricular zone, in a pattern similar to that of cyclinD2. Finally, we showed that HSPC280 is a nuclear protein which, when overexpressed in Neuro2a cells, it inhibited neuronal differentiation in vitro, suggesting its involvement in the mechanisms controlling neural progenitor cells proliferation. PMID:26537243

  19. Basal forebrain neuronal inhibition enables rapid behavioral stopping

    PubMed Central

    Mayse, Jeffrey D.; Nelson, Geoffrey M.; Avila, Irene; Gallagher, Michela; Lin, Shih-Chieh

    2015-01-01

    Cognitive inhibitory control, the ability to rapidly suppress responses inappropriate for the context, is essential for flexible and adaptive behavior. While most studies on inhibitory control have focused on the fronto-basal-ganglia circuit, here we explore a novel hypothesis and show that rapid behavioral stopping is enabled by neuronal inhibition in the basal forebrain (BF). In rats performing the stop signal task, putative noncholinergic BF neurons with phasic bursting responses to the go signal were inhibited nearly completely by the stop signal. The onset of BF neuronal inhibition was tightly coupled with and temporally preceded the latency to stop, the stop signal reaction time. Artificial inhibition of BF activity in the absence of the stop signal was sufficient to reproduce rapid behavioral stopping. These results reveal a novel subcortical mechanism of rapid inhibitory control by the BF, which provides bidirectional control over the speed of response generation and inhibition. PMID:26368943

  20. Subventricular zone progenitors in time and space: generating neuronal diversity

    PubMed Central

    Sequerra, Eduardo B.

    2014-01-01

    The adult mammalian brain harbors a population of cells around their lateral ventricles capable of giving rise to new neurons throughout life. The so-called subventricular zone (SVZ) is a heterogeneous germinative niche in regard to the neuronal types it generates. SVZ progenitors give rise to different olfactory bulb (OB) interneuron types in accordance to their position along the ventricles. Here, I review data showing the difference between progenitors located along different parts of the SVZ axes and ages. I also discuss possible mechanisms for the origin of this diversity. PMID:25565967

  1. Serotonin 5-HT4 receptors and forebrain cholinergic system: receptor expression in identified cell populations.

    PubMed

    Peñas-Cazorla, Raúl; Vilaró, M Teresa

    2015-11-01

    Activation of serotonin 5-HT4 receptors has pro-cognitive effects on memory performance. The proposed underlying neurochemical mechanism is the enhancement of acetylcholine release in frontal cortex and hippocampus elicited by 5-HT4 agonists. Although 5-HT4 receptors are present in brain areas related to cognition, e.g., hippocampus and cortex, the cellular localization of the receptors that might modulate acetylcholine release is unknown at present. We have analyzed, using dual label in situ hybridization, the cellular localization of 5-HT4 receptor mRNA in identified neuronal populations of the rat basal forebrain, which is the source of the cholinergic innervation to cortex and hippocampus. 5-HT4 receptor mRNA was visualized with isotopically labeled oligonucleotide probes, whereas cholinergic, glutamatergic, GABAergic and parvalbumin-synthesizing neurons were identified with digoxigenin-labeled oligonucleotide probes. 5-HT4 receptor mRNA was not detected in the basal forebrain cholinergic cell population. In contrast, basal forebrain GABAergic, parvalbumin synthesizing, and glutamatergic cells contained 5-HT4 receptor mRNA. Hippocampal and cortical glutamatergic neurons also express this receptor. These results indicate that 5-HT4 receptors are not synthesized by cholinergic cells, and thus would be absent from cholinergic terminals. In contrast, several non-cholinergic cell populations within the basal forebrain and its target hippocampal and cortical areas express these receptors and are thus likely to mediate the enhancement of acetylcholine release elicited by 5-HT4 agonists. PMID:25183542

  2. Differential vascular permeability along the forebrain ventricular neurogenic niche in the adult murine brain.

    PubMed

    Colín-Castelán, Dannia; Ramírez-Santos, Jesús; Gutiérrez-Ospina, Gabriel

    2016-02-01

    Adult neurogenesis is influenced by blood-borne factors. In this context, greater or lesser vascular permeability along neurogenic niches would expose differentially neural stem cells (NSCs), transit amplifying cells (TACs), and neuroblasts to such factors. Here we evaluate endothelial cell morphology and vascular permeability along the forebrain neurogenic niche in the adult brain. Our results confirm that the subventricular zone (SVZ) contains highly permeable, discontinuous blood vessels, some of which allow the extravasation of molecules larger than those previously reported. In contrast, the rostral migratory stream (RMS) and the olfactory bulb core (OBc) display mostly impermeable, continuous blood vessels. These results imply that NSCs, TACs, and neuroblasts located within the SVZ are exposed more readily to blood-borne molecules, including those with very high molecular weights, than those positioned along the RMS and the OBc, subregions in which every stage of neurogenesis also takes place. These observations suggest that the existence of specialized vascular niches is not a precondition for neurogenesis to occur; specialized vascular beds might be essential for keeping high rates of proliferation and/or differential differentiation of neural precursors located at distinct domains. PMID:26492830

  3. Long-term hydrocephalus alters the cytoarchitecture of the adult subventricular zone.

    PubMed

    Campos-Ordoñez, Tania; Herranz-Pérez, Vicente; Chaichana, Kaisorn L; Rincon-Torroella, Jordina; Rigamonti, Daniele; García-Verdugo, Jose M; Quiñones-Hinojosa, Alfredo; Gonzalez-Perez, Oscar

    2014-11-01

    Hydrocephalus can develop secondarily to a disturbance in production, flow and/or absorption of cerebrospinal fluid. Experimental models of hydrocephalus, especially subacute and chronic hydrocephalus, are few and limited, and the effects of hydrocephalus on the subventricular zone are unclear. The aim of this study was to analyze the effects of long-term obstructive hydrocephalus on the subventricular zone, which is the neurogenic niche lining the lateral ventricles. We developed a new method to induce hydrocephalus by obstructing the aqueduct of Sylvius in the mouse brain, thus simulating aqueductal stenosis in humans. In 120-day-old rodents (n=18 per group), the degree of ventricular dilatation and cellular composition of the subventricular zone were studied by immunofluorescence and transmission electron microscopy. In adult patients (age>18years), the sizes of the subventricular zone, corpus callosum, and internal capsule were analyzed by magnetic resonance images obtained from patients with and without aqueductal stenosis (n=25 per group). Mice with 60-day hydrocephalus had a reduced number of Ki67+ and doublecortin+cells on immunofluorescence, as well as decreased number of neural progenitors and neuroblasts in the subventricular zone on electron microscopy analysis as compared to non-hydrocephalic mice. Remarkably, a number of extracellular matrix structures (fractones) contacting the ventricular lumen and blood vessels were also observed around the subventricular zone in mice with hydrocephalus. In humans, the widths of the subventricular zone, corpus callosum, and internal capsule in patients with aqueductal stenosis were significantly smaller than age and gender-matched patients without aqueductal stenosis. In summary, supratentorial hydrocephalus reduces the proliferation rate of neural progenitors and modifies the cytoarchitecture and extracellular matrix compounds of the subventricular zone. In humans, this similar process reduces the subventricular

  4. Long-term hydrocephalus alters the cytoarchitecture of the adult subventricular zone

    PubMed Central

    Campos-Ordoñez, Tania; Herranz-Pérez, Vicente; Chaichana, Kaisorn L.; Rincon-Torroella, Jordina; Rigamonti, Daniele; García-Verdugo, Jose M.; Quiñones-Hinojosa, Alfredo; Gonzalez-Perez, Oscar

    2014-01-01

    Hydrocephalus can develop secondarily to a disturbance in production, flow and/or absorption of cerebrospinal fluid. Experimental models of hydrocephalus, especially subacute and chronic hydrocephalus, are few and limited, and the effects of hydrocephalus on the subventricular zone are unclear. The aim of this study was to analyze the effects of long-term obstructive hydrocephalus on the subventricular zone, which is the neurogenic niche lining the lateral ventricles. We developed a new method to induce hydrocephalus by obstructing the aqueduct of Sylvius in the mouse brain, thus simulating aqueductal stenosis in humans. In 120-day-old rodents (n = 18 per group), the degree of ventricular dilatation and cellular composition of the subventricular zone were studied by immunofluorescence and transmission electron microscopy. In adult patients (age > 18 years), the sizes of the subventricular zone, corpus callosum, and internal capsule were analyzed by magnetic resonance images obtained from patients with and without aqueductal stenosis (n=25 per group). Mice with 60-day hydrocephalus had a reduced number of Ki67+ and doublecortin+ cells on immunofluorescence, as well as decreased number of neural progenitors and neuroblasts in the subventricular zone on electron microscopy analysis as compared to non-hydrocephalic mice. Remarkably, a number of extracellular matrix structures (fractones) contacting the ventricular lumen and blood vessels were also observed around the subventricular zone in mice with hydrocephalus. In humans, the widths of the subventricular zone, corpus callosum, and internal capsule in patients with aqueductal stenosis were significantly smaller than age and gender-matched patients without aqueductal stenosis. In summary, supratentorial hydrocephalus reduces the proliferation rate of neural progenitors and modifies the cytoarchitecture and extracellular matrix compounds of the subventricular zone. In humans, this similar process reduces the

  5. Fast Modulation of Visual Perception by Basal Forebrain Cholinergic Neurons

    PubMed Central

    Estandian, Daniel; Xu, Min; Kwan, Alex C.; Lee, Seung-Hee; Harrison, Thomas C.; Feng, Guoping; Dan, Yang

    2014-01-01

    The basal forebrain provides the primary source of cholinergic input to the cortex, and it plays a crucial role in promoting wakefulness and arousal. However, whether rapid changes in basal forebrain neuron spiking in awake animals can dynamically influence sensory perception is unclear. Here we show that basal forebrain cholinergic neurons rapidly regulate cortical activity and visual perception in awake, behaving mice. Optogenetic activation of the cholinergic neurons or their V1 axon terminals improved performance of a visual discrimination task on a trial-by-trial basis. In V1, basal forebrain activation enhanced visual responses and desynchronized neuronal spiking, which could partly account for the behavioral improvement. Conversely, optogenetic basal forebrain inactivation decreased behavioral performance, synchronized cortical activity and impaired visual responses, indicating the importance of cholinergic activity in normal visual processing. These results underscore the causal role of basal forebrain cholinergic neurons in fast, bidirectional modulation of cortical processing and sensory perception. PMID:24162654

  6. Widespread expression of BDNF but not NT3 by target areas of basal forebrain cholinergic neurons

    SciTech Connect

    Phillips, H.S.; Hains, J.M.; Laramee, G.R.; Rosenthal, A.; Winslow, J.W. )

    1990-10-12

    Brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3) are homologs of the well-known neurotrophic factor nerve growth factor. The three members of this family display distinct patterns of target specificity. To examine the distribution in brain of messenger RNA for these molecules, in situ hybridization was performed. Cells hybridizing intensely to antisense BDNF probe were located throughout the major targets of the rat basal forebrain cholinergic system, that is, the hippocampus, amygdala, and neocortex. Strongly hybridizing cells were also observed in structures associated with the olfactory system. The distribution of NT3 mRNA in forebrain was much more limited. Within the hippocampus, labeled cells were restricted to CA2, the most medial portion of CA1, and the dentate gyrus. In human hippocampus, cells expressing BDNF and mRNA are distributed in a fashion similar to that observed in the rat. These findings point to both basal forebrain cholinergic cells and olfactory pathways as potential central targets for BDNF.

  7. Neurotransmitters couple brain activity to subventricular zone neurogenesis

    PubMed Central

    Young, Stephanie Z.; Taylor, M. Morgan; Bordey, Angélique

    2011-01-01

    Adult neurogenesis occurs in two privileged microenvironments, the hippocampal subgranular zone of the dentate gyrus and the subventricular zone (SVZ) along the lateral ventricle. This review focuses on accumulating evidence suggesting that the activity of specific brain regions or bodily states influences SVZ cell proliferation and neurogenesis. Neuromodulators such as dopamine and serotonin have been shown to have long-range effects through neuronal projections into the SVZ. Local GABA and glutamate signaling have demonstrated effects on SVZ proliferation and neurogenesis, but an extra-niche source of these neurotransmitters remains to be explored and options will be discussed. There is also accumulating evidence that diseases and bodily states such as Alzheimer's disease, seizures, sleep, and pregnancy influence SVZ cell proliferation. With such complex behavior and environmentally-driven factors that control subregion-specific activity, it will become necessary to account for overlapping roles of multiple neurotransmitter systems on neurogenesis when developing cell therapies or drug treatments. PMID:21395856

  8. Glioblastoma Multiforme: Relationship to Subventricular Zone and Recurrence

    PubMed Central

    Kimura, Margareth; Lee, Yeuh; Miller, Ryan; Castillo, Mauricio

    2013-01-01

    Summary Neurogenesis in the adult mammalian brain is active in two areas: the subgranular zone in the dentate gyrus of the hippocampus and the subventricular zone. Cancer stem cells have been isolated from malignant brain tumors and it is widely believed they arise from transformed endogenous stem cells. We sought to determine if the initial location of glioblastoma (GB) as seen on conventional MRI and its relationship to the subventricular zone (SVZ) predicts the pattern of recurrence. We analyzed the initial (prior to any treatment) and last follow-up MR studies in 49 patients with GB. On post contrast images all non-treated GB were divided into three groups according to the relationship of their enhancing margins to the SVZ: Group I (directly in contact with the SVZ), Group II (in the subcortical [SC] region) and Group III (in both the SVZ and SC regions). Recurrences or continuous growth seen as enhancing areas on follow-up studies were characterized as local, spread, or distant according to their contact with the surgical bed and correlated with the locations of the initial tumors. Local and spread patterns of recurrence occurred with nearly equal frequency (45 and 43% each, respectively) and distant in 12%. In Group I, 80% showed a spread pattern, 20% a local pattern, and none a distant pattern. In Group II, 45% showed a spread pattern, 35% a local pattern, and a 20% distant one. In Group III, 58% showed a local pattern, 33% a spread pattern, and 8% distant one. Unlike other reports, the location of GB in relation to the SVZ in our patients did not predict the pattern of tumor recurrence and/or extension in our patients. PMID:24199814

  9. Inhibition of microRNA-181 reduces forebrain ischemia-induced neuronal loss

    PubMed Central

    Moon, Jeong-mi; Xu, Lijun; Giffard, Rona G

    2013-01-01

    MicroRNA (miRNA), miR-181a, is enriched in the brain, and inhibition of miR-181a reduced astrocyte death in vitro and infarct volume after stroke in vivo. This study investigated the role of miR-181a in neuronal injury in vitro and hippocampal neuronal loss in vivo after forebrain ischemia. miR-181a levels were altered by transfection with mimic or antagomir. N2a cells subjected to serum deprivation and oxidative stress showed less cell death when miR-181a was reduced and increased death when miR-181a increased; protection was associated with increased Bcl-2 protein. In contrast, transfected primary neurons did not show altered levels of cell death when miR-181a levels changed. Naive male rats and rats stereotactically infused with miR-181a antagomir or control were subjected to forebrain ischemia and cornus ammonis (CA)1 neuronal survival and protein levels were assessed. Forebrain ischemia increased miR-181a expression and decreased Bcl-2 protein in the hippocampal CA1 region. miR-181a antagomir reduced miR-181a levels, reduced CA1 neuronal loss, increased Bcl-2 protein, and significantly prevented the decrease of glutamate transporter 1. Thus, miR-181a antagomir reduced evidence of astrocyte dysfunction and increased CA1 neuronal survival. miR-181a inhibition is thus a potential target in the setting of forebrain or global cerebral ischemia as well as focal ischemia. PMID:24002437

  10. Expression of a novel serine/threonine kinase gene, Ulk4, in neural progenitors during Xenopus laevis forebrain development.

    PubMed

    Domínguez, L; Schlosser, G; Shen, S

    2015-04-01

    We have analyzed the expression pattern of a novel serine/threonine kinase gene Ulk4 during forebrain development in Xenopus laevis. To this aim, we firstly cloned a Ulk4 cDNA fragment from X.laevis and generated a RNA probe that was used for its detection by in situ hybridization. Throughout development xUlk4 expression was detected along the ventricular (vz) and subventricular zones (svz) of all forebrain regions, with the exception of the vz of the striatum. In the adult, xUlk4 was also mainly located in the vz, with some xUlk4 expressing cells reaching the svz/mantle zone (mz). This xUlk4 expression was especially remarkable in forebrain regions involving the homeostatic control of the brain such as the preoptic region, the hypothalamic territory and some neurosecretory circumventricular organs (CVOs). We further combined in situ hybridization for xUlk4 with immunohistochemistry for the neural progenitor cell marker SOX3, the radial glial marker brain lipid-binding protein (BLBP), neuronal markers MAP2 and doublecortin (DCX) and the specific neuronal marker tyrosine hydroxylase (TH). xUlk4 was co-expressed with the neural stem/progenitor cell marker SOX3 in the vz of all the forebrain regions throughout development and in the adult, and this co-expression was also especially evident in the svz of the hypothalamic region. xUlk4 was also expressed in the radial glia along the whole brain. We have also found minor expression of xUlk4 in some DCX- or MAP2-positive cells but not in TH-positive neurons. These findings suggest that Ulk4 may play roles in neural stem/progenitor cells during neurogenesis both in development and in the adulthood, in migrating cells as well as in cells committed to neuronal fate in Xenopus. Moreover, the results obtained in this study argue for an involvement of Ulk4 in the control of the neuroendocrine homeostatic functions in the brain. PMID:25637795

  11. In vivo and ex vivo magnetic resonance spectroscopy of the infarct and the subventricular zone in experimental stroke

    PubMed Central

    Jiménez-Xarrié, Elena; Davila, Myriam; Gil-Perotín, Sara; Jurado-Rodríguez, Andrés; Candiota, Ana Paula; Delgado-Mederos, Raquel; Lope-Piedrafita, Silvia; García-Verdugo, José Manuel; Arús, Carles; Martí-Fàbregas, Joan

    2015-01-01

    Ex vivo high-resolution magic-angle spinning (HRMAS) provides metabolic information with higher sensitivity and spectral resolution than in vivo magnetic resonance spectroscopy (MRS). Therefore, we used both techniques to better characterize the metabolic pattern of the infarct and the neural progenitor cells (NPCs) in the ipsilateral subventricular zone (SVZi). Ischemic stroke rats were divided into three groups: G0 (non-stroke controls, n=6), G1 (day 1 after stroke, n=6), and G7 (days 6 to 8 after stroke, n=12). All the rats underwent MRS. Three rats per group were analyzed by HRMAS. The remaining rats were used for immunohistochemical studies. In the infarct, both techniques detected significant metabolic changes. The most relevant change was in mobile lipids (2.80 ppm) in the G7 group (a 5.53- and a 3.95-fold increase by MRS and HRMAS, respectively). In the SVZi, MRS did not detect any significant metabolic change. However, HRMAS detected a 2.70-fold increase in lactate and a 0.68-fold decrease in N-acetylaspartate in the G1 group. None of the metabolites correlated with the 1.37-fold increase in NPCs detected by immunohistochemistry in the G7 group. In conclusion, HRMAS improves the metabolic characterization of the brain in experimental ischemic stroke. However, none of the metabolites qualifies as a surrogate biomarker of NPCs. PMID:25605287

  12. Carbon nanotubes impregnated with subventricular zone neural progenitor cells promotes recovery from stroke

    PubMed Central

    Moon, Sung Ung; Kim, Jihee; Bokara, Kiran Kumar; Kim, Jong Youl; Khang, Dongwoo; Webster, Thomas J; Lee, Jong Eun

    2012-01-01

    The present in vivo study was conducted to evaluate whether hydrophilic (HL) or hydrophobic (HP) carbon nanotubes (CNTs) impregnated with subventricular zone neural progenitor cells (SVZ NPCs) could repair damaged neural tissue following stroke. For this purpose, stroke damaged rats were transplanted with HL CNT-SVZ NPCs, HP CNT-SVZ NPCs, or SVZ NPCs alone for 1, 3, 5, and 8 weeks. Results showed that the HP CNT-SVZ NPC transplants improved rat behavior and reduced infarct cyst volume and infarct cyst area compared with the experimental control and the HL CNT-SVZ NPC and SVZ NPCs alone groups. The transplantation groups showed an increase in the expression of nestin (cell stemness marker) and proliferation which was evident with the increased number of doublecortin and bromodeoxyuridine double-stained immunopositive cells around the lesion site. But, these effects were more prominent in the HP CNT-SVZ NPC group compared with the other transplantation groups. The HP CNT-SVZ NPC and HL CNT-SVZ NPC transplants increased the number of microtubule-associated protein 2 (marker for neurons) and decreased the number of glial fibrillary acidic protein (marker for astroglial cells) positive cells within the injury epicenter. The majority of the transplanted HP CNT-SVZ NPCs collectively broadened around the ischemic injured region and the SVZ NPCs differentiated into mature neurons, attained the synapse morphology (TUJ1, synaptophysin), and decreased microglial activation (CD11b/c [OX-42]). For these reasons, this study provided the first evidence that CNTs can improve stem cell differentiation to heal stroke damage and, thus, deserve further attention. PMID:22701320

  13. Genes involved in forebrain development in the zebrafish, Danio rerio.

    PubMed

    Heisenberg, C P; Brand, M; Jiang, Y J; Warga, R M; Beuchle, D; van Eeden, F J; Furutani-Seiki, M; Granato, M; Haffter, P; Hammerschmidt, M; Kane, D A; Kelsh, R N; Mullins, M C; Odenthal, J; Nusslein-Volhard, C

    1996-12-01

    We identified four zebrafish mutants with defects in forebrain induction and patterning during embryogenesis. The four mutants define three genes: masterblind (mbl), silberblick (slb), and knollnase (kas). In mbl embryos, the anterior forebrain acquires posterior forebrain characteristics: anterior structures such as the eyes, olfactory placodes and the telencephalon are missing, whereas the epiphysis located in the posterior forebrain is expanded. In slb embryos, the extension of the embryonic axis is initially delayed and eventually followed by a partial fusion of the eyes. Finally, in kas embryos, separation of the telencephalic primordia is incomplete and dorsal midline cells fail to form a differentiated roof plate. Analysis of the mutant phenotypes indicates that we have identified genes essential for the specification of the anterior forebrain (mbl), positioning of the eyes (slb) and differentiation of the roof plate (kas). In an appendix to this study we list mutants showing alterations in the size of the eyes and abnormal differentiation of the lenses. PMID:9007240

  14. Terminal field specificity of forebrain efferent axons to brainstem gustatory nuclei.

    PubMed

    Kang, Yi; Lundy, Robert F

    2009-01-12

    Rostral forebrain structures like the gustatory cortex (GC), bed nucleus of the stria terminalis (BNST), central nucleus of the amygdala (CeA), and lateral hypothalamus (LH) send projections to the nucleus of solitary tract (NST) and the parabrachial nucleus (PBN) that modulate taste-elicited responses. However, the proportion of forebrain-induced excitatory and inhibitory effects often differs when taste cell recording changes from the NST to the PBN. The present study investigated whether this descending influence originates from a shared or distinct population of forebrain neurons. Under electrophysiological guidance, the retrograde tracers fast blue (FB) and fluorogold (FG) or green (GFB) and red (RFB) fluorescent latex microbeads were injected iontophoretically or by pressure pulses (10 ms at 20 psi) into the taste-responsive regions of the NST and the ipsilateral PBN in six rats. Seven days later, the animals were euthanized and tissue sections containing the LH, CeA, BNST, and GC were processed for co-localization of FB and FG or GFB and RFB. The results showed that the CeA is the major source of input to the NST (82.3+/-7.6 cells/section) and the PBN (76.7+/-11.5), compared to the BNST (31.8+/-4.5; 37.0+/-4.8), the LH (35.0+/-5.4; 33.6+/-5.7), and the GC (27.5+/-4.0; 29.0+/-4.6). Of the total number of retrogradely labeled cells, the incidence of tracer co-localization was 17+/-3% in the GC, 17+/-2% in the CeA, 15+/-3% in the BNST and 16+/-1% in the LH. Thus, irrespective of forebrain source the majority of descending input to the gustatory NST and PBN originates from distinct neuronal populations. This arrangement provides an anatomical substrate for differential modulation of taste processing in the first and second central relays of the ascending gustatory system. PMID:19028464

  15. Extracellular signal-regulated kinase phosphorylation in forebrain neurones contributes to osmoregulatory mechanisms

    PubMed Central

    Dine, Julien; Ducourneau, Vincent R R; Fénelon, Valérie S; Fossat, Pascal; Amadio, Aurélie; Eder, Matthias; Israel, Jean-Marc; Oliet, Stéphane H R; Voisin, Daniel L

    2014-01-01

    Vasopressin secretion from the magnocellular neurosecretory cells (MNCs) is crucial for body fluid homeostasis. Osmotic regulation of MNC activity involves the concerted modulation of intrinsic mechanosensitive ion channels, taurine release from local astrocytes as well as excitatory inputs derived from osmosensitive forebrain regions. Extracellular signal-regulated protein kinases (ERK) are mitogen-activated protein kinases that transduce extracellular stimuli into intracellular post-translational and transcriptional responses, leading to changes in intrinsic neuronal properties and synaptic function. Here, we investigated whether ERK activation (i.e. phosphorylation) plays a role in the functioning of forebrain osmoregulatory networks. We found that within 10 min after intraperitoneal injections of hypertonic saline (3 m, 6 m) in rats, many phosphoERK-immunopositive neurones were observed in osmosensitive forebrain regions, including the MNC containing supraoptic nuclei. The intensity of ERK labelling was dose-dependent. Reciprocally, slow intragastric infusions of water that lower osmolality reduced basal ERK phosphorylation. In the supraoptic nucleus, ERK phosphorylation predominated in vasopressin neurones vs. oxytocin neurones and was absent from astrocytes. Western blot experiments confirmed that phosphoERK expression in the supraoptic nucleus was dose dependent. Intracerebroventricular administration of the ERK phosphorylation inhibitor U 0126 before a hyperosmotic challenge reduced the number of both phosphoERK-immunopositive neurones and Fos expressing neurones in osmosensitive forebrain regions. Blockade of ERK phosphorylation also reduced hypertonically induced depolarization and an increase in firing of the supraoptic MNCs recorded in vitro. It finally reduced hypertonically induced vasopressin release in the bloodstream. Altogether, these findings identify ERK phosphorylation as a new element contributing to the osmoregulatory mechanisms of

  16. Pbx1 is required for adult subventricular zone neurogenesis.

    PubMed

    Grebbin, Britta Moyo; Hau, Ann-Christin; Groß, Anja; Anders-Maurer, Marie; Schramm, Jasmine; Koss, Matthew; Wille, Christoph; Mittelbronn, Michel; Selleri, Licia; Schulte, Dorothea

    2016-07-01

    TALE-homeodomain proteins function as components of heteromeric complexes that contain one member each of the PBC and MEIS/PREP subclasses. We recently showed that MEIS2 cooperates with the neurogenic transcription factor PAX6 in the control of adult subventricular zone (SVZ) neurogenesis in rodents. Expression of the PBC protein PBX1 in the SVZ has been reported, but its functional role(s) has not been investigated. Using a genetic loss-of-function mouse model, we now show that Pbx1 is an early regulator of SVZ neurogenesis. Targeted deletion of Pbx1 by retroviral transduction of Cre recombinase into Pbx2-deficient SVZ stem and progenitor cells carrying floxed alleles of Pbx1 significantly reduced the production of neurons and increased the generation of oligodendrocytes. Loss of Pbx1 expression in neuronally committed neuroblasts in the rostral migratory stream in a Pbx2 null background, by contrast, severely compromised cell survival. By chromatin immunoprecipitation from endogenous tissues or isolated cells, we further detected PBX1 binding to known regulatory regions of the neuron-specific genes Dcx and Th days or even weeks before the respective genes are expressed during the normal program of SVZ neurogenesis, suggesting that PBX1 might act as a priming factor to mark these genes for subsequent activation. Collectively, our results establish that PBX1 regulates adult neural cell fate determination in a manner beyond that of its heterodimerization partner MEIS2. PMID:27226325

  17. Implications of irradiating the subventricular zone stem cell niche.

    PubMed

    Capilla-Gonzalez, Vivian; Bonsu, Janice M; Redmond, Kristin J; Garcia-Verdugo, Jose Manuel; Quiñones-Hinojosa, Alfredo

    2016-03-01

    Radiation therapy is a standard treatment for brain tumor patients. However, it comes with side effects, such as neurological deficits. While likely multi-factorial, the effect may in part be associated with the impact of radiation on the neurogenic niches. In the adult mammalian brain, the neurogenic niches are localized in the subventricular zone (SVZ) of the lateral ventricles and the dentate gyrus of the hippocampus, where the neural stem cells (NSCs) reside. Several reports showed that radiation produces a drastic decrease in the proliferative capacity of these regions, which is related to functional decline. In particular, radiation to the SVZ led to a reduced long-term olfactory memory and a reduced capacity to respond to brain damage in animal models, as well as compromised tumor outcomes in patients. By contrast, other studies in humans suggested that increased radiation dose to the SVZ may be associated with longer progression-free survival in patients with high-grade glioma. In this review, we summarize the cellular and functional effects of irradiating the SVZ niche. In particular, we review the pros and cons of using radiation during brain tumor treatment, discussing the complex relationship between radiation dose to the SVZ and both tumor control and toxicity. PMID:26921873

  18. Habituation and extinction of fear recruit overlapping forebrain structures.

    PubMed

    Furlong, Teri M; Richardson, Rick; McNally, Gavan P

    2016-02-01

    Establishing the neurocircuitry involved in inhibiting fear is important for understanding and treating anxiety disorders. To date, extinction procedures have been predominately used to examine the inhibition of learned fear, where fear is reduced to a conditioned stimulus (CS) by presenting it in the absence of the unconditioned stimulus (US). However, learned fear can also be reduced by habituation procedures where the US is presented in the absence of the CS. Here we used expression of the activity marker c-Fos in rats to compare the recruitment of several forebrain structures following fear habituation and extinction. Following fear conditioning where a tone CS was paired with a loud noise US, fear was then reduced the following day by either presentation of the CS or US alone (i.e. CS extinction or US habituation, respectively). This extinction and habituation training recruited several common structures, including infralimbic cortex, basolateral amygdala, midline thalamus and medial hypothalamus (orexin neurons). Moreover, this overlap was shared when examining the neural correlates of the expression of habituation and extinction, with common recruitment of infralimbic cortex and midline thalamus. However, there were also important differences. Specifically, acquisition of habituation was associated with greater recruitment of prelimbic cortex whereas expression of habituation was associated with greater recruitment of paraventricular thalamus. There was also less recruitment of central amygdala for habituation compared to extinction in the retention phase. These findings indicate that largely overlapping neurocircuitries underlie habituation and fear extinction and imply common mechanisms for reducing fear across different inhibitory treatments. PMID:26690954

  19. Gliogenic and neurogenic progenitors of the subventricular zone: who are they, where did they come from, and where are they going?

    PubMed

    Marshall, Christine A G; Suzuki, Satoshi O; Goldman, James E

    2003-07-01

    The subventricular zone (SVZ) of the perinatal forebrain gives rise to both neurons and glia. The mechanisms governing the phenotypic specification of progenitors within this heterogeneous germinal zone are unclear. However, the characterization of subpopulations of SVZ cells has given us a better understanding of the basic architecture of the SVZ and presents us with the opportunity to ask more detailed questions regarding phenotype specification and cell fate. Recent work demonstrating the embryonic origins of SVZ cells is summarized, and a model describing the formation of the perinatal SVZ, noting contributions of cells from pallial as well as subpallial germinal zones, is presented. We further address differences among classes of SVZ cells based on molecular profile, phenotype, and migration behavior and present a model summarizing the organization of perinatal SVZ cells along coronal, sagittal, and horizontal axes. A detailed description of the SVZ in the adult, outlining classes of cells based on morphology, molecular profile, and proliferative behavior, was recently reported by Doetsch et al. (Proc Natl Acad Sci USA 93:14895-14900, 1997). Potential relationships among cells within the perinatal and adult SVZ will be discussed. GLIA 43:52-61, 2003. PMID:12761867

  20. Thalamic reticular nucleus in Caiman crocodilus: forebrain connections.

    PubMed

    Pritz, Michael B

    2016-08-01

    Forebrain connections of the thalamic reticular nucleus associated with the lateral forebrain bundle were analyzed in Caiman crocodilus. Both the compact portion, the dorsal peduncular nucleus, and the diffuse part, the perireticular region, associated with the lateral forebrain bundle, were studied. A small tracer injection into the dorsal peduncular nucleus demonstrated reciprocal connections with a restricted portion of the dorsal thalamus. Tracer placements into this nucleus retrogradely labeled cells in a caudal portion of the ventrolateral area of the telencephalon. These results are compared with similar studies in other amniotes. PMID:27233216

  1. Genomic Perspectives of Transcriptional Regulation in Forebrain Development

    PubMed Central

    Nord, Alex S.; Pattabiraman, Kartik; Visel, Axel; Rubenstein, John L. R.

    2015-01-01

    The forebrain is the seat of higher order brain functions, and many human neuropsychiatric disorders are due to genetic defects affecting forebrain development, making it imperative to understand the underlying genetic circuitry. Recent progress now makes it possible to begin fully elucidating the genomic regulatory mechanisms that control forebrain gene expression. Herein, we discuss the current knowledge of how transcription factors drive gene expression programs through their interactions with cis-acting genomic elements, such as enhancers; how analyses of chromatin and DNA modifications provide insights into gene expression states; and how these approaches yield insights into the evolution of the human brain. PMID:25569346

  2. PDGF-responsive progenitors persist in the subventricular zone across the lifespan

    PubMed Central

    Moore, Lisamarie; Bain, Jennifer M.; Loh, Ji Meng; Levison, Steven W.

    2013-01-01

    The SVZ (subventricular zone) contains neural stem cells and progenitors of various potentialities. Although initially parsed into A, B, and C cells, this germinal zone is comprised of a significantly more diverse population of cells. Here, we characterized a subset of postnatal PRPs (PDGF-AA-responsive precursors) that express functional PDGFα and β receptors from birth to adulthood. When grown in PDGF-AA, dissociated neonatal rat SVZ cells divided to produce non-adherent clusters of progeny. Unlike the self-renewing EGF/FGF-2-responsive precursors that produce neurospheres, these PRPs failed to self-renew after three passages; therefore, we refer to the colonies they produce as spheroids. Upon differentiation these spheroids could produce neurons, type 1 astrocytes and oligodendrocytes. When maintained in medium supplemented with BMP-4 they also produced type 2 astrocytes. Using lineage tracing methods, it became evident that there were multiple types of PRPs, including a subset that could produce neurons, oligodendrocytes, and type 1 and type 2 astrocytes; thus some of these PRPs represent a unique population of precursors that are quatropotential. Spheroids also could be generated from the newborn neocortex and they had the same potentiality as those from the SVZ. By contrast, the adult neocortex produced less than 20% of the numbers of spheroids than the adult SVZ and spheroids from the adult neocortex only differentiated into glial cells. Interestingly, SVZ spheroid producing capacity diminished only slightly from birth to adulthood. Altogether these data demonstrate that there are PRPs that persist in the SVZ that includes a unique population of quatropotential PRPs. PMID:24367913

  3. Neural stem cells, the subventricular zone and radiotherapy: implications for treating glioblastoma.

    PubMed

    Smith, Andrew W; Mehta, Minesh P; Wernicke, A Gabriella

    2016-06-01

    Over the past decade, advances in neuroscience have suggested that neural stem cells resident in specific regions of the adult brain may be involved in development of both primary and recurrent glioblastoma. Neurogenesis and malignant transformation occurs in the subventricular zone adjacent to the lateral ventricles. This region holds promise as a potential target for therapeutic intervention with radiotherapy. However, irradiation of a larger brain volume is not without risk, and significant side effects have been observed. The current literature remains contradictory regarding the efficacy of deliberate intervention with radiation to the subventricular zone. This critical review discusses the connection between neural stem cells and development of glioblastoma, explores the behavior of tumors associated with the subventricular zone, summarizes the discordant literature with respect to the effects of irradiation, and reviews other targeted therapies to this intriguing region. PMID:27108274

  4. Periadolescent ethanol exposure reduces adult forebrain ChAT+IR neurons: correlation with behavioral pathology.

    PubMed

    Ehlers, C L; Criado, J R; Wills, D N; Liu, W; Crews, F T

    2011-12-29

    Substance abuse typically begins in adolescence; therefore, the impact of alcohol during this critical time in brain development is of particular importance. Epidemiological data indicate that excessive alcohol consumption is prevalent among adolescents and may have lasting neurobehavioral consequences. Loss of cholinergic input to the forebrain has been demonstrated following fetal alcohol exposure and in adults with Wernicke-Korsakoff syndrome. In the present study, immunohistochemistry for choline acetyltransferase (ChAT) was determined to assess forebrain cholinergic neurons (Ch1-4), and behavioral changes following periadolescent alcohol exposure. Wistar rats were exposed to intermittent ethanol vapor (14 h on/10 h off/day) for 35 days from postnatal day (PD) 22 to PD 57 (average blood alcohol concentration (BAC): 163 mg%). Rats were withdrawn from vapor and assessed for locomotor activity, startle response, conflict behavior in the open field, and immobility in the forced swim test, as adults. Rats were then sacrificed at day 71/72 and perfused for histochemical analyses. Ethanol vapor-exposed rats displayed: increased locomotor activity 8 h after the termination of vapor delivery for that 24 h period at day 10 and day 20 of alcohol vapor exposure, significant reductions in the amplitude of their responses to prepulse stimuli during the startle paradigm at 24 h withdrawal, and at 2 weeks following withdrawal, less anxiety-like and/or more "disinhibitory" behavior in the open field conflict, and more immobility in the forced swim test. Quantitative analyses of ChAT immunoreactivity revealed a significant reduction in cell counts in the Ch1-2 and Ch3-4 regions of the basal forebrain in ethanol vapor-exposed rats. This reduction in cell counts was significantly correlated with less anxiety-like and/or more "disinhibitory" behavior in the open field conflict test. These studies demonstrate that behavioral measures of arousal, affective state, disinhibitory

  5. Expression of constitutively active FoxO3 in murine forebrain leads to a loss of neural progenitors.

    PubMed

    Schmidt-Strassburger, Uta; Schips, Tobias G; Maier, Harald J; Kloiber, Katharina; Mannella, Francesca; Braunstein, Kerstin E; Holzmann, Karlheinz; Ushmorov, Alexey; Liebau, Stefan; Boeckers, Tobias M; Wirth, Thomas

    2012-12-01

    Inactivation of FoxO proteins by phosphorylation is the result of a number of stimuli, including the insulin/IGF pathway. We were interested in the consequence of blunting this pathway by employing transgenic mice with tetracycline-controllable conditional expression of a constitutively active allele of FOXO3 under the control of the forebrain-specific CaMKIIα promoter. Although transgene-expressing mice were viable, brain weight was reduced by 30% in adult animals. Brains showed an isocortex compression with normal cortical layering, and a size reduction in regions known to depend on adult neurogenesis, i.e., the olfactory bulbs and the dentate gyrus. On postnatal activation of the transgene, adult neurogenesis was also severely affected. Investigating the molecular basis of this phenotype, we observed enhanced apoptosis starting from embryonic day E10.5 and a subsequent loss of progenitors in the ventricular/subventricular zones, but not in the isocortex or the striatum of adult mice. The enhanced apoptosis was accompanied by increased expression of PIK3IP1, which we identified as a direct transcriptional target of FOXO3. Transfection of Pik3ip1 into differentiating neural progenitors resulted in a significant reduction of viable cells. We therefore conclude that neural progenitors are particularly vulnerable to FOXO3-induced apoptosis, which is mediated by PIK3IP1, a negative PI3 kinase regulator. PMID:22935140

  6. THREE-DIMENSIONAL CHEMOARCHITECTURE OF THE BASAL FOREBRAIN: SPATIALLY SPECIFIC ASSOCIATION OF CHOLINERGIC AND CALCIUM BINDING PROTEIN-CONTAINING NEURONS

    PubMed Central

    ZABORSZKY, L.; BUHL, D. L.; POBALASHINGHAM, S.; BJAALIE, J. G.; NADASDY, Z.

    2007-01-01

    The basal forebrain refers to heterogeneous structures located close to the medial and ventral surfaces of the cerebral hemispheres. It contains diverse populations of neurons, including the cholinergic cortically projecting cells that show severe loss in Alzheimer’s and related neurodegenerative diseases. The basal forebrain does not display any cytoarchitectural or other structural features that make it easy to demarcate functional boundaries, a problem that allowed different investigators to propose different organizational schemes. The present paper uses novel three-dimensional reconstructions and numerical analyses for studying the spatial organization of four major basal forebrain cell populations, the cholinergic, parvalbumin, calbindin and calretinin containing neurons in the rat. Our analyses suggest that the distribution of these four cell populations is not random but displays a general pattern of association. Within the cholinergic space (i.e. the volume occupied by the cortically projecting cholinergic cell bodies) the three other cell types form twisted bands along the longitudinal axis of a central dense core of cholinergic cells traversing the traditionally defined basal forebrain regions, (i.e. the medial septum, diagonal bands, the substantia innominata, pallidal regions and the bed nucleus of the stria terminalis). At a smaller scale, the different cell types within the cholinergic space occupy overlapping high-density cell clusters that are either chemically uniform or mixed. However, the cell composition of these high-density clusters is regionally specific. The proposed scheme of basal forebrain organization, using cell density or density relations as criteria, offers a new perspective on structure–function relationship, unconstrained by traditional region boundaries. PMID:16344145

  7. Neuroprotection by Exendin-4 Is GLP-1 Receptor Specific but DA D3 Receptor Dependent, Causing Altered BrdU Incorporation in Subventricular Zone and Substantia Nigra.

    PubMed

    Harkavyi, A; Rampersaud, N; Whitton, P S

    2013-01-01

    Glucagon-like peptide-1 receptor (GLP-1R) activation by exendin-4 (EX-4) is effective in preclinical models of Parkinson's disease (PD) and appears to promote neurogenesis even in severely lesioned rats. In the present study, we determined the effects of EX-4 on cellular BrdU incorporation in the rat subventricular zone (SVZ) and substantia nigra (SN). We also determined the specificity of this effect with the GLP-1R antagonist EX-(9-39) as well as the potential role of dopamine (DA) D3 receptors. Rats were administered 6-OHDA and 1 week later given EX-4 alone, with EX-(9-39) or nafadotride (D3 antagonist) and BrdU. Seven days later, rats were challenged with apomorphine to evaluate circling. Extracellular DA was measured using striatal microdialysis and subsequently tissue DA measured. Tyrosine hydroxylase and BrdU were verified using immunohistochemistry. Apomorphine circling was reversed by EX-4 in lesioned rats, an effect reduced by EX-4, while both EX-(9-39) and NAF attenuated this. 6-OHDA decreased extracellular and tissue DA, both reversed by EX-4 but again attenuated by EX-(9-39) or NAF. Analysis of BrdU+ cells in the SVZ revealed increases in 6-OHDA-treated rats which were reversed by EX-4 and antagonised by either EX-(9-39) or NAF, while in the SN the opposite profile was seen. PMID:26316987

  8. Neuroprotection by Exendin-4 Is GLP-1 Receptor Specific but DA D3 Receptor Dependent, Causing Altered BrdU Incorporation in Subventricular Zone and Substantia Nigra

    PubMed Central

    Harkavyi, A.; Rampersaud, N.; Whitton, P. S.

    2013-01-01

    Glucagon-like peptide-1 receptor (GLP-1R) activation by exendin-4 (EX-4) is effective in preclinical models of Parkinson's disease (PD) and appears to promote neurogenesis even in severely lesioned rats. In the present study, we determined the effects of EX-4 on cellular BrdU incorporation in the rat subventricular zone (SVZ) and substantia nigra (SN). We also determined the specificity of this effect with the GLP-1R antagonist EX-(9-39) as well as the potential role of dopamine (DA) D3 receptors. Rats were administered 6-OHDA and 1 week later given EX-4 alone, with EX-(9-39) or nafadotride (D3 antagonist) and BrdU. Seven days later, rats were challenged with apomorphine to evaluate circling. Extracellular DA was measured using striatal microdialysis and subsequently tissue DA measured. Tyrosine hydroxylase and BrdU were verified using immunohistochemistry. Apomorphine circling was reversed by EX-4 in lesioned rats, an effect reduced by EX-4, while both EX-(9-39) and NAF attenuated this. 6-OHDA decreased extracellular and tissue DA, both reversed by EX-4 but again attenuated by EX-(9-39) or NAF. Analysis of BrdU+ cells in the SVZ revealed increases in 6-OHDA-treated rats which were reversed by EX-4 and antagonised by either EX-(9-39) or NAF, while in the SN the opposite profile was seen. PMID:26316987

  9. Combined administration of secretin and oxytocin inhibits chronic colitis and associated activation of forebrain neurons

    PubMed Central

    Welch, Martha G.; Anwar, Muhammad; Chang, Christine Y.; Gross, Kara J.; Ruggiero, David A.; Gershon, Michael D.

    2011-01-01

    Background The pathogenesis of inflammatory bowel disease is unknown; however, the disorder is aggravated by psychological stress and is itself psychologically stressful. Chronic intestinal inflammation, moreover, has been reported to activate forebrain neurons. We tested the hypotheses that the chronically inflamed bowel signals to the brain through the vagi and that administration of a combination of secretin (S) and oxytocin (OT) inhibits this signaling. Methods Three daily enemas containing 2,4,6-trinitrobenzene sulfonic acid (TNBS), which were given to rats produced chronic colitis and ongoing activation of Fos in brain neurons. Key Results Fos was induced in neurons in the paraventricular nucleus of the hypothalamus, basolateral amygdala, central amygdala, and piriform cortex. Subdiaphragmatic vagotomy failed to inhibit this activation of Fos, suggesting that colitis activates forebrain neurons independently of the vagi. When administered intravenously, but not when given intracerebroventricularly, in doses that were individually ineffective, combined S/OT prevented colitis-associated activation of central neurons. Strikingly, S/OT decreased inflammatory infiltrates into the colon and colonic expression of tumor necrosis factor-α and interferon-γ. Conclusions & Inferences These observations suggest that chronic colonic inflammation is ameliorated by the systemic administration of S/OT, which probably explains the parallel ability of systemic S/OT to inhibit the colitis-associated activation of forebrain neurons. It is possible that S and OT, which are endogenous to the colon, might normally combine to restrict the severity of colonic inflammatory responses and that advantage might be taken of this system to develop novel means of treating inflammation-associated intestinal disorders. PMID:20210978

  10. Evolution of vertebrate forebrain development: how many different mechanisms?

    PubMed Central

    FOLEY, ANN C.; STERN, CLAUDIO D.

    2001-01-01

    Over the past 50 years and more, many models have been proposed to explain how the nervous system is initially induced and how it becomes subdivided into gross regions such as forebrain, midbrain, hindbrain and spinal cord. Among these models is the 2-signal model of Nieuwkoop & Nigtevecht (1954), who suggested that an initial signal (‘activation’) from the organiser both neuralises and specifies the forebrain, while later signals (‘transformation’) from the same region progressively caudalise portions of this initial territory. An opposing idea emerged from the work of Otto Mangold (1933) and other members of the Spemann laboratory: 2 or more distinct organisers, emitting different signals, were proposed to be responsible for inducing the head, trunk and tail regions. Since then, evidence has accumulated that supports one or the other model, but it has been very difficult to distinguish between them. Recently, a considerable body of work from mouse embryos has been interpreted as favouring the latter model, and as suggesting that a ‘head organiser’, required for the induction of the forebrain, is spatially separate from the classic organiser (Hensen's node). An extraembryonic tissue, the ‘anterior visceral endoderm’ (AVE), was proposed to be the source of forebrain-inducing signals. It is difficult to find tissues that are directly equivalent embryologically or functionally to the AVE in other vertebrates, which led some (e.g. Kessel, 1998) to propose that mammals have evolved a new way of patterning the head. We will present evidence from the chick embryo showing that the hypoblast is embryologically and functionally equivalent to the mouse AVE. Like the latter, the hypoblast also plays a role in head development. However, it does not act like a true organiser. It induces pre-neural and pre-forebrain markers, but only transiently. Further development of neural and forebrain phenotypes requires additional signals not provided by the hypoblast. In

  11. Forebrain pathway for auditory space processing in the barn owl.

    PubMed

    Cohen, Y E; Miller, G L; Knudsen, E I

    1998-02-01

    The forebrain plays an important role in many aspects of sound localization behavior. Yet, the forebrain pathway that processes auditory spatial information is not known for any species. Using standard anatomic labeling techniques, we used a "top-down" approach to trace the flow of auditory spatial information from an output area of the forebrain sound localization pathway (the auditory archistriatum, AAr), back through the forebrain, and into the auditory midbrain. Previous work has demonstrated that AAr units are specialized for auditory space processing. The results presented here show that the AAr receives afferent input from Field L both directly and indirectly via the caudolateral neostriatum. Afferent input to Field L originates mainly in the auditory thalamus, nucleus ovoidalis, which, in turn, receives input from the central nucleus of the inferior colliculus. In addition, we confirmed previously reported projections of the AAr to the basal ganglia, the external nucleus of the inferior colliculus (ICX), the deep layers of the optic tectum, and various brain stem nuclei. A series of inactivation experiments demonstrated that the sharp tuning of AAr sites for binaural spatial cues depends on Field L input but not on input from the auditory space map in the midbrain ICX: pharmacological inactivation of Field L eliminated completely auditory responses in the AAr, whereas bilateral ablation of the midbrain ICX had no appreciable effect on AAr responses. We conclude, therefore, that the forebrain sound localization pathway can process auditory spatial information independently of the midbrain localization pathway. PMID:9463450

  12. Lhx2 Regulates the Development of the Forebrain Hem System

    PubMed Central

    Roy, Achira; Gonzalez-Gomez, Miriam; Pierani, Alessandra; Meyer, Gundela; Tole, Shubha

    2014-01-01

    Early brain development is regulated by the coordinated actions of multiple signaling centers at key boundaries between compartments. Three telencephalic midline structures are in a position to play such roles in forebrain patterning: The cortical hem, the septum, and the thalamic eminence at the diencephalic–telencephalic boundary. These structures express unique complements of signaling molecules, and they also produce distinct populations of Cajal–Retzius cells, which are thought to act as “mobile patterning units,” migrating tangentially to cover the telencephalic surface. We show that these 3 structures require the transcription factor Lhx2 to delimit their extent. In the absence of Lhx2 function, all 3 structures are greatly expanded, and the Cajal–Retzius cell population is dramatically increased. We propose that the hem, septum, and thalamic eminence together form a “forebrain hem system” that defines and regulates the formation of the telencephalic midline. Disruptions in the forebrain hem system may be implicated in severe brain malformations such as holoprosencephaly. Lhx2 functions as a central regulator of this system's development. Since all components of the forebrain hem system have been identified across several vertebrate species, the mechanisms that regulate them may have played a fundamental role in driving key aspects of forebrain evolution. PMID:23307637

  13. Aberrant Adult Neurogenesis in the Subventricular Zone-Rostral Migratory Stream-Olfactory Bulb System Following Subchronic Manganese Exposure.

    PubMed

    Fu, Sherleen; Jiang, Wendy; Gao, Xiang; Zeng, Andrew; Cholger, Daniel; Cannon, Jason; Chen, Jinhui; Zheng, Wei

    2016-04-01

    Adult neurogenesis occurs in brain subventricular zone (SVZ). Our recent data reveal an elevated proliferation of BrdU(+) cells in SVZ following subchronic manganese (Mn) exposure in rats. This study was designed to distinguish Mn effect on the critical stage of adult neurogenesis, ie, proliferation, migration, survival and differentiation from the SVZ via the rostral migratory stream to the olfactory bulb (OB). Adult rats received a single ip-dose of BrdU at the end of 4-week Mn exposure to label proliferating cells. Immunostaining and cell-counting showed a 48% increase of BrdU(+) cells in Mn-exposed SVZ than in controls (P< .05). These BrdU(+) cells were identified as a mixed population of mainly GFAP(+) type-B neural stem cells, Nestin(+) type-C transit progenitor cells, DCX(+) migratory neuroblasts and Iba1(+) microglial cells. Another group of adult rats received 3 daily ip-injections of BrdU followed by subchronic Mn exposure. By 4-week post BrdU labeling, most of the surviving BrdU(+) cells in the OB were differentiated into NeuN(+) matured neurons. However, survival rates of BrdU/NeuN/DAPI triple-labeled cells in OB were 33% and 64% in Mn-exposed and control animals, respectively (P< .01). Infusion of Cu directly into the lateral ventricle significantly decreased the cell proliferation in the SVZ. Taken together, these results suggest that Mn exposure initially enhances the cell proliferation in adult SVZ. In the OB, however, Mn exposure significantly reduces the surviving adult-born cells and markedly inhibits their differentiation into mature neurons, resulting in an overall decreased adult neurogenesis in the OB. PMID:26794142

  14. Delivery of In Vivo Acute Intermittent Hypoxia in Neonatal Rodents to Prime Subventricular Zone-derived Neural Progenitor Cell Cultures.

    PubMed

    Ross, Heather H; Sandhu, Milap S; Sharififar, Sharareh; Fuller, David D

    2015-01-01

    Extended culture of neural stem/progenitor cells facilitates in vitro analyses to understand their biology while enabling expansion of cell populations to adequate numbers prior to transplantation. Identifying approaches to refine this process, to augment the production of all CNS cell types (i.e., neurons), and to possibly contribute to therapeutic cell therapy protocols is a high research priority. This report describes an easily applied in vivo "pre-conditioning" stimulus which can be delivered to awake, non-anesthetized animals. Thus, it is a non-invasive and non-stressful procedure. Specifically described are the procedures for exposing mouse or rat pups (aged postnatal day 1-8) to a brief (40-80 min) period of intermittent hypoxia (AIH). The procedures included in this video protocol include calibration of the whole-body plethysmography chamber in which pups are placed during AIH and the technical details of AIH exposure. The efficacy of this approach to elicit tissue-level changes in the awake animal is demonstrated through the enhancement of subsequent in vitro expansion and neuronal differentiation in cells harvested from the subventricular zone (SVZ). These results support the notion that tissue level changes across multiple systems could be observed following AIH, and support the continued optimization and establishment of AIH as a priming or conditioning modality for therapeutic cell populations. PMID:26556530

  15. The subventricular zone is the developmental milestone of a 6-layered neocortex: comparisons in metatherian and eutherian mammals.

    PubMed

    Cheung, Amanda F P; Kondo, Shinichi; Abdel-Mannan, Omar; Chodroff, Rebecca A; Sirey, Tamara M; Bluy, Lisa E; Webber, Natalie; DeProto, Jamin; Karlen, Sarah J; Krubitzer, Leah; Stolp, Helen B; Saunders, Norman R; Molnár, Zoltán

    2010-05-01

    The major lineages of mammals (Eutheria, Metatheria, and Monotremata) diverged more than 100 million years ago and have undergone independent changes in the neocortex. We found that adult South American gray short-tailed opossum (Monodelphis domestica) and tammar wallaby (Macropus eugenii) possess a significantly lower number of cerebral cortical neurons compared with the mouse (Mus musculus). To determine whether the difference is reflected in the development of the cortical germinal zones, the location of progenitor cell divisions was examined in opossum, tammar wallaby, and rat. The basic pattern of the cell divisions was conserved, but the emergence of a distinctive band of dividing cells in the subventricular zone (SVZ) occurred relatively later in the opossum (postnatal day [P14]) and the tammar wallaby (P40) than in rodents. The planes of cell divisions in the ventricular zone (VZ) were similar in all species, with comparable mRNA expression patterns of Brn2, Cux2, NeuroD6, Tbr2, and Pax6 in opossum (P12 and P20) and mouse (embryonic day 15 and P0). In conclusion, the marsupial neurodevelopmental program utilizes an organized SVZ, as indicated by the presence of intermediate (or basal) progenitor cell divisions and gene expression patterns, suggesting that the SVZ emerged prior to the Eutherian-Metatherian split. PMID:19726493

  16. Indomethacin treatment reduces microglia activation and increases numbers of neuroblasts in the subventricular zone and ischaemic striatum after focal ischaemia.

    PubMed

    Lopes, Rosana S; Cardoso, Marcelo M; Sampaio, Arthur O; Barbosa, Mario Santos; Souza, Celice C; DA Silva, Michelle C; Ferreira, Elane Magno N; Freire, Marco Aurelio M; Lima, Rafael Rodrigues; Gomes-Leal, Walace

    2016-09-01

    Neuroblasts from the subventricular zone (SVZ) migrate to striatum following stroke, but most of them die in the ischaemic milieu and this can be related to exacerbated microglial activation. Here, we explored the effects of the non-steroidal anti-inflammatory indomethacin on microglial activation, neuronal preservation and neuroblast migration following experimental striatal stroke in adult rats. Animals were submitted to endothelin-1 (ET-1)-induced focal striatal ischaemia and were treated with indomethacin or sterile saline (i.p.) for 7 days, being perfused after 8 or 14 days. Immunohistochemistry was performed to assess neuronal loss (anti-NeuN), microglial activation (anti-Iba1, ED1) and migrating neuroblasts (anti-DCX) by counting NeuN, ED1 and DCX-positive cells in the ischaemic striatum or SVZ. Indomethacin treatment reduced microglia activation and the number of ED1+ cells in both 8 and 14 days post injury as compared with controls. There was an increase in the number of DCX+ cells in both SVZ and striatum at the same survival times. Moreover, there was a decrease in the number of NeuN+ cells in indomethacin-treated animals as compared with the control group at 8 days but not after 14 days post injury. Our results suggest that indomethacin treatment modulates microglia activation, contributing to increased neuroblast proliferation in the SVZ and migration to the ischaemic striatum following stroke. PMID:27581930

  17. Therapeutic potential of CERE-110 (AAV2-NGF): Targeted, stable, and sustained NGF delivery and trophic activity on rodent basal forebrain cholinergic neurons

    PubMed Central

    Bishop, Kathie M.; Hofer, Eva K.; Mehta, Arpesh; Ramirez, Anthony; Sun, Liangwu; Tuszynski, Mark; Bartus, Raymond T.

    2009-01-01

    Treatment of degenerating basal forebrain cholinergic neurons with nerve growth factor (NGF) in Alzheimer’s disease has long been contemplated, but an effective and safe delivery method has been lacking. Towards achieving this goal, we are currently developing CERE-110, an adeno-associated virus-based gene delivery vector that encodes for human NGF, for stereotactic surgical delivery to the human nucleus basalis of Meynert. Results indicate that NGF transgene delivery to the targeted brain region via CERE-110 is reliable and accurate, that NGF transgene distribution can be controlled by altering CERE-110 dose, and that it is possible to achieve restricted NGF expression limited to but covering the target brain region. Results from animals examined at longer time periods of 3, 6, 9 and 12 months after CERE-110 delivery indicate that NGF transgene expression is stable and sustained at all time points, with no loss or build-up of protein over the long-term. In addition, results from a series of experiments indicate that CERE-110 is neuroprotective and neurorestorative to basal forebrain cholinergic neurons in the rat fimbria-fornix lesion and aged rat models, and has bioactive effects on young rat basal forebrain cholinergic neurons. These findings, as well as those from several additional non-clinical experiments conducted in both rats and monkeys, led to the initiation of a Phase I clinical study to evaluate the safety and efficacy of CERE-110 in Alzheimer’s disease subjects, which is currently ongoing. PMID:18439998

  18. Time-lapse imaging of neuroblast migration in acute slices of the adult mouse forebrain.

    PubMed

    Khlghatyan, Jivan; Saghatelyan, Armen

    2012-01-01

    There is a substantial body of evidence indicating that new functional neurons are constitutively generated from an endogenous pool of neural stem cells in restricted areas of the adult mammalian brain. Newborn neuroblasts from the subventricular zone (SVZ) migrate along the rostral migratory stream (RMS) to their final destination in the olfactory bulb (OB). In the RMS, neuroblasts migrate tangentially in chains ensheathed by astrocytic processes using blood vessels as a structural support and a source of molecular factors required for migration. In the OB, neuroblasts detach from the chains and migrate radially into the different bulbar layers where they differentiate into interneurons and integrate into the existing network. In this manuscript we describe the procedure for monitoring cell migration in acute slices of the rodent brain. The use of acute slices allows the assessment of cell migration in the microenvironment that closely resembling to in vivo conditions and in brain regions that are difficult to access for in vivo imaging. In addition, it avoids long culturing condition as in the case of organotypic and cell cultures that may eventually alter the migration properties of the cells. Neuronal precursors in acute slices can be visualized using DIC optics or fluorescent proteins. Viral labeling of neuronal precursors in the SVZ, grafting neuroblasts from reporter mice into the SVZ of wild-type mice, and using transgenic mice that express fluorescent protein in neuroblasts are all suitable methods for visualizing neuroblasts and following their migration. The later method, however, does not allow individual cells to be tracked for long periods of time because of the high density of labeled cells. We used a wide-field fluorescent upright microscope equipped with a CCD camera to achieve a relatively rapid acquisition interval (one image every 15 or 30 sec) to reliably identify the stationary and migratory phases. A precise identification of the duration of

  19. Elevated aromatase activity in forebrain synaptic terminals during song

    PubMed Central

    Remage-Healey, Luke; Oyama, Randi K.; Schlinger, Barney A.

    2009-01-01

    The enzyme aromatase (which converts androgens into oestrogens) is expressed throughout the brain in zebra finches. Aromatase is enzymatically active in both cell bodies and synaptic terminals of neurones of the songbird brain, particularly within forebrain motor and auditory networks. Aromatisation within synaptic terminals could thus provide localised and acute modulatory oestrogens within the forebrain during singing and/or audition. In male zebra finches, we tested the hypothesis that forebrain aromatase activity is elevated during singing behaviour and/or hearing male song. This study reports that aromatase activity is elevated in males that were singing for 30 min as compared to non-singing males, and that this elevation occurs only within the cellular compartment that contains synaptic terminals. In a separate experiment, males that heard acoustic playback of song for 30 min exhibited no differences in aromatase activity or in aromatase mRNA levels as revealed by quantitative PCR analysis. Therefore, these results indicate that activation of the motor pathway for song production is linked to local elevations in synaptic aromatase activity within the forebrain of male zebra finches. Future experiments could assess whether elevated synaptic aromatase activity during song is dependent on acute regulation of the aromatase protein. PMID:19207827

  20. Retinoids control anterior and dorsal properties in the developing forebrain.

    PubMed

    Halilagic, Aida; Ribes, Vanessa; Ghyselinck, Norbert B; Zile, Maija H; Dollé, Pascal; Studer, Michèle

    2007-03-01

    We have previously shown that retinoic acid (RA) synthesized by the retinaldehyde dehydrogenase 2 (RALDH2) is required in forebrain development. Deficiency in RA due to inactivation of the mouse Raldh2 gene or to complete absence of retinoids in vitamin-A-deficient (VAD) quails, leads to abnormal morphogenesis of various forebrain derivatives. In this study we show that double Raldh2/Raldh3 mouse mutants have a more severe phenotype in the craniofacial region than single null mutants. In particular, the nasal processes are truncated and the eye abnormalities are exacerbated. It has been previously shown that retinoids act mainly on cell proliferation and survival in the ventral forebrain by regulating SHH and FGF8 signaling. Using the VAD quail model, which survives longer than the Raldh-deficient mouse embryos, we found that retinoids act in maintaining the correct position of anterior and dorsal boundaries in the forebrain by modulating FGF8 anteriorly and WNT signaling dorsally. Furthermore, BMP4 and FGF8 signaling are affected in the nasal region and BMP4 is ventrally expanded in the optic vesicle. At the optic cup stage, Pax6, Tbx5 and Bmp4 are ectopically expressed in the presumptive retinal pigmented epithelium (RPE), while Otx2 and Mitf are not induced, leading to a dorsal transdifferentiation of RPE to neural retina. Therefore, besides being required for survival of ventral structures, retinoids are involved in restricting anterior identity in the telencephalon and dorsal identity in the diencephalon and the retina. PMID:17184764

  1. Task-phase-specific dynamics of basal forebrain neuronal ensembles

    PubMed Central

    Tingley, David; Alexander, Andrew S.; Kolbu, Sean; de Sa, Virginia R.; Chiba, Andrea A.; Nitz, Douglas A.

    2014-01-01

    Cortically projecting basal forebrain neurons play a critical role in learning and attention, and their degeneration accompanies age-related impairments in cognition. Despite the impressive anatomical and cell-type complexity of this system, currently available data suggest that basal forebrain neurons lack complexity in their response fields, with activity primarily reflecting only macro-level brain states such as sleep and wake, onset of relevant stimuli and/or reward obtainment. The current study examined the spiking activity of basal forebrain neuron populations across multiple phases of a selective attention task, addressing, in particular, the issue of complexity in ensemble firing patterns across time. Clustering techniques applied to the full population revealed a large number of distinct categories of task-phase-specific activity patterns. Unique population firing-rate vectors defined each task phase and most categories of task-phase-specific firing had counterparts with opposing firing patterns. An analogous set of task-phase-specific firing patterns was also observed in a population of posterior parietal cortex neurons. Thus, consistent with the known anatomical complexity, basal forebrain population dynamics are capable of differentially modulating their cortical targets according to the unique sets of environmental stimuli, motor requirements, and cognitive processes associated with different task phases. PMID:25309352

  2. Laser-scanning photostimulation of optogenetically targeted forebrain circuits.

    PubMed

    Lee, Charles C; Lam, Ying-Wan; Imaizumi, Kazuo; Sherman, S Murray

    2013-01-01

    The sensory forebrain is composed of intricately connected cell types, of which functional properties have yet to be fully elucidated. Understanding the interactions of these forebrain circuits has been aided recently by the development of optogenetic methods for light-mediated modulation of neuronal activity. Here, we describe a protocol for examining the functional organization of forebrain circuits in vitro using laser-scanning photostimulation of channelrhodopsin, expressed optogenetically via viral-mediated transfection. This approach also exploits the utility of cre-lox recombination in transgenic mice to target expression in specific neuronal cell types. Following transfection, neurons are physiologically recorded in slice preparations using whole-cell patch clamp to measure their evoked responses to laser-scanning photostimulation of channelrhodopsin expressing fibers. This approach enables an assessment of functional topography and synaptic properties. Morphological correlates can be obtained by imaging the neuroanatomical expression of channelrhodopsin expressing fibers using confocal microscopy of the live slice or post-fixed tissue. These methods enable functional investigations of forebrain circuits that expand upon more conventional approaches. PMID:24430760

  3. Functional response to SDF1α through over-expression of CXCR4 on adult subventricular zone progenitor cells

    PubMed Central

    Liu, Xian Shuang; Chopp, Michael; Santra, Manoranjan; Hozeska-Solgot, Ann; Zhang, Rui Lan; Wang, Lei; Teng, Hua; Liu, Mei; Zhang, Zheng Gang

    2008-01-01

    The chemokine receptor CXCR4 and its ligand, stromal cell derived factor-1α (SDF1α) regulate neuroblast migration towards the ischemic boundary after stroke. Using loss-and gain-function, we investigated the biological effect of CXCR4/SDF1α on neural progenitor cells. Neural progenitor cells, from the subventricular zone (SVZ) of the adult rat, were transfected with rat CXCR4-pLEGFP-C1 and pSIREN-RetroQ-CXCR4-siRNA retroviral vectors. Migration assay analysis showed that inhibition of CXCR4 by siRNA significantly reduced cell migration compared to the empty vector, indicating that CXCR4 mediated neural progenitor cell motility. When neural progenitor cells were cultured in growth medium containing bFGF (20 ng/ml), over-expression of CXCR4 significantly reduced the cell proliferation as measured by the number of bromodeoxyuridine+ (BrdU+) cells (26.4%) compared with the number in the control group (54.0%). Addition of a high concentration of SDF1α (500 ng/ml) into the progenitor cells with over-expression of CXCR4 reversed the cell proliferation back to the control levels (57.6%). Immunostaining analysis showed that neither over-expression nor inhibition of CXCR4 altered the population of neurons and astrocytes, when neural progenitor cells were cultured in differentiation medium. These in vitro results suggest that CXCR4/SDF1α primarily regulates adult neural progenitor cell motility but not differentiation, while over-expression of CXCR4 in the absence of SDF1α decreases neural progenitor cell proliferation. PMID:18598677

  4. Protooncogene expression identifies a transient columnar organization of the forebrain within the late embryonic ventricular zone

    SciTech Connect

    Johnston, J.G.; Van Der Kooy, D. )

    1989-02-01

    Immunocytochemical studies using monoclonal antibodies directed against oncogenic peptides revealed a heterogeneous distribution of the peptides within the ventricular zone of the embryonic day 18 rat forebrain. This sis-, src-, ras-, and myc-encoded peptides were concentrated in the same isolated clusters of 5-25 radial glial cells (also identified by vimentin staining), providing a transient columnar compartmentalization to the ventricular zone. An increased number of ({sup 3}H)thymidine-labeled ventricular zone cells were observed within the protooncogene stained radial glial cell columns as compared to noncolumn areas. The columnar heterogeneity of radial glial cells reveals the mosaicism of the embryonic ventricular zone and the differential proliferation of its cells.

  5. Role of prefrontal cortex and striatal output systems in short-term memory deficits associated with ageing, basal forebrain lesions, and cholinergic-rich grafts.

    PubMed

    Dunnett, S B

    1990-06-01

    The cholinergic hypothesis of geriatric memory dysfunction suggests (a) that basal forebrain lesions in animals should mimic cognitive and mnemonic impairments of human dementia and (b) that cholinergic grafts in the cortex and hippocampus may alleviate such impairments, whether induced by basal forebrain lesions or due to the intrinsic processes of ageing. Our own studies addressing these issues are reviewed. Although aged rats manifest impairments in short-term memory that are reversed by cholinergic grafts in the cortex and hippocampus, basal forebrain lesions have produced ambiguous results, which in part are attributable to nonspecific effects of the lesions. Acetylcholinesterase histochemistry and the topography of NBM-cortical connections indicate that basal forebrain lesions that include the NBM in general spare the cholinergic innervation of the prefrontal cortex, but can damage prefrontal cortical outflows via the globus pallidus. Two experiments are presented to indicate that the medial prefrontal cortex and its ventral striatal outputs provide a critical substrate for normal short-term memory performance in delayed matching and nonmatching tasks. These observations can resolve many of the discrepancies in previous lesion and graft studies. PMID:2383812

  6. Is forebrain neurogenesis a potential repair mechanism after stroke?

    PubMed

    Inta, Dragos; Gass, Peter

    2015-07-01

    The use of adult subventricular zone (SVZ) neurogenesis as brain repair strategy after stroke represents a hot topic in neurologic research. Recent radiocarbon-14 dating has revealed a lack of poststroke neurogenesis in the adult human neocortex; however, adult neurogenesis has been shown to occur, even under physiologic conditions, in the human striatum. Here, these results are contrasted with experimental poststroke neurogenesis in the murine brain. Both in humans and in rodents, the SVZ generates predominantly calretinin (CR)-expressing GABAergic interneurons, which cannot replace the broad spectrum of neuronal subtypes damaged by stroke. Therefore, SVZ neurogenesis may represent a repair mechanism only after genetic manipulation redirecting its differentiation. PMID:25966955

  7. Reduced Cerebral Oxygen Content in the DG and SVZ In Situ Promotes Neurogenesis in the Adult Rat Brain In Vivo

    PubMed Central

    Wu, Liying; Huang, Xin; Wu, Kuiwu; Xu, Lun; Li, Dahu; Liu, Shuhong; Zhao, Yongqi; Fan, Ming; Zhu, Lingling

    2015-01-01

    Neurogenesis in the adult brain occurs mainly within two neurogenic structures, the dentate gyrus (DG) of the hippocampus and the sub-ventricular zone (SVZ) of the forebrain. It has been reported that mild hypoxia promoted the proliferation of Neural Stem Cells (NSCs)in vitro. Our previous study further demonstrated that an external hypoxic environment stimulated neurogenesis in the adult rat brain in vivo. However, it remains unknown how external hypoxic environments affect the oxygen content in the brain and result in neurogenesis. Here we use an optical fiber luminescent oxygen sensor to detect the oxygen content in the adult rat brain in situ under normoxia and hypoxia. We found that the distribution of oxygen in cerebral regions is spatiotemporally heterogeneous. The Po2 values in the ventricles (45∼50 Torr) and DG (approximately 10 Torr) were much higher than those of other parts of the brain, such as the cortex and thalamus (approximately 2 Torr). Interestingly, our in vivo studies showed that an external hypoxic environment could change the intrinsic oxygen content in brain tissues, notably reducing oxygen levels in both the DG and SVZ, the major sites of adult neurogenesis. Furthermore, the hypoxic environment also increased the expression of HIF-1α and VEGF, two factors that have been reported to regulate neurogenesis, within the DG and SVZ. Thus, we have demonstrated that reducing the oxygen content of the external environment decreased Po2 levels in the DG and SVZ. This reduced oxygen level in the DG and SVZ might be the main mechanism triggering neurogenesis in the adult brain. More importantly, we speculate that varying oxygen levels may be the physiological basis of the regionally restricted neurogenesis in the adult brain. PMID:26466323

  8. Origins of serotonin innervation of forebrain structures

    NASA Technical Reports Server (NTRS)

    Kellar, K. J.; Brown, P. A.; Madrid, J.; Bernstein, M.; Vernikos-Danellis, J.; Mehler, W. R.

    1977-01-01

    The tryptophan hydroxylase activity and high-affinity uptake of (3H) serotonin ((3H)5-HT) were measured in five discrete brain regions of rats following lesions of the dorsal or median raphe nuclei. Dorsal raphe lesions reduced enzyme and uptake activity in the striatum only. Median raphe lesions reduced activities in the hippocampus, septal area, frontal cortex, and, to a lesser extent, in the hypothalamus. These data are consistent with the suggestion that the dorsal and median raphe nuclei are the origins of two separate ascending serotonergic systems - one innervating striatal structures and the other mesolimbic structures, predominantly. In addition, the data suggest that measurements of high-affinity uptake of (3H)5-HT may be a more reliable index of innervation than either 5-HT content or tryptophan hydroxylase activity.

  9. Basal forebrain control of wakefulness and cortical rhythms.

    PubMed

    Anaclet, Christelle; Pedersen, Nigel P; Ferrari, Loris L; Venner, Anne; Bass, Caroline E; Arrigoni, Elda; Fuller, Patrick M

    2015-01-01

    Wakefulness, along with fast cortical rhythms and associated cognition, depend on the basal forebrain (BF). BF cholinergic cell loss in dementia and the sedative effect of anti-cholinergic drugs have long implicated these neurons as important for cognition and wakefulness. The BF also contains intermingled inhibitory GABAergic and excitatory glutamatergic cell groups whose exact neurobiological roles are unclear. Here we show that genetically targeted chemogenetic activation of BF cholinergic or glutamatergic neurons in behaving mice produced significant effects on state consolidation and/or the electroencephalogram but had no effect on total wake. Similar activation of BF GABAergic neurons produced sustained wakefulness and high-frequency cortical rhythms, whereas chemogenetic inhibition increased sleep. Our findings reveal a major contribution of BF GABAergic neurons to wakefulness and the fast cortical rhythms associated with cognition. These findings may be clinically applicable to manipulations aimed at increasing forebrain activation in dementia and the minimally conscious state. PMID:26524973

  10. Basal forebrain control of wakefulness and cortical rhythms

    PubMed Central

    Anaclet, Christelle; Pedersen, Nigel P.; Ferrari, Loris L.; Venner, Anne; Bass, Caroline E.; Arrigoni, Elda; Fuller, Patrick M.

    2015-01-01

    Wakefulness, along with fast cortical rhythms and associated cognition, depend on the basal forebrain (BF). BF cholinergic cell loss in dementia and the sedative effect of anti-cholinergic drugs have long implicated these neurons as important for cognition and wakefulness. The BF also contains intermingled inhibitory GABAergic and excitatory glutamatergic cell groups whose exact neurobiological roles are unclear. Here we show that genetically targeted chemogenetic activation of BF cholinergic or glutamatergic neurons in behaving mice produced significant effects on state consolidation and/or the electroencephalogram but had no effect on total wake. Similar activation of BF GABAergic neurons produced sustained wakefulness and high-frequency cortical rhythms, whereas chemogenetic inhibition increased sleep. Our findings reveal a major contribution of BF GABAergic neurons to wakefulness and the fast cortical rhythms associated with cognition. These findings may be clinically applicable to manipulations aimed at increasing forebrain activation in dementia and the minimally conscious state. PMID:26524973

  11. Switching control of sympathetic activity from forebrain to hindbrain in chronic dehydration

    PubMed Central

    Colombari, Débora S A; Colombari, Eduardo; Freiria-Oliveira, Andre H; Antunes, Vagner R; Yao, Song T; Hindmarch, Charles; Ferguson, Alastair V; Fry, Mark; Murphy, David; Paton, Julian F R

    2011-01-01

    Abstract We investigated the mechanisms responsible for increased blood pressure and sympathetic nerve activity (SNA) caused by 2–3 days dehydration (DH) both in vivo and in situ preparations. In euhydrated (EH) rats, systemic application of the AT1 receptor antagonist Losartan and subsequent pre-collicular transection (to remove the hypothalamus) significantly reduced thoracic (t)SNA. In contrast, in DH rats, Losartan, followed by pre-collicular and pontine transections, failed to reduce tSNA, whereas transection at the medulla–spinal cord junction massively reduced tSNA. In DH but not EH rats, selective inhibition of the commissural nucleus tractus solitarii (cNTS) significantly reduced tSNA. Comparable data were obtained in both in situ and in vivo (anaesthetized/conscious) rats and suggest that following chronic dehydration, the control of tSNA transfers from supra-brainstem structures (e.g. hypothalamus) to the medulla oblongata, particularly the cNTS. As microarray analysis revealed up-regulation of AP1 transcription factor JunD in the dehydrated cNTS, we tested the hypothesis that AP1 transcription factor activity is responsible for dehydration-induced functional plasticity. When AP1 activity was blocked in the cNTS using a viral vector expressing a dominant negative FosB, cNTS inactivation was ineffective. However, tSNA was decreased after pre-collicular transection, a response similar to that seen in EH rats. Thus, the dehydration-induced switch in control of tSNA from hypothalamus to cNTS seems to be mediated via activation of AP1 transcription factors in the cNTS. If AP1 activity is blocked in the cNTS during dehydration, sympathetic activity control reverts back to forebrain regions. This unique reciprocating neural structure-switching plasticity between brain centres emphasizes the multiple mechanisms available for the adaptive response to dehydration. PMID:21708906

  12. Adolescent Intermittent Alcohol Exposure: Deficits in Object Recognition Memory and Forebrain Cholinergic Markers.

    PubMed

    Swartzwelder, H Scott; Acheson, Shawn K; Miller, Kelsey M; Sexton, Hannah G; Liu, Wen; Crews, Fulton T; Risher, Mary-Louise

    2015-01-01

    The long-term effects of intermittent ethanol exposure during adolescence (AIE) are of intensive interest and investigation. The effects of AIE on learning and memory and the neural functions that drive them are of particular interest as clinical findings suggest enduring deficits in those cognitive domains in humans after ethanol abuse during adolescence. Although studies of such deficits after AIE hold much promise for identifying mechanisms and therapeutic interventions, the findings are sparse and inconclusive. The present results identify a specific deficit in memory function after AIE and establish a possible neural mechanism of that deficit that may be of translational significance. Male rats (starting at PND-30) received exposure to AIE (5g/kg, i.g.) or vehicle and were allowed to mature into adulthood. At PND-71, one group of animals was assessed using the spatial-temporal object recognition (stOR) test to evaluate memory function. A separate group of animals was used to assess the density of cholinergic neurons in forebrain areas Ch1-4 using immunohistochemistry. AIE exposed animals manifested deficits in the temporal component of the stOR task relative to controls, and a significant decrease in the number of ChAT labeled neurons in forebrain areas Ch1-4. These findings add to the growing literature indicating long-lasting neural and behavioral effects of AIE that persist into adulthood and indicate that memory-related deficits after AIE depend upon the tasks employed, and possibly their degree of complexity. Finally, the parallel finding of diminished cholinergic neuron density suggests a possible mechanism underlying the effects of AIE on memory and hippocampal function as well as possible therapeutic or preventive strategies for AIE. PMID:26529506

  13. Adolescent Intermittent Alcohol Exposure: Deficits in Object Recognition Memory and Forebrain Cholinergic Markers

    PubMed Central

    Swartzwelder, H. Scott; Acheson, Shawn K.; Miller, Kelsey M.; Sexton, Hannah G.; Liu, Wen; Crews, Fulton T.; Risher, Mary-Louise

    2015-01-01

    The long-term effects of intermittent ethanol exposure during adolescence (AIE) are of intensive interest and investigation. The effects of AIE on learning and memory and the neural functions that drive them are of particular interest as clinical findings suggest enduring deficits in those cognitive domains in humans after ethanol abuse during adolescence. Although studies of such deficits after AIE hold much promise for identifying mechanisms and therapeutic interventions, the findings are sparse and inconclusive. The present results identify a specific deficit in memory function after AIE and establish a possible neural mechanism of that deficit that may be of translational significance. Male rats (starting at PND-30) received exposure to AIE (5g/kg, i.g.) or vehicle and were allowed to mature into adulthood. At PND-71, one group of animals was assessed using the spatial-temporal object recognition (stOR) test to evaluate memory function. A separate group of animals was used to assess the density of cholinergic neurons in forebrain areas Ch1-4 using immunohistochemistry. AIE exposed animals manifested deficits in the temporal component of the stOR task relative to controls, and a significant decrease in the number of ChAT labeled neurons in forebrain areas Ch1-4. These findings add to the growing literature indicating long-lasting neural and behavioral effects of AIE that persist into adulthood and indicate that memory-related deficits after AIE depend upon the tasks employed, and possibly their degree of complexity. Finally, the parallel finding of diminished cholinergic neuron density suggests a possible mechanism underlying the effects of AIE on memory and hippocampal function as well as possible therapeutic or preventive strategies for AIE. PMID:26529506

  14. Forebrain damage following prenatal exposure to low-dose X-irradiation

    SciTech Connect

    Norton, S.; Donoso, J.A.

    1985-02-01

    Exposure of fetal rats to X-irradiation on gestational day 15 resulted postnatally in dose-related effects on body weight, growth of forebrain structures, and branching of dendrites of caudate neurons. Rats were followed for 4 months postnatally after 125, 75, 50, or 25 R whole-body irradiation to the dam. Significant decreases in body weight were present at birth after the three high doses and continued as long as 4 months after 125 or 75 R. Decreased thickness of the cerebral cortex and decreased area of the caudate nucleus were also seen. Cortical thickness was reduced by 125 R to half the size of the control cortex and the caudate nucleus to two-thirds of the control. Significant decreases were present to 50 R. Dendritic branching was reduced in caudate neurons by 125 R but not in the basilar dendrites of cortical pyramidal cells. No reduction in number of cortical synapses was seen from electron micrographs of cortical layers 1 or 5. The effect on the cerebral cortex was interpreted as a loss of neurons with retention of branching and synaptogenesis of remaining neurons. In contrast, the caudate nucleus, which develops somewhat before the cerebral cortex, showed effects as a consequence either of direct damage to caudate neurons or of reduced neuropil from reduced afferent input.

  15. Heparan sulfate deficiency in autistic postmortem brain tissue from the subventricular zone of the lateral ventricles

    PubMed Central

    Pearson, Brandon L.; Corley, Michael J.; Vasconcellos, Amy; Blanchard, D. Caroline; Blanchard, Robert J.

    2013-01-01

    Abnormal cellular growth and organization have been characterized in postmortem tissue from brains of autistic individuals, suggestive of pathology in a critical neurogenic niche, the subventricular zone (SVZ) of the brain lateral ventricles (LV). We examined cellular organization, cell proliferation, and constituents of the extracellular matrix such as N-sulfated heparan sulfate (HS) and laminin (LAM) in postmortem brain tissue from the LV-SVZ of young to elderly individuals with autism (n = 4) and age-matched typically developing (TD) individuals (n = 4) using immunofluorescence techniques. Strong and systematic reductions in HS immunofluorescence were observed in the LV-SVZ of the TD individuals with increasing age. For young through mature, but not elderly, autistic pair members, HS was reduced compared to their matched TDs. Cellular proliferation (Ki67+) was higher in the autistic individual of the youngest age-matched pair. These preliminary data suggesting that HS may be reduced in young to mature autistic individuals are in agreement with previous findings from the BTBR T+tf/J mouse, an animal model of autism; from mice with genetic modifications reducing HS; and with genetic variants in HS-related genes in autism. They suggest that aberrant extracellular matrix glycosaminoglycan function localized to the subventricular zone of the lateral ventricles may be a biomarker for autism, and potentially involved in the etiology of the disorder. PMID:23318464

  16. Oligodendrocyte Lineage and Subventricular Zone Response to Traumatic Axonal Injury in the Corpus Callosum

    PubMed Central

    Sullivan, Genevieve M.; Mierzwa, Amanda J.; Kijpaisalratana, Naruchorn; Tang, *Haiying; Wang, Yong; Song, Sheng-Kwei; Selwyn, Reed

    2013-01-01

    Abstract Traumatic brain injury frequently causes traumatic axonal injury (TAI) in white matter tracts. Experimental TAI in the corpus callosum of adult mice was used to examine the effects on oligodendrocyte lineage cells and myelin in conjunction with neuroimaging. The injury targeted the corpus callosum over the subventricular zone, a source of neural stem/progenitor cells. Traumatic axonal injury was produced in the rostral body of the corpus callosum by impact onto the skull at the bregma. During the first week after injury, magnetic resonance diffusion tensor imaging showed that axial diffusivity decreased in the corpus callosum and that corresponding regions exhibited significant axon damage accompanied by hypertrophic microglia and reactive astrocytes. Oligodendrocyte progenitor proliferation increased in the subventricular zone and corpus callosum. Oligodendrocytes in the corpus callosum shifted toward upregulation of myelin gene transcription. Plp/CreERT:R26IAP reporter mice showed normal reporter labeling of myelin sheaths 0 to 2 days after injury but labeling was increased between 2 and 7 days after injury. Electron microscopy revealed axon degeneration, demyelination, and redundant myelin figures. These findings expand the cell types and responses to white matter injuries that inform diffusion tensor imaging evaluation and identify pivotal white matter changes after TAI that may affect axon vulnerability vs. recovery after brain injury. PMID:24226267

  17. The carbocyanine dye DiD labels in vitro and in vivo neural stem cells of the subventricular zone as well as myelinated structures following in vivo injection in the lateral ventricle.

    PubMed

    Carradori, Dario; Barreau, Kristell; Eyer, Joël

    2016-02-01

    Carbocyanines are fluorescent lipophilic cationic dyes used since the early 1980s as neuronal tracers. Several applications of these compounds have been developed thanks to their low cell toxicity, lateral diffusion within the cellular membranes, and good photostability. 1,1'-Dioctadecyl-3,3,3',3'-tetramethylindodicarbocyanine 4-chlorobenzenesulfonate (DiD) is an interesting component of this family because, in addition to the classic carbocyanine properties, it has a longer wavelength compared with its analogues. That makes DiD an excellent carbocyanine for labeling cells and tissues with significant intrinsic fluorescence. Drug encapsulation, drug delivery, and cellular transplantation are also fields using DiD-based systems where having detailed knowledge about its behavior as a single entity is important. Recently, promising studies concerned neural stem cells from the subventricular zone of the lateral ventricle in the brain (their natural niche) and their potential therapeutic use. Here, we show that DiD is able to label these stem cells in vitro and present basilar information concerning its pharmacokinetics, concentrations, and microscope protocols. Moreover, when DiD is injected in vivo in the cerebrospinal fluid present in the lateral ventricle of rat, it also labels stem cells as well as myelinated structures of the caudoputamen. This analysis provides a database to consult when planning experiments concerning DiD and neural stem cells from the subventricular zone. PMID:26566852

  18. (II) Physiological profiling of an endogenous peptide in the basal forebrain: Age-related bioactivity and blockade with a novel modulator.

    PubMed

    Badin, Antoine-Scott; Morrill, Paul; Devonshire, Ian M; Greenfield, Susan A

    2016-06-01

    Previous studies have suggested that neurodegeneration is an aberrant form of development, mediated by a novel peptide from the C-terminus of acetylcholinesterase (AChE). Using voltage-sensitive dye imaging we have investigated the effects of a synthetic version of this peptide in the in vitro rat basal forebrain, a key site of degeneration in Alzheimer's disease. The brain slice preparation enables direct visualisation in real-time of sub-second meso-scale neuronal coalitions ('Neuronal Assemblies') that serve as a powerful index of brain functional activity. Here we show that (1) assemblies are site-specific in their activity profile with the cortex displaying a significantly more extensive network activity than the sub-cortical basal forebrain; (2) there is an age-dependency, in both cortical and sub-cortical sites, with the younger brain (p14 rats) exhibiting more conspicuous assemblies over space and time compared to their older counterparts (p35-40 rats). (3) AChE-derived peptide significantly modulates the dynamics of neuronal assemblies in the basal forebrain of the p14 rat with the degree of modulation negatively correlated with age, (4) the differential in assembly size with age parallels the level of endogenous peptide in the brain, which also declines with maturity, and (5) this effect is completely reversed by a cyclised variant of AChE-peptide, 'NBP14'. These observations are attributed to an enhanced calcium entry that, according to developmental stage, could be either trophic or toxic, and as such may provide insight into the basic neurodegenerative process as well as an eventual therapeutic intervention. PMID:26773199

  19. Dynamic variation in forebrain estradiol levels during song learning

    PubMed Central

    Chao, Andrew; Paon, Ashley; Remage-Healey, Luke

    2014-01-01

    Estrogens shape brain circuits during development, and the capacity to synthesize estrogens locally has consequences for both sexual differentiation and the acute modulation of circuits during early learning. A recently-optimized method to detect and quantify fluctuations in brain estrogens in vivo provides a direct means to explore how brain estrogen production contributes to both differentiation and neuromodulation during development. Here, we use this method to test the hypothesis that neuroestrogens are sexually-differentiated as well as dynamically responsive to song tutoring (via passive video/audio playback) during the period of song learning in juvenile zebra finches. Our results show that baseline neuroestradiol levels in the caudal forebrain do not differ between males and females during an early critical masculinization window. Instead, we observe a prominent difference between males and females in baseline neuroestradiol that emerges during the subadult stage as animals approach sexual maturity. Second, we observe that fluctuating neuroestradiol levels during periods of passive song tutoring exhibit a markedly different profile in juveniles as compared to adults. Specifically, neuroestrogens in the caudal forebrain are elevated following (rather than during) tutor song exposure in both juvenile males and females, suggesting an important role for the early consolidation of tutor song memories. These results further reveal a circadian influence on the fluctuations in local neuroestrogens during sensory/cognitive tasks. Taken together, these findings uncover several unexpected features of brain estrogen synthesis in juvenile animals that may have implications for secondary masculinization as well as the consolidation of recent sensory experiences. PMID:25205304

  20. Dynamic variation in forebrain estradiol levels during song learning.

    PubMed

    Chao, Andrew; Paon, Ashley; Remage-Healey, Luke

    2015-03-01

    Estrogens shape brain circuits during development, and the capacity to synthesize estrogens locally has consequences for both sexual differentiation and the acute modulation of circuits during early learning. A recently optimized method to detect and quantify fluctuations in brain estrogens in vivo provides a direct means to explore how brain estrogen production contributes to both differentiation and neuromodulation during development. Here, we use this method to test the hypothesis that neuroestrogens are sexually differentiated as well as dynamically responsive to song tutoring (via passive video/audio playback) during the period of song learning in juvenile zebra finches. Our results show that baseline neuroestradiol levels in the caudal forebrain do not differ between males and females during an early critical masculinization window. Instead, we observe a prominent difference between males and females in baseline neuroestradiol that emerges during the subadult stage as animals approach sexual maturity. Second, we observe that fluctuating neuroestradiol levels during periods of passive song tutoring exhibit a markedly different profile in juveniles as compared to adults. Specifically, neuroestrogens in the caudal forebrain are elevated following (rather than during) tutor song exposure in both juvenile males and females, suggesting an important role for the early consolidation of tutor song memories. These results further reveal a circadian influence on the fluctuations in local neuroestrogens during sensory/cognitive tasks. Taken together, these findings uncover several unexpected features of brain estrogen synthesis in juvenile animals that may have implications for secondary masculinization as well as the consolidation of recent sensory experiences. PMID:25205304

  1. Nicotine administration in the wake-promoting basal forebrain attenuates sleep-promoting effects of alcohol.

    PubMed

    Sharma, Rishi; Lodhi, Shafi; Sahota, Pradeep; Thakkar, Mahesh M

    2015-10-01

    Nicotine and alcohol co-abuse is highly prevalent, although the underlying causes are unclear. It has been suggested that nicotine enhances pleasurable effects of alcohol while reducing aversive effects. Recently, we reported that nicotine acts via the basal forebrain (BF) to activate nucleus accumbens and increase alcohol consumption. Does nicotine suppress alcohol-induced aversive effects via the BF? We hypothesized that nicotine may act via the BF to suppress sleep-promoting effects of alcohol. To test this hypothesis, adult male Sprague-Dawley rats were implanted with sleep-recording electrodes and bilateral guides targeted toward the BF. Nicotine (75 pmol/500 nL/side) or artificial cerebrospinal fluid (ACSF; 500 nL/side) was microinjected into the BF followed by intragastric alcohol (ACSF + EtOH and NiC + EtOH groups; 3 g/kg) or water (NiC + W and ACSF + W groups; 10 mL/kg) administration. On completion, rats were killed and processed to localize injection sites in the BF. The statistical analysis revealed a significant effect of treatment on sleep-wakefulness. While rats exposed to alcohol (ACSF + EtOH) displayed strong sleep promotion, nicotine pre-treatment in the BF (NiC + EtOH) attenuated alcohol-induced sleep and normalized sleep-wakefulness. These results suggest that nicotine acts via the BF to suppress the aversive, sleep-promoting effects of alcohol, further supporting the role of BF in alcohol-nicotine co-use. PMID:26119352

  2. Traumatic Brain Injury Activation of the Adult Subventricular Zone Neurogenic Niche.

    PubMed

    Chang, Eun Hyuk; Adorjan, Istvan; Mundim, Mayara V; Sun, Bin; Dizon, Maria L V; Szele, Francis G

    2016-01-01

    Traumatic brain injury (TBI) is common in both civilian and military life, placing a large burden on survivors and society. However, with the recognition of neural stem cells in adult mammals, including humans, came the possibility to harness these cells for repair of damaged brain, whereas previously this was thought to be impossible. In this review, we focus on the rodent adult subventricular zone (SVZ), an important neurogenic niche within the mature brain in which neural stem cells continue to reside. We review how the SVZ is perturbed following various animal TBI models with regards to cell proliferation, emigration, survival, and differentiation, and we review specific molecules involved in these processes. Together, this information suggests next steps in attempting to translate knowledge from TBI animal models into human therapies for TBI. PMID:27531972

  3. Traumatic Brain Injury Activation of the Adult Subventricular Zone Neurogenic Niche

    PubMed Central

    Chang, Eun Hyuk; Adorjan, Istvan; Mundim, Mayara V.; Sun, Bin; Dizon, Maria L. V.; Szele, Francis G.

    2016-01-01

    Traumatic brain injury (TBI) is common in both civilian and military life, placing a large burden on survivors and society. However, with the recognition of neural stem cells in adult mammals, including humans, came the possibility to harness these cells for repair of damaged brain, whereas previously this was thought to be impossible. In this review, we focus on the rodent adult subventricular zone (SVZ), an important neurogenic niche within the mature brain in which neural stem cells continue to reside. We review how the SVZ is perturbed following various animal TBI models with regards to cell proliferation, emigration, survival, and differentiation, and we review specific molecules involved in these processes. Together, this information suggests next steps in attempting to translate knowledge from TBI animal models into human therapies for TBI. PMID:27531972

  4. Controlling neural stem cell division within the adult subventricular zone: an APPealing job.

    PubMed

    Conti, Luciano; Cattaneo, Elena

    2005-02-01

    For years, scientists investigating amyloid precursor protein (APP) have focused on its pathogenetic role in the brains of Alzheimer's disease patients. Now, a study by Caille et al. adds new sites of action and new physiological functions for APP. They show that there are binding sites for secreted N-terminal nonamyloidogenic APP (sAPP) on epidermal growth factor (EGF)-responsive neural stem cells in the subventricular zone of the adult brain, where sAPP acts as an EGF cofactor to stimulate proliferation of these cells. This result opens the hypothesis that changes in the levels of sAPP could influence activity of the neurogenic regions of the adult brain in normal and pathological conditions. PMID:15667924

  5. Roles of Wnt Signaling in the Neurogenic Niche of the Adult Mouse Ventricular-Subventricular Zone.

    PubMed

    Hirota, Yuki; Sawada, Masato; Huang, Shih-Hui; Ogino, Takashi; Ohata, Shinya; Kubo, Akiharu; Sawamoto, Kazunobu

    2016-02-01

    In many animal species, the production of new neurons (neurogenesis) occurs throughout life, in a specialized germinal region called the ventricular-subventricular zone (V-SVZ). In this region, neural stem cells undergo self-renewal and generate neural progenitor cells and new neurons. In the olfactory system, the new neurons migrate rostrally toward the olfactory bulb, where they differentiate into mature interneurons. V-SVZ-derived new neurons can also migrate toward sites of brain injury, where they contribute to neural regeneration. Recent studies indicate that two major branches of the Wnt signaling pathway, the Wnt/β-catenin and Wnt/planar cell polarity pathways, play essential roles in various facets of adult neurogenesis. Here, we review the Wnt signaling-mediated regulation of adult neurogenesis in the V-SVZ under physiological and pathological conditions. PMID:26572545

  6. A Distinct Population of Microglia Supports Adult Neurogenesis in the Subventricular Zone

    PubMed Central

    Ribeiro Xavier, Anna L.; Kress, Benjamin T.; Goldman, Steven A.; Lacerda de Menezes, João R.

    2015-01-01

    Microglia are involved in synaptic pruning both in development and in the mature CNS. In this study, we investigated whether microglia might further contribute to circuit plasticity by modulating neuronal recruitment from the neurogenic subventricular zone (SVZ) of the adult mouse striatum. We found that microglia residing in the SVZ and adjacent rostral migratory stream (RMS) comprise a morphologically and antigenically distinct phenotype of immune effectors. Whereas exhibiting characteristics of alternatively activated microglia, the SVZ/RMS microglia were clearly distinguished by their low expression of purinoceptors and lack of ATP-elicitable chemotaxis. Furthermore, the in vivo depletion of these microglia hampered the survival and migration of newly generated neuroblasts through the RMS to the olfactory bulb. SVZ and RMS microglia thus appear to comprise a functionally distinct class that is selectively adapted to the support and direction of neuronal integration into the olfactory circuitry. Therefore, this unique microglial subpopulation may serve as a novel target with which to modulate cellular addition from endogenous neural stem and progenitor cells of the adult brain. SIGNIFICANCE STATEMENT Microglial cells are a specialized population of macrophages in the CNS, playing key roles as immune mediators. As integral components in the CNS, the microglia stand out for using the same mechanisms, phagocytosis and cytochemokine release, to promote homeostasis, synaptic pruning, and neural circuitry sculpture. Here, we addressed microglial functions in the subventricular zone (SVZ), the major postnatal neurogenic niche. Our results depict microglia as a conspicuous component of SVZ and its anterior extension, the rostral migratory stream, a pathway used by neuroblasts during their transit toward olfactory bulb layers. In addition to other unique populations residing in the SVZ niche, microglia display distinct morphofunctional properties that boost neuronal

  7. The Effect of Pro-Neurogenic Gene Expression on Adult Subventricular Zone Precursor Cell Recruitment and Fate Determination After Excitotoxic Brain Injury

    PubMed Central

    Jones, Kathryn S; Connor, Bronwen J

    2016-01-01

    Despite the presence of on-going neurogenesis in the adult mammalian brain, neurons are generally not replaced after injury. Using a rodent model of excitotoxic cell loss and retroviral (RV) lineage tracing, we previously demonstrated transient recruitment of precursor cells from the subventricular zone (SVZ) into the lesioned striatum. In the current study we determined that these cells included migratory neuroblasts and oligodendrocyte precursor cells (OPC), with the predominant response from glial cells. We attempted to override this glial response by ectopic expression of the pro-neurogenic genes Pax6 or Dlx2 in the adult rat SVZ following quinolinic acid lesioning. RV-Dlx2 over-expression stimulated repair at a previously non-neurogenic time point by enhancing neuroblast recruitment and the percentage of cells that retained a neuronal fate within the lesioned area, compared to RV-GFP controls. RV-Pax6 expression was unsuccessful at inhibiting glial fate and intriguingly, increased OPC cell numbers with no change in neuronal recruitment. These findings suggest that gene choice is important when attempting to augment endogenous repair as the lesioned environment can overcome pro-neurogenic gene expression. Dlx2 over-expression however was able to partially overcome an anti-neuronal environment and therefore is a promising candidate for further study of striatal regeneration. PMID:27397999

  8. Does age matter? Behavioral and neuro-anatomical effects of neonatal and adult basal forebrain cholinergic lesions.

    PubMed

    De Bartolo, Paola; Cutuli, Debora; Ricceri, Laura; Gelfo, Francesca; Foti, Francesca; Laricchiuta, Daniela; Scattoni, Maria Luisa; Calamandrei, Gemma; Petrosini, Laura

    2010-01-01

    The "cholinergic hypothesis" of dementia posits that the progressive loss of basal forebrain cholinergic neurons and the consequent decrease of acetylcholine levels in the deafferented projection sites are correlated with degree of cognitive decline in dementia. It has also been proposed that early dysfunction of the basal forebrain (BF) cholinergic system may be a risk factor for subsequent cognitive decline and possibly dementia. To characterize how age when BF cholinergic system is lesioned affects behavioral performances and morphology of neocortical neurons, seven-day-old rats were bilaterally i.c.v. injected with 192 IgG-saporin. In adulthood, these animals were subjected to spatial and associative tests. Subsequently, the morphology of parietal pyramidal neurons was assessed. The same behavioral and morphological evaluations were made in 80-day-old rats tested three weeks after bilateral i.c.v. injections of 192 IgG-saporin. The behavioral consequences of both cholinergic depletions were markedly similar. While both groups of lesioned animals exhibited very subtle deficits in the Morris water maze, they were significantly impaired in spatial discrimination in the open field and the radial maze. Paralleling behavioral data, the results of the morphological analysis revealed comparable increases in number and density of spines in apical and basal dendrites in layer-III parietal pyramidal neurons following both neonatal and adult cholinergic depletions. The present results demonstrate that the consequences of abnormal maturation of the cholinergic system are not substantially different from those evoked by cholinergic dysfunction in adulthood and provide a developmental psychobiological perspective of the neuronal foundations of the impaired cognitive functions. PMID:20164586

  9. Basal Forebrain Atrophy Contributes to Allocentric Navigation Impairment in Alzheimer’s Disease Patients

    PubMed Central

    Kerbler, Georg M.; Nedelska, Zuzana; Fripp, Jurgen; Laczó, Jan; Vyhnalek, Martin; Lisý, Jiří; Hamlin, Adam S.; Rose, Stephen; Hort, Jakub; Coulson, Elizabeth J.

    2015-01-01

    The basal forebrain degenerates in Alzheimer’s disease (AD) and this process is believed to contribute to the cognitive decline observed in AD patients. Impairment in spatial navigation is an early feature of the disease but whether basal forebrain dysfunction in AD is responsible for the impaired navigation skills of AD patients is not known. Our objective was to investigate the relationship between basal forebrain volume and performance in real space as well as computer-based navigation paradigms in an elderly cohort comprising cognitively normal controls, subjects with amnestic mild cognitive impairment and those with AD. We also tested whether basal forebrain volume could predict the participants’ ability to perform allocentric- vs. egocentric-based navigation tasks. The basal forebrain volume was calculated from 1.5 T magnetic resonance imaging (MRI) scans, and navigation skills were assessed using the human analog of the Morris water maze employing allocentric, egocentric, and mixed allo/egocentric real space as well as computerized tests. When considering the entire sample, we found that basal forebrain volume correlated with spatial accuracy in allocentric (cued) and mixed allo/egocentric navigation tasks but not the egocentric (uncued) task, demonstrating an important role of the basal forebrain in mediating cue-based spatial navigation capacity. Regression analysis revealed that, although hippocampal volume reflected navigation performance across the entire sample, basal forebrain volume contributed to mixed allo/egocentric navigation performance in the AD group, whereas hippocampal volume did not. This suggests that atrophy of the basal forebrain contributes to aspects of navigation impairment in AD that are independent of hippocampal atrophy. PMID:26441643

  10. Basal Forebrain Atrophy Contributes to Allocentric Navigation Impairment in Alzheimer's Disease Patients.

    PubMed

    Kerbler, Georg M; Nedelska, Zuzana; Fripp, Jurgen; Laczó, Jan; Vyhnalek, Martin; Lisý, Jiří; Hamlin, Adam S; Rose, Stephen; Hort, Jakub; Coulson, Elizabeth J

    2015-01-01

    The basal forebrain degenerates in Alzheimer's disease (AD) and this process is believed to contribute to the cognitive decline observed in AD patients. Impairment in spatial navigation is an early feature of the disease but whether basal forebrain dysfunction in AD is responsible for the impaired navigation skills of AD patients is not known. Our objective was to investigate the relationship between basal forebrain volume and performance in real space as well as computer-based navigation paradigms in an elderly cohort comprising cognitively normal controls, subjects with amnestic mild cognitive impairment and those with AD. We also tested whether basal forebrain volume could predict the participants' ability to perform allocentric- vs. egocentric-based navigation tasks. The basal forebrain volume was calculated from 1.5 T magnetic resonance imaging (MRI) scans, and navigation skills were assessed using the human analog of the Morris water maze employing allocentric, egocentric, and mixed allo/egocentric real space as well as computerized tests. When considering the entire sample, we found that basal forebrain volume correlated with spatial accuracy in allocentric (cued) and mixed allo/egocentric navigation tasks but not the egocentric (uncued) task, demonstrating an important role of the basal forebrain in mediating cue-based spatial navigation capacity. Regression analysis revealed that, although hippocampal volume reflected navigation performance across the entire sample, basal forebrain volume contributed to mixed allo/egocentric navigation performance in the AD group, whereas hippocampal volume did not. This suggests that atrophy of the basal forebrain contributes to aspects of navigation impairment in AD that are independent of hippocampal atrophy. PMID:26441643

  11. Beyond the olfactory bulb: An odotopic map in the forebrain

    PubMed Central

    Nikonov, Alexander A.; Finger, Thomas E.; Caprio, John

    2005-01-01

    We report electrophysiological evidence that a simple odotopy, the spatial mapping of different odorants, is maintained above the level of the olfactory bulb (OB). Three classes of biologically relevant odorants for fish are processed in distinct regions of the forebrain (FB) in the channel catfish. Feeding cues, mainly amino acids and nucleotides, are represented in lateral, pallial portions of the FB, equivalent to the olfactory cortex of amniote vertebrates, whereas social signals mediated by bile salts are represented in medial FB centers, possibly homologous to portions of the amygdala. As in the OB, the different odorant classes map onto different territories; however, the response properties of units of the olfactory areas of the FB do not simply mirror those of the OB. For some units, distinctive response properties emerged, because the FB is the first center where odors subserving a common behavioral function (i.e., food function) converge. PMID:16339016

  12. The dopaminergic projection system, basal forebrain macrosystems, and conditioned stimuli

    PubMed Central

    Zahm, Daniel S.

    2011-01-01

    This review begins with a description of some problems that in recent years have beset an influential circuit model of fear-conditioning and goes on to look at neuroanatomy that might subserve conditioning viewed in a broader perspective, including not only fear, but also appetitive, conditioning. The paper then focuses on basal forebrain functional-anatomical systems, or macrosystems, as they have come to be called, which Lennart Heimer and colleagues described beginning in the 1970’s. Yet more specific attention is then given to the relationships of the dorsal and ventral striatopallidal systems and extended amygdala with the dopaminergic mesotelencephalic projection systems, culminating with the hypothesis that all macrosystems contribute to behavioral conditioning. PMID:18204412

  13. The effects of environmental diversity on well fed and previously undernourished rats: neuronal and glial cell measurements in the visual cortex (area 17).

    PubMed Central

    Bhide, P G; Bedi, K S

    1984-01-01

    Black and white hooded Lister rats were undernourished from the sixteenth day of gestation until 25 postnatal days of age. Around 85 days of age, 12 previously undernourished male rats were assigned to an 'enriched environmental condition' and 12 to an 'isolated environmental condition'. Well fed controls were similarly assigned. After 30 days in these environmental conditions all rats were killed by perfusion with 2% buffered glutaraldehyde. Body and forebrain weights and forebrain lengths and widths were determined for each animal. Cortical depths were measured from sections through the left occipital cortical region. Neuronal and glial cell nuclear diameters and numerical densities as well as neuronal perikaryal volumes were determined from sections through the right visual cortex. In both well fed and previously undernourished groups, the environmentally enriched rats had heavier forebrains and greater forebrain lengths compared to isolated rats. There were no significant differences between enriched and isolated rats in forebrain width or cortical depth measurements in either nutritional group. In both the well fed and previously undernourished groups there were no consistently significant differences between enriched and isolated rats in any of the measurements on neurons and glial cells. Two-way analysis of variance tests on combined data from both nutritional groups indicated significant effects of environment on forebrain weight, forebrain length and on cortical depth in one of the three sections studied (section 10). Nutrition had a significant effect on body weight, forebrain weight and forebrain width. The interaction between nutrition and environment was not statistically significant for any of the measurements carried out. PMID:6735907

  14. Distinct neuronal populations in the basal forebrain encode motivational salience and movement

    PubMed Central

    Avila, Irene; Lin, Shih-Chieh

    2014-01-01

    Basal forebrain (BF) is one of the largest cortically-projecting neuromodulatory systems in the mammalian brain, and plays a key role in attention, arousal, learning and memory. The cortically projecting BF neurons, comprised of mainly magnocellular cholinergic and GABAergic neurons, are widely distributed across several brain regions that spatially overlap with the ventral striatopallidal system at the ventral pallidum (VP). As a first step toward untangling the respective functions of spatially overlapping BF and VP systems, the goal of this study was to comprehensively characterize the behavioral correlates and physiological properties of heterogeneous neuronal populations in the BF region. We found that, while rats performed a reward-biased simple reaction time task, distinct neuronal populations encode either motivational salience or movement information. The motivational salience of attended stimuli is encoded by phasic bursting activity of a large population of slow-firing neurons that have large, broad, and complex action potential waveforms. In contrast, two other separate groups of neurons encode movement-related information, and respectively increase and decrease firing rates while rats maintained fixation. These two groups of neurons mostly have higher firing rates and small, narrow action potential waveforms. These results support the conclusion that multiple neurophysiologically distinct neuronal populations in the BF region operate independently of each other as parallel functional circuits. These observations also caution against interpreting neuronal activity in this region as a homogeneous population reflecting the function of either BF or VP alone. We suggest that salience- and movement-related neuronal populations likely correspond to BF corticopetal neurons and VP neurons, respectively. PMID:25538586

  15. Novel in vivo imaging techniques for trafficking the behavior of subventricular zone neural stem cells (SVZSC) and SVZSC induced functional repair

    SciTech Connect

    Anna-Liisa Brownell

    2003-11-28

    Adult progenitor cells hold promise for therapeutic treatment where there has been a disabling loss of function due to death of cells from trauma, disease or aging. However, it will be essential in clinical application to be able to follow the fate of the transplanted cells over time using in vivo tracking methods. We have developed protocol for labeling of progenitor cells to monitor cell trafficking by high resolution magnetic resonance imaging (MRI) and super high resolution positron emission tomography (PET). We have transfected rat subventricular zone stem cells (SVZ, progenitor cell line) and another control cell line (PC12, pheochromocytoma cells) utilizing super paramagnetic iron oxide and poly-L-lysine complex for MR imaging or radiolabeling with 18F-fluor deoxy-D- glucose for PET imaging. The labeled cells were transplanted into the rostral migratory stream (RMS) or striatum of normal or 6-hydroxydopamine lesioned Spraque-Dawley rats. Longitudinal MRI studies (up to 40 days) showed that transplantation site has significant impact to the fate of the cells; when SVZ cells were transplanted into the RMS, cells migrated several centimeter into the olfactory bulb; after transplantation into the striatum, the migration was minimal, only 2 mm. PC 12 cells grew a massive tumor after the striatal implantation and significantly smaller tumor after the RMS implantation. PET studies conducted immediately after transplantation verified the transplantation site. MRI studies were able to show the whole path of migration in one image, since part of the cells die during migration and will get detected because of iron content. Endpoint histological studies verified the cell survival and immunohistochemical studies revealed the differentiation of the transplanted cells into astrocytes and neurons.

  16. Neurodevelopment Genes in Lampreys Reveal Trends for Forebrain Evolution in Craniates

    PubMed Central

    Guérin, Adèle; d'Aubenton-Carafa, Yves; Marrakchi, Emna; Da Silva, Corinne; Wincker, Patrick; Mazan, Sylvie; Rétaux, Sylvie

    2009-01-01

    The forebrain is the brain region which has undergone the most dramatic changes through vertebrate evolution. Analyses conducted in lampreys are essential to gain insight into the broad ancestral characteristics of the forebrain at the dawn of vertebrates, and to understand the molecular basis for the diversifications that have taken place in cyclostomes and gnathostomes following their splitting. Here, we report the embryonic expression patterns of 43 lamprey genes, coding for transcription factors or signaling molecules known to be involved in cell proliferation, stemcellness, neurogenesis, patterning and regionalization in the developing forebrain. Systematic expression patterns comparisons with model organisms highlight conservations likely to reflect shared features present in the vertebrate ancestors. They also point to changes in signaling systems –pathways which control the growth and patterning of the neuroepithelium-, which may have been crucial in the evolution of forebrain anatomy at the origin of vertebrates. PMID:19399187

  17. In vivo knockdown of basal forebrain p75 neurotrophin receptor stimulates choline acetyltransferase activity in the mature hippocampus.

    PubMed

    Barrett, Graham L; Naim, Timur; Trieu, Jennifer; Huang, Mengjie

    2016-05-01

    This study seeks to determine whether knockdown of basal forebrain p75 neurotrophin receptor (p75(NTR) ) expression elicits increased hippocampal choline acetyltransferase (ChAT) activity in mature animals. Antisense (AS) oligonucleotides (oligos) targeting p75(NTR) were infused into the medial septal area of mature rats continuously for 4 weeks. In all rats, the cannula outlet was placed equidistant between the left and the right sides of the vertical diagonal band of Broca. We tested phosphorothioate (PS), morpholino (Mo), and gapmer (mixed PS/RNA) oligos. Gapmer AS infusions of 7.5 and 22 μg/day decreased septal p75(NTR) mRNA by 34% and 48%, respectively. The same infusions increased hippocampal ChAT activity by 41% and 55%. Increased hippocampal ChAT activity correlated strongly with septal p75(NTR) downregulation in individual rats. Infusions of PS and Mo AS oligos did not downregulate p75(NTR) mRNA or stimulate ChAT activity. These results demonstrate that p75(NTR) can dynamically regulate hippocampal ChAT activity in the mature CNS. They also reveal the different efficacies of three diverse AS oligo chemistries when infused intracerebrally. Among the three types, gapmer oligos worked best. PMID:26864466

  18. Forebrain glucocorticoid receptor gene deletion attenuates behavioral changes and antidepressant responsiveness during chronic stress.

    PubMed

    Jacobson, Lauren

    2014-10-01

    Stress is an important risk factor for mood disorders. Stress also stimulates the secretion of glucocorticoids, which have been found to influence mood. To determine the role of forebrain glucocorticoid receptors (GR) in behavioral responses to chronic stress, the present experiments compared behavioral effects of repeated social defeat in mice with forebrain GR deletion and in floxed GR littermate controls. Repeated defeat produced alterations in forced swim and tail suspension immobility in floxed GR mice that did not occur in mice with forebrain GR deletion. Defeat-induced changes in immobility in floxed GR mice were prevented by chronic antidepressant treatment, indicating that these behaviors were dysphoria-related. In contrast, although mice with forebrain GR deletion exhibited antidepressant-induced decreases in tail suspension immobility in the absence of stress, this response did not occur in mice with forebrain GR deletion after defeat. There were no marked differences in plasma corticosterone between genotypes, suggesting that behavioral differences depended on forebrain GR rather than on abnormal glucocorticoid secretion. Defeat-induced gene expression of the neuronal activity marker c-fos in the ventral hippocampus, paraventricular thalamus and lateral septum correlated with genotype-related differences in behavioral effects of defeat, whereas c-fos induction in the nucleus accumbens and central and basolateral amygdala correlated with genotype-related differences in behavioral responses to antidepressant treatment. The dependence of both negative (dysphoria-related) and positive (antidepressant-induced) behaviors on forebrain GR is consistent with the contradictory effects of glucocorticoids on mood, and implicates these or other forebrain regions in these effects. PMID:25168761

  19. Forebrain glucocorticoid receptor gene deletion attenuates behavioral changes and antidepressant responsiveness during chronic stress

    PubMed Central

    Jacobson, Lauren

    2014-01-01

    Stress is an important risk factor for mood disorders. Stress also stimulates the secretion of glucocorticoids, which have been found to influence mood. To determine the role of forebrain glucocorticoid receptors (GR) in behavioral responses to chronic stress, the present experiments compared behavioral effects of repeated social defeat in mice with forebrain GR deletion and in floxed GR littermate controls. Repeated defeat produced alterations in forced swim and tail suspension immobility in floxed GR mice that did not occur in mice with forebrain GR deletion. Defeat-induced changes in immobility in floxed GR mice were prevented by chronic antidepressant treatment, indicating that these behaviors were dysphoria-related. In contrast, although mice with forebrain GR deletion exhibited antidepressant-induced decreases in tail suspension immobility in the absence of stress, this response did not occur in mice with forebrain GR deletion after defeat. There were no marked differences in plasma corticosterone between genotypes, suggesting that behavioral differences depended on forebrain GR rather than on abnormal glucocorticoid secretion. Defeat-induced gene expression of the neuronal activity marker c-fos in the ventral hippocampus, paraventricular thalamus and lateral septum correlated with genotype-related differences in behavioral effects of defeat, whereas c-fos induction in the nucleus accumbens and central and basolateral amygdala correlated with genotype-related differences in behavioral responses to antidepressant treatment. The dependence of both negative (dysphoria-related) and positive (antidepressant-induced) behaviors on forebrain GR is consistent with the contradictory effects of glucocorticoids on mood, and implicates these or other forebrain regions in these effects. PMID:25168761

  20. From pluripotency to forebrain patterning: an in vitro journey astride embryonic stem cells.

    PubMed

    Lupo, Giuseppe; Bertacchi, Michele; Carucci, Nicoletta; Augusti-Tocco, Gabriella; Biagioni, Stefano; Cremisi, Federico

    2014-08-01

    Embryonic stem cells (ESCs) have been used extensively as in vitro models of neural development and disease, with special efforts towards their conversion into forebrain progenitors and neurons. The forebrain is the most complex brain region, giving rise to several fundamental structures, such as the cerebral cortex, the hypothalamus, and the retina. Due to the multiplicity of signaling pathways playing different roles at distinct times of embryonic development, the specification and patterning of forebrain has been difficult to study in vivo. Research performed on ESCs in vitro has provided a large body of evidence to complement work in model organisms, but these studies have often been focused more on cell type production than on cell fate regulation. In this review, we systematically reassess the current literature in the field of forebrain development in mouse and human ESCs with a focus on the molecular mechanisms of early cell fate decisions, taking into consideration the specific culture conditions, exogenous and endogenous molecular cues as described in the original studies. The resulting model of early forebrain induction and patterning provides a useful framework for further studies aimed at reconstructing forebrain development in vitro for basic research or therapy. PMID:24643740

  1. Lesions of the Basal Forebrain Cholinergic System in Mice Disrupt Idiothetic Navigation

    PubMed Central

    Hamlin, Adam S.; Windels, Francois; Boskovic, Zoran; Sah, Pankaj; Coulson, Elizabeth J.

    2013-01-01

    Loss of integrity of the basal forebrain cholinergic neurons is a consistent feature of Alzheimer’s disease, and measurement of basal forebrain degeneration by magnetic resonance imaging is emerging as a sensitive diagnostic marker for prodromal disease. It is also known that Alzheimer’s disease patients perform poorly on both real space and computerized cued (allothetic) or uncued (idiothetic) recall navigation tasks. Although the hippocampus is required for allothetic navigation, lesions of this region only mildly affect idiothetic navigation. Here we tested the hypothesis that the cholinergic medial septo-hippocampal circuit is important for idiothetic navigation. Basal forebrain cholinergic neurons were selectively lesioned in mice using the toxin saporin conjugated to a basal forebrain cholinergic neuronal marker, the p75 neurotrophin receptor. Control animals were able to learn and remember spatial information when tested on a modified version of the passive place avoidance test where all extramaze cues were removed, and animals had to rely on idiothetic signals. However, the exploratory behaviour of mice with cholinergic basal forebrain lesions was highly disorganized during this test. By contrast, the lesioned animals performed no differently from controls in tasks involving contextual fear conditioning and spatial working memory (Y maze), and displayed no deficits in potentially confounding behaviours such as motor performance, anxiety, or disturbed sleep/wake cycles. These data suggest that the basal forebrain cholinergic system plays a specific role in idiothetic navigation, a modality that is impaired early in Alzheimer’s disease. PMID:23320088

  2. Roof plate mediated morphogenesis of the forebrain: New players join the game.

    PubMed

    Gupta, Sandeep; Sen, Jonaki

    2016-05-15

    The roof plate is a crucial signaling center located at the dorsal midline of the developing central nervous system (CNS) along its rostro-caudal axis. By virtue of secreting multiple signaling molecules, it regulates diverse processes such as specification of dorsal fate, proliferation and axon guidance. In the forebrain, the roof plate is not only involved in patterning but is also involved in the division of the single forebrain vesicle into the two cerebral hemispheres, the failure of which leads to certain forms of holoprosencephaly. Although several molecular players such as Fgfs, BMPs, Wnts and Shh have been identified as crucial regulators of development of the forebrain, little is known about how they interact to bring about the morphological changes associated with the division of the forebrain vesicle into the cerebral hemispheres. Recent studies have now identified the dorsal mesenchyme as an additional source of signaling cues, which is likely to influence the division of the forebrain vesicle into cerebral hemispheres. In this review, we discuss the current understanding about the molecular mechanisms of roof plate mediated patterning and morphogenesis of the forebrain including some recently identified factors that influence this process and also highlight the gaps in our knowledge that remain. PMID:27012761

  3. Neuronal activities of forebrain structures with respect to bladder contraction in cats.

    PubMed

    Yamamoto, Tatsuya; Sakakibara, Ryuji; Nakazawa, Ken; Uchiyama, Tomoyuki; Shimizu, Eiji; Hattori, Takamichi; Kuwabara, Satoshi

    2010-03-31

    The forebrain is one of the important suprapontine micturition centres. Previous studies have shown that electrical stimulation of the frontal lobe and the anterior cingulate gyrus elicited either inhibition or facilitation of bladder contraction. Patients with frontal lobe tumours and aneurysms showed micturition disorders. Functional brain imaging studies showed that several parts of the forebrain are activated during bladder filling. We aimed to examine neuronal activities of forebrain structures with respect to bladder contraction in cats. In 14 adult male cats under ketamine anaesthesia in which a spontaneous isovolumetric bladder-contraction/relaxation cycle had been generated, we carried out extracellular single-unit recording in forebrain with respect to the contraction/relaxation cycles in the bladder. We recorded 112 neurons that were related to the bladder-contraction/relaxation cycles. Ninety-four neurons were found to be tonically activated during the bladder-relaxation phase, whereas the remaining 18 neurons were tonically activated during the bladder-contraction phase. Both types of neuron were widely distributed around the cruciate sulcus. Most were located medially (medial and superior frontal gyrus) and the rest were located laterally (middle and inferior frontal gyrus). Neurons recorded in forebrain structures were activated with respect to the contraction/relaxation cycles in the bladder. Forebrain structures may have a significant role in regulating bladder contraction in cats. PMID:20153810

  4. Aging results in copper accumulations in GFAP-positive cells in the subventricular zone

    PubMed Central

    Pushkar, Yulia; Robison, Gregory; Sullivan, Brendan; Zheng, Wei; Fu, Sherleen X.; Kohne, Meghan; Jiang, Wendy; Rohr, Sven; Lai, Barry; Marcus, Matthew A.; Zakharova, Taisiya

    2013-01-01

    Analysis of rodent brains with X-ray fluorescence (XRF) microscopy combined with immunohistochemistry allowed us to demonstrate that local Cu concentrations are thousands of times higher in the glia of the subventricular zone than in other cells. Using XRF microscopy with subcellular resolution and intracellular X-ray absorption spectroscopy we determined the copper (I) oxidation state and the sulfur ligand environment. Cu K-edge XANES is consistent with Cu being bound as a multimetallic Cu-S cluster similar to one present in Cu-metallothionein. Analysis of age related changes show that Cu content in astrocytes of the SVZ increases 4 fold from 3 weeks to 9 months while Cu concentration in other brain areas remain essentially constant. This increase in Cu correlates with a decrease in adult neurogenesis assessed using the Ki67 marker (both, however, can be age related effects). We demonstrate that the Cu distribution and age-related concentration changes in the brain are highly cell-specific. PMID:23738916

  5. Postnatal deletion of Numb/Numblike reveals repair and remodeling capacity in the subventricular neurogenic niche.

    PubMed Central

    Kuo, Chay T.; Mirzadeh, Zaman; Soriano-Navarro, Mario; Rašin, Mladen; Wang, Denan; Shen, Jie; Šestan, Nenad; Garcia-Verdugo, Jose; Alvarez-Buylla, Arturo; Jan, Lily Y.; Jan, Yuh-Nung

    2007-01-01

    SUMMARY Neural stem cells are retained in the postnatal subventricular zone (SVZ), a specialized neurogenic niche with unique cytoarchitecture and cell-cell contacts. Although the SVZ stem cells continuously regenerate, how they and the niche respond to local changes is unclear. Here we generated nestin-creERtm transgenic mice with inducible Cre recombinase in the SVZ, and removed Numb/Numblike, key regulators of embryonic neurogenesis from postnatal SVZ progenitors and ependymal cells. This resulted in severe damage to brain lateral ventricle integrity, and identified previously unknown roles for Numb/Numblike in regulating ependymal wall integrity and SVZ neuroblast survival. Surprisingly, the ventricular damage was eventually repaired: SVZ reconstitution and ventricular wall remodeling were mediated by progenitors that escaped Numb deletion. Our results show a self-repair mechanism in the mammalian brain, and may have implications for niche plasticity in other areas of stem cell biology, and for the therapeutic use of neural stem cells in neurodegenerative diseases. PMID:17174898

  6. The aged brain: genesis and fate of residual progenitor cells in the subventricular zone

    PubMed Central

    Capilla-Gonzalez, Vivian; Herranz-Pérez, Vicente; García-Verdugo, Jose Manuel

    2015-01-01

    Neural stem cells (NSCs) persist in the adult mammalian brain through life. The subventricular zone (SVZ) is the largest source of stem cells in the nervous system, and continuously generates new neuronal and glial cells involved in brain regeneration. During aging, the germinal potential of the SVZ suffers a widespread decline, but the causes of this turn down are not fully understood. This review provides a compilation of the current knowledge about the age-related changes in the NSC population, as well as the fate of the newly generated cells in the aged brain. It is known that the neurogenic capacity is clearly disrupted during aging, while the production of oligodendroglial cells is not compromised. Interestingly, the human brain seems to primarily preserve the ability to produce new oligodendrocytes instead of neurons, which could be related to the development of neurological disorders. Further studies in this matter are required to improve our understanding and the current strategies for fighting neurological diseases associated with senescence. PMID:26441536

  7. Anatomical Involvement of the Subventricular Zone Predicts Poor Survival Outcome in Low-Grade Astrocytomas

    PubMed Central

    Liu, Shuai; Wang, Yinyan; Fan, Xing; Ma, Jun; Ma, Wenbin; Wang, Renzhi; Jiang, Tao

    2016-01-01

    The subventricular zone (SVZ) has been implicated in the origination, development, and biological behavior of gliomas. Tumor-SVZ contact is also postulated to be a poor prognostic factor in glioblastomas. We aimed to evaluate the prognostic consequence of the anatomical involvement of low-grade gliomas with the SVZ. To that end, we reviewed 143 patients with diffuse astrocytomas, and tumor lesions were manually delineated on magnetic resonance images. We initially investigated the prognostic role of SVZ contact in all patients. Additionally, we investigated the influence of the anatomical proximity of the tumor lesion centroids to the SVZ in the SVZ-involved patient cohorts, as well as location within the SVZ. We found SVZ contact with tumors to be a significant prognostic factor of overall survival in all patients with diffuse astrocytomas (p = 0.027). In the SVZ-involved cohort, a shorter distance from the tumor centroid to the SVZ (≤30 mm) correlated with shorter overall survival (p = 0.022) on univariate analysis. However, there was no significant difference in overall survival with respect to the SVZ region involved with the tumor (p = 0.930). Multivariate analysis showed that a shorter distance between the tumor centroid and the SVZ (p = 0.039) was significantly associated with poor overall survival in SVZ-involved patients. Hence, this study helps establish the prognostic role of the anatomical interaction of tumors with the SVZ in low-grade astrocytomas. PMID:27120204

  8. The Molecular Profiles of Neural Stem Cell Niche in the Adult Subventricular Zone

    PubMed Central

    Lee, Cheol; Hu, Jingqiong; Ralls, Sherry; Kitamura, Toshio; Loh, Y. Peng; Yang, Yanqin; Mukouyama, Yoh-suke; Ahn, Sohyun

    2012-01-01

    Neural stem cells (NSCs) reside in a unique microenvironment called the neurogenic niche and generate functional new neurons. The neurogenic niche contains several distinct types of cells and interacts with the NSCs in the subventricular zone (SVZ) of the lateral ventricle. While several molecules produced by the niche cells have been identified to regulate adult neurogenesis, a systematic profiling of autocrine/paracrine signaling molecules in the neurogenic regions involved in maintenance, self-renewal, proliferation, and differentiation of NSCs has not been done. We took advantage of the genetic inducible fate mapping system (GIFM) and transgenic mice to isolate the SVZ niche cells including NSCs, transit-amplifying progenitors (TAPs), astrocytes, ependymal cells, and vascular endothelial cells. From the isolated cells and microdissected choroid plexus, we obtained the secretory molecule expression profiling (SMEP) of each cell type using the Signal Sequence Trap method. We identified a total of 151 genes encoding secretory or membrane proteins. In addition, we obtained the potential SMEP of NSCs using cDNA microarray technology. Through the combination of multiple screening approaches, we identified a number of candidate genes with a potential relevance for regulating the NSC behaviors, which provide new insight into the nature of neurogenic niche signals. PMID:23209762

  9. Subventricular Zone Cell Migration: Lessons from Quantitative Two-Photon Microscopy

    PubMed Central

    James, Rachel; Kim, Yongsoo; Hockberger, Philip E.; Szele, Francis G.

    2011-01-01

    Neuroblasts born in the adult subventricular zone (SVZ) migrate long distances in the rostral migratory stream (RMS) to the olfactory bulbs where they integrate into circuitry as functional interneurons. As very little was known about the dynamic parameters of SVZ neuroblast migration, we used two-photon time-lapse microscopy to analyze migration in acute slices. This involved analyzing 3D stacks of images over time and uncovered several novel aspects of SVZ migration: chains remain stable, cells can be immotile for extensive periods, morphology does not necessarily correlate with motility, neuroblasts exhibit local exploratory motility, dorsoventral migration occurs throughout the striatal SVZ, and neuroblasts turn at distinctive angles. We investigated these novel findings in the SVZ and RMS from the population to the single cell level. In this review we also discuss some technical considerations when setting up a two-photon microscope imaging system. Throughout the review we identify several unsolved questions about SVZ neuroblast migration that might be addressed with current or emerging techniques. PMID:21472025

  10. New insights into the role of histamine in subventricular zone-olfactory bulb neurogenesis

    PubMed Central

    Eiriz, Maria F.; Valero, Jorge; Malva, João O.; Bernardino, Liliana

    2014-01-01

    The subventricular zone (SVZ) contains neural stem cells (NSCs) that generate new neurons throughout life. Many brain diseases stimulate NSCs proliferation, neuronal differentiation and homing of these newborns cells into damaged regions. However, complete cell replacement has never been fully achieved. Hence, the identification of proneurogenic factors crucial for stem cell-based therapies will have an impact in brain repair. Histamine, a neurotransmitter and immune mediator, has been recently described to modulate proliferation and commitment of NSCs. Histamine levels are increased in the brain parenchyma and at the cerebrospinal fluid (CSF) upon inflammation and brain injury, thus being able to modulate neurogenesis. Herein, we add new data showing that in vivo administration of histamine in the lateral ventricles has a potent proneurogenic effect, increasing the production of new neuroblasts in the SVZ that ultimately reach the olfactory bulb (OB). This report emphasizes the multidimensional effects of histamine in the modulation of NSCs dynamics and sheds light into the promising therapeutic role of histamine for brain regenerative medicine. PMID:24982610

  11. Imaging and Recording Subventricular Zone Progenitor Cells in Live Tissue of Postnatal Mice

    PubMed Central

    Lacar, Benjamin; Young, Stephanie Z.; Platel, Jean-Claude; Bordey, Angélique

    2010-01-01

    The subventricular zone (SVZ) is one of two regions where neurogenesis persists in the postnatal brain. The SVZ, located along the lateral ventricle, is the largest neurogenic zone in the brain that contains multiple cell populations including astrocyte-like cells and neuroblasts. Neuroblasts migrate in chains to the olfactory bulb where they differentiate into interneurons. Here, we discuss the experimental approaches to record the electrophysiology of these cells and image their migration and calcium activity in acute slices. Although these techniques were in place for studying glial cells and neurons in mature networks, the SVZ raises new challenges due to the unique properties of SVZ cells, the cellular diversity, and the architecture of the region. We emphasize different methods, such as the use of transgenic mice and in vivo electroporation that permit identification of the different SVZ cell populations for patch clamp recording or imaging. Electroporation also permits genetic labeling of cells using fluorescent reporter mice and modification of the system using either RNA interference technology or floxed mice. In this review, we aim to provide conceptual and technical details of the approaches to perform electrophysiological and imaging studies of SVZ cells. PMID:20700392

  12. Interplay of hormones and p53 in modulating gender dimorphism of subventricular zone cell number.

    PubMed

    Kim, Jin Young; Casaccia-Bonnefil, Patrizia

    2009-11-15

    Previous studies have suggested the existence of a gender bias in repair after demyelination. Here we report the existence of gender dimorphism for the regulation of cell number in the subventricular zone (SVZ), an area that has been studied for its repair potential. The number of Sox2(+) multipotential cells in the SVZ of young adult female mice was greater than in age-matched male siblings, but this difference was not evident prior to the surge of sex hormones (i.e., in prepubertal mice). To begin asking whether hormonally derived signals were responsible for these gender-related differences, we analyzed proliferation and survival of cultured male- and female-derived SVZ cells. Estrogen, but not testosterone treatment increased cell proliferation and survival of cultured cells after IFN-gamma treatment or after UV irradiation, regardless of the gender of origin. Because apoptosis in UV-irradiated SVZ cells correlated with the expression of the proapoptotic molecule p53, we postulated that this molecule could be responsible for the gender dimorphism in the SVZ. In agreement with this prediction, no difference in the SVZ cell number was detected in male and female p53 null mice. Together with previous reports, these results implicate p53 as an important component of the mechanism regulating gender dimorphism in the SVZ. PMID:19025772

  13. The Subventricular Zone Is Able to Respond to a Demyelinating Lesion After Localized Radiation

    PubMed Central

    Capilla-Gonzalez, Vivian; Guerrero-Cazares, Hugo; Bonsu, Janice M.; Gonzalez-Perez, Oscar; Achanta, Pragathi; Wong, John; Garcia-Verdugo, Jose Manuel; Quiñones-Hinojosa, Alfredo

    2016-01-01

    Radiation is a common tool in the treatment of brain tumors that induces neurological deficits as a side effect. Some of these deficits appear to be related to the impact of radiation on the neurogenic niches, producing a drastic decrease in the proliferative capacity of these regions. In the adult mammalian brain, the subventricular zone (SVZ) of the lateral ventricles is the main neurogenic niche. Neural stem/precursor cells (NSCs) within the SVZ play an important role in brain repair following injuries. However, the irradiated NSCs' ability to respond to damage has not been previously elucidated. In this study, we evaluated the effects of localized radiation on the SVZ ability to respond to a lysolecithin-induced demyelination of the striatum. We demonstrated that the proliferation rate of the irradiated SVZ was increased after brain damage and that residual NSCs were reactivated. The irradiated SVZ had an expansion of doublecortin positive cells that appeared to migrate from the lateral ventricles toward the demyelinated striatum, where newly generated oligodendrocytes were found. In addition, in the absence of demyelinating damage, remaining cells in the irradiated SVZ appeared to repopulate the neurogenic niche a year post-radiation. These findings support the hypothesis that NSCs are radioresistant and can respond to a brain injury, recovering the neurogenic niche. A more complete understanding of the effects that localized radiation has on the SVZ may lead to improvement of the current protocols used in the radiotherapy of cancer. PMID:24038623

  14. The Adult Ventricular-Subventricular Zone (V-SVZ) and Olfactory Bulb (OB) Neurogenesis.

    PubMed

    Lim, Daniel A; Alvarez-Buylla, Arturo

    2016-01-01

    A large population of neural stem/precursor cells (NSCs) persists in the ventricular-subventricular zone (V-SVZ) located in the walls of the lateral brain ventricles. V-SVZ NSCs produce large numbers of neuroblasts that migrate a long distance into the olfactory bulb (OB) where they differentiate into local circuit interneurons. Here, we review a broad range of discoveries that have emerged from studies of postnatal V-SVZ neurogenesis: the identification of NSCs as a subpopulation of astroglial cells, the neurogenic lineage, new mechanisms of neuronal migration, and molecular regulators of precursor cell proliferation and migration. It has also become evident that V-SVZ NSCs are regionally heterogeneous, with NSCs located in different regions of the ventricle wall generating distinct OB interneuron subtypes. Insights into the developmental origins and molecular mechanisms that underlie the regional specification of V-SVZ NSCs have also begun to emerge. Other recent studies have revealed new cell-intrinsic molecular mechanisms that enable lifelong neurogenesis in the V-SVZ. Finally, we discuss intriguing differences between the rodent V-SVZ and the corresponding human brain region. The rapidly expanding cellular and molecular knowledge of V-SVZ NSC biology provides key insights into postnatal neural development, the origin of brain tumors, and may inform the development regenerative therapies from cultured and endogenous human neural precursors. PMID:27048191

  15. Neurotoxic effects of ochratoxin A on the subventricular zone of adult mouse brain.

    PubMed

    Paradells, Sara; Rocamonde, Brenda; Llinares, Cristina; Herranz-Pérez, Vicente; Jimenez, Misericordia; Garcia-Verdugo, Jose Manuel; Zipancic, Ivan; Soria, Jose Miguel; Garcia-Esparza, Ma Angeles

    2015-07-01

    Ochratoxin A (OTA), a mycotoxin that was discovered as a secondary metabolite of the fungal species Aspergillus and Penicillium, is a common contaminant in food and animal feed. This mycotoxin has been described as teratogenic, carcinogenic, genotoxic, immunotoxic and has been proven a potent neurotoxin. Other authors have previously reported the effects of OTA in different structures of the central nervous system as well as in some neurogenic regions. However, the impact of OTA exposure in the subventricular zone (SVZ) has not been assessed yet. To elucidate whether OTA affects neural precursors of the mouse SVZ we investigated, in vitro and in vivo, the effects of OTA exposure on the SVZ and on the neural precursors obtained from this neurogenic niche. In this work, we prove the cumulative effect of OTA exposure on proliferation, differentiation and depletion of neural stem cells cultured from the SVZ. In addition, we corroborated these results in vivo by immunohistochemistry and electron microscopy. As a result, we found a significant alteration in the proliferation process, which was evidenced by a decrease in the number of 5-bromo-2-deoxyuridine-positive cells and glial cells, as well as, a significant decrease in the number of neuroblasts in the SVZ. To summarize, in this study we demonstrate how OTA could be a threat to the developing and the adult SVZ through its impact in cell viability, proliferation and differentiation in a dose-dependent manner. PMID:25256750

  16. Adenosine A1 receptor inhibits postnatal neurogenesis and sustains astrogliogenesis from the subventricular zone.

    PubMed

    Benito-Muñoz, Monica; Matute, Carlos; Cavaliere, Fabio

    2016-09-01

    We previously demonstrated that activation of ATP P2X receptors during oxygen and glucose deprivation inhibits neuroblast migration and in vitro neurogenesis from the subventricular zone (SVZ). Here, we have studied the effects of adenosine, the natural end-product of ATP hydrolysis, in modulating neurogenesis and gliogenesis from the SVZ. We provide immunochemical, molecular and pharmacological evidence that adenosine via A1 receptors reduces neuronal differentiation of neurosphere cultures generated from postnatal SVZ. Furthermore, activation of A1 receptors induces downregulation of genes related to neurogenesis as demonstrated by gene expression analysis. Specifically, we found that A1 receptors trigger a signaling cascade that, through the release of IL10, turns on the Bmp2/SMAD pathway. Furthermore, activating A1 receptors in SVZ-neural progenitor cells inhibits neurogenesis and stimulates astrogliogenesis as assayed in vitro in neurosphere cultures and in vivo in the olfactory bulb. Together, these data indicate that adenosine acting at A1 receptors negatively regulates adult neurogenesis while promoting astrogliogenesis, and that this feature may be relevant to pathological conditions whereby purines are profusely released. GLIA 2016;64:1465-1478. PMID:27301342

  17. Sleep-Wake Sensitive Mechanisms of Adenosine Release in the Basal Forebrain of Rodents: An In Vitro Study

    PubMed Central

    Sims, Robert Edward; Wu, Houdini Ho Tin; Dale, Nicholas

    2013-01-01

    Adenosine acting in the basal forebrain is a key mediator of sleep homeostasis. Extracellular adenosine concentrations increase during wakefulness, especially during prolonged wakefulness and lead to increased sleep pressure and subsequent rebound sleep. The release of endogenous adenosine during the sleep-wake cycle has mainly been studied in vivo with microdialysis techniques. The biochemical changes that accompany sleep-wake status may be preserved in vitro. We have therefore used adenosine-sensitive biosensors in slices of the basal forebrain (BFB) to study both depolarization-evoked adenosine release and the steady state adenosine tone in rats, mice and hamsters. Adenosine release was evoked by high K+, AMPA, NMDA and mGlu receptor agonists, but not by other transmitters associated with wakefulness such as orexin, histamine or neurotensin. Evoked and basal adenosine release in the BFB in vitro exhibited three key features: the magnitude of each varied systematically with the diurnal time at which the animal was sacrificed; sleep deprivation prior to sacrifice greatly increased both evoked adenosine release and the basal tone; and the enhancement of evoked adenosine release and basal tone resulting from sleep deprivation was reversed by the inducible nitric oxide synthase (iNOS) inhibitor, 1400 W. These data indicate that characteristics of adenosine release recorded in the BFB in vitro reflect those that have been linked in vivo to the homeostatic control of sleep. Our results provide methodologically independent support for a key role for induction of iNOS as a trigger for enhanced adenosine release following sleep deprivation and suggest that this induction may constitute a biochemical memory of this state. PMID:23326515

  18. Evolution and development of interhemispheric connections in the vertebrate forebrain

    PubMed Central

    Suárez, Rodrigo; Gobius, Ilan; Richards, Linda J.

    2014-01-01

    Axonal connections between the left and right sides of the brain are crucial for bilateral integration of lateralized sensory, motor, and associative functions. Throughout vertebrate species, forebrain commissures share a conserved developmental plan, a similar position relative to each other within the brain and similar patterns of connectivity. However, major events in the evolution of the vertebrate brain, such as the expansion of the telencephalon in tetrapods and the origin of the six-layered isocortex in mammals, resulted in the emergence and diversification of new commissural routes. These new interhemispheric connections include the pallial commissure, which appeared in the ancestors of tetrapods and connects the left and right sides of the medial pallium (hippocampus in mammals), and the corpus callosum, which is exclusive to eutherian (placental) mammals and connects both isocortical hemispheres. A comparative analysis of commissural systems in vertebrates reveals that the emergence of new commissural routes may have involved co-option of developmental mechanisms and anatomical substrates of preexistent commissural pathways. One of the embryonic regions of interest for studying these processes is the commissural plate, a portion of the early telencephalic midline that provides molecular specification and a cellular scaffold for the development of commissural axons. Further investigations into these embryonic processes in carefully selected species will provide insights not only into the mechanisms driving commissural evolution, but also regarding more general biological problems such as the role of developmental plasticity in evolutionary change. PMID:25071525

  19. Subregional Basal Forebrain Atrophy in Alzheimer's Disease: A Multicenter Study

    PubMed Central

    Kilimann, Ingo; Grothe, Michel; Heinsen, Helmut; Alho, Eduardo Joaquim Lopez; Grinberg, Lea; Amaro, Edson; dos Santos, Gláucia Aparecida Bento; da Silva, Rafael Emídio; Mitchell, Alex J.; Frisoni, Giovanni B.; Bokde, Arun L.W.; Fellgiebel, Andreas; Filippi, Massimo; Hampel, Harald; Klöppel, Stefan; Teipel, Stefan J.

    2014-01-01

    Histopathological studies in Alzheimer's disease (AD) suggest severe and region-specific neurodegeneration of the basal forebrain cholinergic system (BFCS). Here, we studied the between-center reliability and diagnostic accuracy of MRI-based BFCS volumetry in a large multicenter data set, including participants with prodromal (n = 41) or clinically manifest AD (n = 134) and 148 cognitively healthy controls. Atrophy was determined using voxel-based and region-of-interest based analyses of high-dimensionally normalized MRI scans using a newly created map of the BFCS based on postmortem in cranio MRI and histology. The AD group showed significant volume reductions of all subregions of the BFCS, which were most pronounced in the posterior nucleus basalis Meynert (NbM). The mild cognitive impairment-AD group showed pronounced volume reductions in the posterior NbM, but preserved volumes of anterior-medial regions. Diagnostic accuracy of posterior NbM volume was superior to hippocampus volume in both groups, despite higher multicenter variability of the BFCS measurements. The data of our study suggest that BFCS morphometry may provide an emerging biomarker in AD. PMID:24503619

  20. Forebrain neurocircuitry associated with human reflex cardiovascular control

    PubMed Central

    Shoemaker, J. Kevin; Goswami, Ruma

    2015-01-01

    Physiological homeostasis depends upon adequate integration and responsiveness of sensory information with the autonomic nervous system to affect rapid and effective adjustments in end organ control. Dysregulation of the autonomic nervous system leads to cardiovascular disability with consequences as severe as sudden death. The neural pathways involved in reflexive autonomic control are dependent upon brainstem nuclei but these receive modulatory inputs from higher centers in the midbrain and cortex. Neuroimaging technologies have allowed closer study of the cortical circuitry related to autonomic cardiovascular adjustments to many stressors in awake humans and have exposed many forebrain sites that associate strongly with cardiovascular arousal during stress including the medial prefrontal cortex, insula cortex, anterior cingulate, amygdala and hippocampus. Using a comparative approach, this review will consider the cortical autonomic circuitry in rodents and primates with a major emphasis on more recent neuroimaging studies in awake humans. A challenge with neuroimaging studies is their interpretation in view of multiple sensory, perceptual, emotive and/or reflexive components of autonomic responses. This review will focus on those responses related to non-volitional baroreflex control of blood pressure and also on the coordinated responses to non-fatiguing, non-painful volitional exercise with particular emphasis on the medial prefrontal cortex and the insula cortex. PMID:26388780

  1. Dynamic changes in GABAA receptors on basal forebrain cholinergic neurons following sleep deprivation and recovery

    PubMed Central

    Modirrousta, Mandana; Mainville, Lynda; Jones, Barbara E

    2007-01-01

    Background The basal forebrain (BF) cholinergic neurons play an important role in cortical activation and arousal and are active in association with cortical activation of waking and inactive in association with cortical slow wave activity of sleep. In view of findings that GABAA receptors (Rs) and inhibitory transmission undergo dynamic changes as a function of prior activity, we investigated whether the GABAARs on cholinergic cells might undergo such changes as a function of their prior activity during waking vs. sleep. Results In the brains of rats under sleep control (SC), sleep deprivation (SD) or sleep recovery (SR) conditions in the 3 hours prior to sacrifice, we examined immunofluorescent staining for β2–3 subunit GABAARs on choline acetyltransferase (ChAT) immunopositive (+) cells in the magnocellular BF. In sections also stained for c-Fos, β2–3 GABAARs were present on ChAT+ neurons which expressed c-Fos in the SD group alone and were variable or undetectable on other ChAT+ cells across groups. In dual-immunostained sections, the luminance of β2–3 GABAARs over the membrane of ChAT+ cells was found to vary significantly across conditions and to be significantly higher in SD than SC or SR groups. Conclusion We conclude that membrane GABAARs increase on cholinergic cells as a result of activity during sustained waking and reciprocally decrease as a result of inactivity during sleep. These changes in membrane GABAARs would be associated with increased GABA-mediated inhibition of cholinergic cells following prolonged waking and diminished inhibition following sleep and could thus reflect a homeostatic process regulating cholinergic cell activity and thereby indirectly cortical activity across the sleep-waking cycle. PMID:17316437

  2. Motivational Salience Signal in the Basal Forebrain Is Coupled with Faster and More Precise Decision Speed

    PubMed Central

    Avila, Irene; Lin, Shih-Chieh

    2014-01-01

    The survival of animals depends critically on prioritizing responses to motivationally salient stimuli. While it is generally believed that motivational salience increases decision speed, the quantitative relationship between motivational salience and decision speed, measured by reaction time (RT), remains unclear. Here we show that the neural correlate of motivational salience in the basal forebrain (BF), defined independently of RT, is coupled with faster and also more precise decision speed. In rats performing a reward-biased simple RT task, motivational salience was encoded by BF bursting response that occurred before RT. We found that faster RTs were tightly coupled with stronger BF motivational salience signals. Furthermore, the fraction of RT variability reflecting the contribution of intrinsic noise in the decision-making process was actively suppressed in faster RT distributions with stronger BF motivational salience signals. Artificially augmenting the BF motivational salience signal via electrical stimulation led to faster and more precise RTs and supports a causal relationship. Together, these results not only describe for the first time, to our knowledge, the quantitative relationship between motivational salience and faster decision speed, they also reveal the quantitative coupling relationship between motivational salience and more precise RT. Our results further establish the existence of an early and previously unrecognized step in the decision-making process that determines both the RT speed and variability of the entire decision-making process and suggest that this novel decision step is dictated largely by the BF motivational salience signal. Finally, our study raises the hypothesis that the dysregulation of decision speed in conditions such as depression, schizophrenia, and cognitive aging may result from the functional impairment of the motivational salience signal encoded by the poorly understood noncholinergic BF neurons. PMID:24642480

  3. Ropinirole regulates emotionality and neuronal activity markers in the limbic forebrain.

    PubMed

    Mavrikaki, Maria; Schintu, Nicoletta; Nomikos, George G; Panagis, George; Svenningsson, Per

    2014-12-01

    Restless legs syndrome (RLS) and Parkinson's disease (PD) are movement disorders usually accompanied by emotional and cognitive deficits. Although D3/D2 receptor agonists are effective against motor and non-motor deficits in RLS and PD, the exact behavioral and neurochemical effects of these drugs are not clearly defined. This study aimed to evaluate the effects of acute ropinirole (0, 0.1, 1 or 10 mg/kg, i.p.), a preferential D3/D2 receptor agonist, on intracranial self-stimulation (ICSS), spontaneous motor activity, anxiety- and depression-like behaviors, spatial reference and working memory in rats as well as on certain markers of neuronal activity, i.e. induction of immediate early genes, such as c-fos and arc, and crucial phosphorylations on GluA1 subunit of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and NA1, NA2A and NA2B subunits of N-methyl-D-aspartate (NMDA) receptors. Ropinirole decreased ICSS thresholds and induced anxiolytic- and antidepressive-like effects without affecting motor activity or spatial memory. The effects on emotionality were associated with a decrease in p-Ser897-NA1 and an increase in p-Tyr1472-NA2B in the ventral striatum as well as an increased induction of c-fos messenger RNA (mRNA) in the prefrontal cortex (PFC) and decreased expression of arc mRNA in the striatum and the shell of the nucleus accumbens. Our data indicate that ropinirole significantly affects emotionality at doses (1-10 mg/kg, i.p.) that exert no robust effects on locomotion or cognition. The data reinforce the use of D3/D2 receptor agonists in the treatment of RLS and PD patients characterized by emotional deficits and suggest that altered NMDA-mediated neurotransmission in the limbic forebrain may underlie some of ropinirole's therapeutic actions. PMID:24852388

  4. Motivational salience signal in the basal forebrain is coupled with faster and more precise decision speed.

    PubMed

    Avila, Irene; Lin, Shih-Chieh

    2014-03-01

    The survival of animals depends critically on prioritizing responses to motivationally salient stimuli. While it is generally believed that motivational salience increases decision speed, the quantitative relationship between motivational salience and decision speed, measured by reaction time (RT), remains unclear. Here we show that the neural correlate of motivational salience in the basal forebrain (BF), defined independently of RT, is coupled with faster and also more precise decision speed. In rats performing a reward-biased simple RT task, motivational salience was encoded by BF bursting response that occurred before RT. We found that faster RTs were tightly coupled with stronger BF motivational salience signals. Furthermore, the fraction of RT variability reflecting the contribution of intrinsic noise in the decision-making process was actively suppressed in faster RT distributions with stronger BF motivational salience signals. Artificially augmenting the BF motivational salience signal via electrical stimulation led to faster and more precise RTs and supports a causal relationship. Together, these results not only describe for the first time, to our knowledge, the quantitative relationship between motivational salience and faster decision speed, they also reveal the quantitative coupling relationship between motivational salience and more precise RT. Our results further establish the existence of an early and previously unrecognized step in the decision-making process that determines both the RT speed and variability of the entire decision-making process and suggest that this novel decision step is dictated largely by the BF motivational salience signal. Finally, our study raises the hypothesis that the dysregulation of decision speed in conditions such as depression, schizophrenia, and cognitive aging may result from the functional impairment of the motivational salience signal encoded by the poorly understood noncholinergic BF neurons. PMID:24642480

  5. Sexually dimorphic effects of the Lhx7 null mutation on forebrain cholinergic function.

    PubMed

    Fragkouli, A; Stamatakis, A; Zographos, E; Pachnis, V; Stylianopoulou, F

    2006-01-01

    It has been reported recently that mice lacking both alleles of the LIM-homeobox gene Lhx7, display dramatically reduced number of forebrain cholinergic neurons. In the present study, we investigated whether the Lhx7 mutation affects male and female mice differently, given the fact that gender differences are consistently observed in forebrain cholinergic function. Our results show that in adult male as well as female Lhx7 homozygous mutants there is a dramatic loss of choline acetyltransferase immunoreactive forebrain neurons, both projection and interneurons. The reduction of forebrain choline acetyltransferase immunoreactive neurons in Lhx7 homozygous mutants is accompanied by a decrease of acetylcholinesterase histochemical staining in all forebrain cholinergic neuron target areas of both male and female homozygous mutants. Furthermore, there was an increase of M1-, but not M2-, muscarinic acetylcholine receptor binding site density in the somatosensory cortex and basal ganglia of only the female homozygous mutant mice. Such an increase can be regarded as a mechanism acting to compensate for the dramatically reduced cholinergic input, raising the possibility that the forebrain cholinergic system in female mice may be more plastic and responsive to situations of limited neurotransmitter availability. Finally, our study provides additional data for the sexual dimorphism of the forebrain cholinergic system, as female mice appear to have a lower density of M1-muscarinic acetylcholine receptors in the striatal areas of the basal ganglia and a higher density of M2-muscarinic acetylcholine receptors, in a number of cortical areas, as well as the striatal areas of the basal ganglia. PMID:16338089

  6. Basal forebrain projections to the lateral habenula modulate aggression reward.

    PubMed

    Golden, Sam A; Heshmati, Mitra; Flanigan, Meghan; Christoffel, Daniel J; Guise, Kevin; Pfau, Madeline L; Aleyasin, Hossein; Menard, Caroline; Zhang, Hongxing; Hodes, Georgia E; Bregman, Dana; Khibnik, Lena; Tai, Jonathan; Rebusi, Nicole; Krawitz, Brian; Chaudhury, Dipesh; Walsh, Jessica J; Han, Ming-Hu; Shapiro, Matt L; Russo, Scott J

    2016-06-30

    Maladaptive aggressive behaviour is associated with a number of neuropsychiatric disorders and is thought to result partly from the inappropriate activation of brain reward systems in response to aggressive or violent social stimuli. Nuclei within the ventromedial hypothalamus, extended amygdala and limbic circuits are known to encode initiation of aggression; however, little is known about the neural mechanisms that directly modulate the motivational component of aggressive behaviour. Here we established a mouse model to measure the valence of aggressive inter-male social interaction with a smaller subordinate intruder as reinforcement for the development of conditioned place preference (CPP). Aggressors develop a CPP, whereas non-aggressors develop a conditioned place aversion to the intruder-paired context. Furthermore, we identify a functional GABAergic projection from the basal forebrain (BF) to the lateral habenula (lHb) that bi-directionally controls the valence of aggressive interactions. Circuit-specific silencing of GABAergic BF-lHb terminals of aggressors with halorhodopsin (NpHR3.0) increases lHb neuronal firing and abolishes CPP to the intruder-paired context. Activation of GABAergic BF-lHb terminals of non-aggressors with channelrhodopsin (ChR2) decreases lHb neuronal firing and promotes CPP to the intruder-paired context. Finally, we show that altering inhibitory transmission at BF-lHb terminals does not control the initiation of aggressive behaviour. These results demonstrate that the BF-lHb circuit has a critical role in regulating the valence of inter-male aggressive behaviour and provide novel mechanistic insight into the neural circuits modulating aggression reward processing. PMID:27357796

  7. Visualization of the medial forebrain bundle using diffusion tensor imaging

    PubMed Central

    Hana, Ardian; Hana, Anisa; Dooms, Georges; Boecher-Schwarz, Hans; Hertel, Frank

    2015-01-01

    Diffusion tensor imaging is a technique that enables physicians the portrayal of white matter tracts in vivo. We used this technique in order to depict the medial forebrain bundle (MFB) in 15 consecutive patients between 2012 and 2015. Men and women of all ages were included. There were six women and nine men. The mean age was 58.6 years (39–77). Nine patients were candidates for an eventual deep brain stimulation. Eight of them suffered from Parkinson‘s disease and one had multiple sclerosis. The remaining six patients suffered from different lesions which were situated in the frontal lobe. These were 2 metastasis, 2 meningiomas, 1 cerebral bleeding, and 1 glioblastoma. We used a 3DT1-sequence for the navigation. Furthermore T2- and DTI- sequences were performed. The FOV was 200 × 200 mm2, slice thickness 2 mm, and an acquisition matrix of 96 × 96 yielding nearly isotropic voxels of 2 × 2 × 2 mm. 3-Tesla-MRI was carried out strictly axial using 32 gradient directions and one b0-image. We used Echo-Planar-Imaging (EPI) and ASSET parallel imaging with an acceleration factor of 2. b-value was 800 s/mm2. The maximal angle was 50°. Additional scanning time was < 9 min. We were able to visualize the MFB in 12 of our patients bilaterally and in the remaining three patients we depicted the MFB on one side. It was the contralateral side of the lesion. These were 2 meningiomas and one metastasis. Portrayal of the MFB is possible for everyday routine for neurosurgical interventions. As part of the reward circuitry it might be of substantial importance for neurosurgeons during deep brain stimulation in patients with psychiatric disorders. Surgery in this part of the brain should always take the preservation of this white matter tract into account. PMID:26581828

  8. Characterization of Seeding Conditions for Studies on Differentiation Patterns of Subventricular Zone Derived Neurospheres.

    PubMed

    Sanchez-Mendoza, Eduardo H; Schlechter, Jana; Hermann, Dirk M; Doeppner, Thorsten R

    2016-01-01

    Stem cell research depends on extensive in vitro research. Poly-D-lysine (PDL) and polyornithine (PornT) are chemically synthesized amino acid chains promoting cell adhesion to solid substrates. Although, PDL and PornT are extensively used, there is no common agreement regarding the most optimal substance and its concentration. We therefore aimed at testing the effect of increasing concentrations (10, 50, and 100 μg/ml) for each compound and their corresponding mixtures (5+5 and 10+10 μg/ml) on the differentiation patterns of subventricular zone derived neurospheres. The latter were cultured for 24 h for protein and morphological analysis or for 8 h for migration analysis. No significant differences were found between increasing concentrations of PDL and PornT alone and the 10+10 condition in Western blots and immunocytochemistry. However, the mixed condition of 5+5 showed decreased glial fibrillary acidic protein and nestin expression with no changes in Akt, pAkt, GSK-3-beta, and pGSK-3-beta expression patterns. The various coating conditions also had no influence on migration of cells emerging from the neurosphere. Nevertheless, stimulation with recombinant human Erythropoietin (rhEpo) reduced migration by 20% regardless of the coating condition. We therefore conclude that a minimal concentration of 10 μg/ml of either compound should be used to produce reliable results with no alterations in protein levels as found for the 5+5 groups, and that the coating has no effect on the response of cells to chemical interventions. As such, a concentration of 10 μg/ml for either substance is sufficient when studying cellular processes of neurospheres in an in vitro or ex vivo environment. PMID:27013970

  9. Subventricular Zone Neural Progenitors from Rapid Brain Autopsies of Elderly Subjects with and without Neurodegenerative Disease

    PubMed Central

    Leonard, Brian W.; Mastroeni, Diego; Grover, Andrew; Liu, Qiang; Yang, Kechun; Gao, Ming; Wu, Jie; Pootrakul, David; van den Berge, Simone A.; Hol, Elly M.; Rogers, Joseph

    2009-01-01

    In mice and young adult humans, the subventricular zone (SVZ) contains multipotent, dividing astrocytes, some of which, when cultured, produce neurospheres that differentiate into neurons and glia. It is unknown whether the SVZ of very old humans has this capacity. Here, we report that neural stem/progenitor cells can also be cultured from rapid autopsy samples of SVZ from elderly human subjects, including patients with age-related neurologic disorders. Histological sections of SVZ from these cases showed a GFAP-positive ribbon of astrocytes similar to the astrocyte ribbon in human periventricular white matter biopsies that is reported to be a rich source of neural progenitors. Cultures of the SVZ contained (1) neurospheres with a core of Musashi-1-, nestin-, and nucleostemin-immunopositive cells, as well as more differentiated GFAP-positive astrocytes; (2) SMI-311-, MAP2a/b-, and β-tubulin (III)-positive neurons; and (3) galactocerebroside-positive oligodendrocytes. Neurospheres continued to generate differentiated progeny for months after primary culturing, in some cases nearly two years post initial plating. Patch clamp studies of differentiated SVZ cells expressing neuron-specific antigens revealed voltage-dependent, tetrodotoxin-sensitive, inward Na+ currents and voltage-dependent, delayed, slowly inactivating K+ currents, electrophysiologic characteristics of neurons. A subpopulation of these cells also exhibited responses consistent with the kinetics and pharmacology of the h current. However, while these cells displayed some aspects of neuronal function, they remained immature, as they did not fire action potentials. These studies suggest that human neural progenitor activity may remain viable throughout much of the life span, even in the face of severe neurodegenerative disease. PMID:19425077

  10. Enhancement of ventricular-subventricular zone-derived neurogenesis and oligodendrogenesis by erythropoietin and its derivatives

    PubMed Central

    Kaneko, Naoko; Kako, Eisuke; Sawamoto, Kazunobu

    2013-01-01

    In the postnatal mammalian brain, stem cells in the ventricular-subventricular zone (V-SVZ) continuously generate neuronal and glial cells throughout life. Genetic labeling of cells of specific lineages have demonstrated that the V-SVZ is an important source of the neuroblasts and/or oligodendrocyte progenitor cells (OPCs) that migrate toward injured brain areas in response to several types of insult, including ischemia and demyelinating diseases. However, this spontaneous regeneration is insufficient for complete structural and functional restoration of the injured brain, so interventions to enhance these processes are sought for clinical applications. Erythropoietin (EPO), a clinically applied erythropoietic factor, is reported to have cytoprotective effects in various kinds of insult in the central nervous system. Moreover, recent studies suggest that EPO promotes the V-SVZ-derived neurogenesis and oligodendrogenesis. EPO increases the proliferation of progenitors in the V-SVZ and/or the migration and differentiation of their progenies in and around injured areas, depending on the dosage, timing, and duration of treatment, as well as the type of animal model used. On the other hand, EPO has undesirable side effects, including thrombotic complications. We recently demonstrated that a 2-week treatment with the EPO derivative asialo-EPO promotes the differentiation of V-SVZ-derived OPCs into myelin-forming mature oligodendrocytes in the injured white matter of neonatal mice without causing erythropoiesis. Here we present an overview of the multifaceted effects of EPO and its derivatives in the V-SVZ and discuss the possible applications of these molecules in regenerative medicine. PMID:24348331

  11. Glioblastoma Recurrence Patterns After Radiation Therapy With Regard to the Subventricular Zone

    SciTech Connect

    Adeberg, Sebastian; König, Laila; Bostel, Tilman; Harrabi, Semi; Welzel, Thomas; Debus, Jürgen; Combs, Stephanie E.

    2014-11-15

    Purpose: We evaluated the influence of tumor location and tumor spread in primary glioblastoma (GBM), with respect to the subventricular zone (SVZ), on recurrence behavior, progression-free survival (PFS), and overall survival (OS). Methods and Materials: 607 patients (376 male and 231 female) with a median age of 61.3 years (range, 3.0-87.9 years) and primary GBM treated with radiation therapy (RT) from 2004 to 2012 at a single institution were included in this retrospective study. Preoperative images and follow-up examination results were assessed to evaluate tumor location. Tumors were classified according to the tumor location in relation to the SVZ. Results: The median PFS of the study population was 5.2 months (range, 1-91 months), and the median OS was 13.8 months (range, 1-102 months). Kaplan-Meier analysis showed that tumor location in close proximity to the SVZ was associated with a significant decline in PFS and OS (4.8 and 12.3 months, respectively; each P<.001). Furthermore, in cases where tumors were involved with the SVZ, distant cerebral progression (43.8%; P=.005) and multifocal progression (39.8%; P=.008) were more common. Interestingly, opening of the ventricle during the previous surgery showed no impact on PFS and OS. Conclusion: GBM in close proximity to the SVZ was associated with decreased survival and had a higher risk of multifocal or distant progression. Ventricle opening during surgery had no effect on survival rates.

  12. Evaluation of High Ipsilateral Subventricular Zone Radiation Therapy Dose in Glioblastoma: A Pooled Analysis

    SciTech Connect

    Lee, Percy; Eppinga, Wietse; Lagerwaard, Frank; Cloughesy, Timothy; Slotman, Benjamin; Nghiemphu, Phioanh L.; Wang, Pin-Chieh; Kupelian, Patrick; Agazaryan, Nzhde; Demarco, John; Selch, Michael T.; Steinberg, Michael; Kang, Jung Julie

    2013-07-15

    Purpose: Cancer stem cells (CSCs) may play a role in the recurrence of glioblastoma. They are believed to originate from neural stem cells in the subventricular zone (SVZ). Because of their radioresistance, we hypothesized that high doses of radiation (>59.4 Gy) to the SVZ are necessary to control CSCs and improve progression-free survival (PFS) or overall survival (OS) in glioblastoma. Methods and Materials: 173 patients with glioblastoma pooled from 2 academic centers were treated with resection followed by chemoradiation therapy. The SVZ was segmented on computed tomography to calculate radiation doses delivered to the presumptive CSC niches. The relationships between high SVZ doses and PFS and OS were examined using Cox proportional hazards models. Five covariates were included to estimate their impact on PFS or OS: ipsilateral and contralateral SVZ doses, clinical target volume dose, age, and extent of resection. Results: Median PFS and OS were 10.4 and 19.6 months for the cohort. The mean ipsilateral SVZ, contralateral SVZ, and clinical target volume doses were 49.2, 35.2, and 60.1 Gy, respectively. Twenty-one patients who received high ipsilateral SVZ dose (>59.4 Gy) had significantly longer median PFS (12.6 vs 9.9 months, P=.042) and longer OS (25.8 vs 19.2 months, P=.173). On multivariate analysis, high radiation therapy doses to ipsilateral SVZ remained a statistically significant independent predictor of improved PFS but not of OS. The extent of surgery affected both PFS and OS on multivariate analysis. Conclusion: High radiation therapy doses to ipsilateral CSC niches are associated with improved PFS in glioblastoma.

  13. Characterization of Seeding Conditions for Studies on Differentiation Patterns of Subventricular Zone Derived Neurospheres

    PubMed Central

    Sanchez-Mendoza, Eduardo H.; Schlechter, Jana; Hermann, Dirk M.; Doeppner, Thorsten R.

    2016-01-01

    Stem cell research depends on extensive in vitro research. Poly-D-lysine (PDL) and polyornithine (PornT) are chemically synthesized amino acid chains promoting cell adhesion to solid substrates. Although, PDL and PornT are extensively used, there is no common agreement regarding the most optimal substance and its concentration. We therefore aimed at testing the effect of increasing concentrations (10, 50, and 100 μg/ml) for each compound and their corresponding mixtures (5+5 and 10+10 μg/ml) on the differentiation patterns of subventricular zone derived neurospheres. The latter were cultured for 24 h for protein and morphological analysis or for 8 h for migration analysis. No significant differences were found between increasing concentrations of PDL and PornT alone and the 10+10 condition in Western blots and immunocytochemistry. However, the mixed condition of 5+5 showed decreased glial fibrillary acidic protein and nestin expression with no changes in Akt, pAkt, GSK-3-beta, and pGSK-3-beta expression patterns. The various coating conditions also had no influence on migration of cells emerging from the neurosphere. Nevertheless, stimulation with recombinant human Erythropoietin (rhEpo) reduced migration by 20% regardless of the coating condition. We therefore conclude that a minimal concentration of 10 μg/ml of either compound should be used to produce reliable results with no alterations in protein levels as found for the 5+5 groups, and that the coating has no effect on the response of cells to chemical interventions. As such, a concentration of 10 μg/ml for either substance is sufficient when studying cellular processes of neurospheres in an in vitro or ex vivo environment. PMID:27013970

  14. Reduced subventricular zone proliferation and white matter damage in juvenile ferrets with kaolin-induced hydrocephalus.

    PubMed

    Di Curzio, Domenico L; Buist, Richard J; Del Bigio, Marc R

    2013-10-01

    Hydrocephalus is a neurological condition characterized by altered cerebrospinal fluid (CSF) flow with enlargement of ventricular cavities in the brain. A reliable model of hydrocephalus in gyrencephalic mammals is necessary to test preclinical hypotheses. Our objective was to characterize the behavioral, structural, and histological changes in juvenile ferrets following induction of hydrocephalus. Fourteen-day old ferrets were given an injection of kaolin (aluminum silicate) into the cisterna magna. Two days later and repeated weekly until 56 days of age, magnetic resonance (MR) imaging was used to assess ventricle size. Behavior was examined thrice weekly. Compared to age-matched saline-injected controls, severely hydrocephalic ferrets weighed significantly less, their postures were impaired, and they were hyperactive prior to extreme debilitation. They developed significant ventriculomegaly and displayed white matter destruction. Reactive astroglia and microglia detected by glial fibrillary acidic protein (GFAP) and Iba-1 immunostaining were apparent in white matter, cortex, and hippocampus. There was a hydrocephalus-related increase in activated caspase 3 labeling of apoptotic cells (7.0 vs. 15.5%) and a reduction in Ki67 labeling of proliferating cells (23.3 vs. 5.9%) in the subventricular zone (SVZ). Reduced Olig2 immunolabeling suggests a depletion of glial precursors. GFAP content was elevated. Myelin basic protein (MBP) quantitation and myelin biochemical enzyme activity showed early maturational increases. Where white matter was not destroyed, the remaining axons developed myelin similar to the controls. In conclusion, the hydrocephalus-induced periventricular disturbances may involve developmental impairments in cell proliferation and glial precursor cell populations. The ferret should prove useful for testing hypotheses about white matter damage and protection in the immature hydrocephalic brain. PMID:23769908

  15. Trimethyltin intoxication induces the migration of ventricular/subventricular zone cells to the injured murine hippocampus.

    PubMed

    Weig, Blair C; Richardson, Jason R; Lowndes, Herbert E; Reuhl, Kenneth R

    2016-05-01

    Following the postnatal decline of cell proliferation in the mammalian central nervous system, the adult brain retains progenitor cells with stem cell-like properties in the subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampus. Brain injury can stimulate proliferation and redirect the migration pattern of SVZ precursor cells to the injury site. Sublethal exposure to the neurotoxicant trimethyltin (TMT) causes dose-dependent necrosis and apoptosis in the hippocampus dentate gyrus and increases SGZ stem cell proliferation to generate new granule cells. To determine whether SVZ cells also contribute to the repopulation of the TMT-damaged dentate gyrus, 6-8 week old male C3H mice were injected with the carbocyanine dye spDiI and bromodeoxyuridine (80mg/kg; ip.) to label ventricular cells prior to TMT exposure. The presence of labeled cells in hippocampus was determined 7 and 28days after TMT exposure. No significant change in the number of BrdU(+) and spDiI(+) cells was observed in the dentate gyrus 7days after TMT treatment. However, 28days after TMT treatment there was a 3-4 fold increase in the number of spDiI-labeled cells in the hippocampal hilus and dentate gyrus. Few spDiI(+) cells stained positive for the mature phenotypic markers NeuN or GFAP, suggesting they may represent undifferentiated cells. A small percentage of migrating cells were BrdU(+)/spDiI(+), indicating some newly produced, SVZ- derived precursors migrated to the hippocampus. Taken together, these data suggest that TMT-induced injury of the hippocampus can stimulate the migration of ventricular zone-derived cells to injured dentate gyrus. PMID:27045884

  16. Developmental shifts in gene expression in the auditory forebrain during the sensitive period for song learning

    PubMed Central

    London, Sarah E.; Dong, Shu; Replogle, Kirstin; Clayton, David F.

    2009-01-01

    A male zebra finch begins to learn to sing by memorizing a tutor’s song during a sensitive period in juvenile development. Tutor song memorization requires molecular signaling within the auditory forebrain. Using microarray and in situ hybridizations, we tested whether the auditory forebrain at an age just prior to tutoring expresses a different set of genes compared to later in life after song learning has ceased. Microarray analysis revealed differences in expression of thousands of genes in the male auditory forebrain at posthatch day 20 (P20) compared to adulthood. Further, song playbacks had essentially no impact on gene expression in P20 auditory forebrain, but altered expression of hundreds of genes in adults. Most genes that were song-responsive in adults were expressed at constitutively high levels at P20. Using in situ hybridization with a representative sample of 44 probes, we confirmed these effects and found that birds at P20 and P45 were similar in their gene expression patterns. Additionally, 8 of the probes showed male-female differences in expression. We conclude that the developing auditory forebrain is in a very different molecular state from the adult, despite its relatively mature gross morphology and electrophysiological responsiveness to song stimuli. Developmental gene expression changes may contribute to fine-tuning of cellular and molecular properties necessary for song learning. PMID:19360720

  17. Brain atrophy in primary progressive aphasia involves the cholinergic basal forebrain and Ayala’s nucleus

    PubMed Central

    Teipel, Stefan J.; Flatz, Wilhelm; Ackl, Nibal; Grothe, Michel; Kilimann, Ingo; Bokde, Arun L.W.; Grinberg, Lea; Amaro, Edson; Kljajevic, Vanja; Alho, Eduardo; Knels, Christina; Ebert, Anne; Heinsen, Helmut; Danek, Adrian

    2014-01-01

    Primary progressive aphasia (PPA) is characterized by left hemispheric frontotemporal cortical atrophy. Evidence from anatomical studies suggests that the nucleus subputaminalis (NSP), a subnucleus of the cholinergic basal forebrain, may be involved in the pathological process of PPA. Therefore, we studied the pattern of cortical and basal forebrain atrophy in 10 patients with a clinical diagnosis of PPA and 18 healthy age-matched controls using high-resolution magnetic resonance imaging (MRI). We determined the cholinergic basal forebrain nuclei according to Mesulam’s nomenclature and the NSP in MRI reference space based on histological sections and the MRI scan of a post-mortem brain in cranio. Using voxel-based analysis, we found left hemispheric cortical atrophy in PPA patients compared with controls, including prefrontal, lateral temporal and medial temporal lobe areas. We detected cholinergic basal forebrain atrophy in left predominant localizations of Ch4p, Ch4am, Ch4al, Ch3 and NSP. For the first time, we have described the pattern of basal forebrain atrophy in PPA and confirmed the involvement of NSP that had been predicted based on theoretical considerations. Our findings may enhance understanding of the role of cholinergic degeneration for the regional specificity of the cortical destruction leading to the syndrome of PPA. PMID:24434193

  18. Fgf16 Is Required for Specification of GABAergic Neurons and Oligodendrocytes in the Zebrafish Forebrain

    PubMed Central

    Miyake, Ayumi; Chitose, Tatsuya; Kamei, Eriko; Murakami, Atsuko; Nakayama, Yoshiaki; Konishi, Morichika; Itoh, Nobuyuki

    2014-01-01

    Fibroblast growth factor (Fgf) signaling plays crucial roles in various developmental processes including those in the brain. We examined the role of Fgf16 in the formation of the zebrafish brain. The knockdown of fgf16 decreased cell proliferation in the forebrain and midbrain. fgf16 was also essential for development of the ventral telencephalon and diencephalon, whereas fgf16 was not required for dorsoventral patterning in the midbrain. fgf16 was additionally required for the specification and differentiation of γ–aminobutyric acid (GABA)ergic interneurons and oligodendrocytes, but not for those of glutamatergic neurons in the forebrain. Cross talk between Fgf and Hedgehog (Hh) signaling was critical for the specification of GABAergic interneurons and oligodendrocytes. The expression of fgf16 in the forebrain was down-regulated by the inhibition of Hh and Fgf19 signaling, but not by that of Fgf3/Fgf8 signaling. The fgf16 morphant phenotype was similar to that of the fgf19 morphant and embryos blocked Hh signaling. The results of the present study indicate that Fgf16 signaling, which is regulated by the downstream pathways of Hh-Fgf19 in the forebrain, is involved in forebrain development. PMID:25357195

  19. Sox2-mediated differential activation of Six3.2 contributes to forebrain patterning.

    PubMed

    Beccari, Leonardo; Conte, Ivan; Cisneros, Elsa; Bovolenta, Paola

    2012-01-01

    The vertebrate forebrain is patterned during gastrulation into telencephalic, retinal, hypothalamic and diencephalic primordia. Specification of each of these domains requires the concerted activity of combinations of transcription factors (TFs). Paradoxically, some of these factors are widely expressed in the forebrain, which raises the question of how they can mediate regional differences. To address this issue, we focused on the homeobox TF Six3.2. With genomic and functional approaches we demonstrate that, in medaka fish, Six3.2 regulates, in a concentration-dependent manner, telencephalic and retinal specification under the direct control of Sox2. Six3.2 and Sox2 have antagonistic functions in hypothalamic development. These activities are, in part, executed by Foxg1 and Rx3, which seem to be differentially and directly regulated by Six3.2 and Sox2. Together, these data delineate the mechanisms by which Six3.2 diversifies its activity in the forebrain and highlight a novel function for Sox2 as one of the main regulators of anterior forebrain development. They also demonstrate that graded levels of the same TF, probably operating in partially independent transcriptional networks, pattern the vertebrate forebrain along the anterior-posterior axis. PMID:22096077

  20. The T-box transcription factor Eomes/Tbr2 regulates neurogenesis in the cortical subventricular zone

    PubMed Central

    Arnold, Sebastian J.; Huang, Guo-Jen; Cheung, Amanda F.P.; Era, Takumi; Nishikawa, Shin-Ichi; Bikoff, Elizabeth K.; Molnár, Zoltán; Robertson, Elizabeth J.; Groszer, Matthias

    2008-01-01

    The embryonic subventricular zone (SVZ) is a critical site for generating cortical projection neurons; however, molecular mechanisms regulating neurogenesis specifically in the SVZ are largely unknown. The transcription factor Eomes/Tbr2 is transiently expressed in cortical SVZ progenitor cells. Here we demonstrate that conditional inactivation of Tbr2 during early brain development causes microcephaly and severe behavioral deficits. In Tbr2 mutants the number of SVZ progenitor cells is reduced and the differentiation of upper cortical layer neurons is disturbed. Neurogenesis in the adult dentate gyrus but not the subependymal zone is abolished. These studies establish Tbr2 as a key regulator of neurogenesis in the SVZ. PMID:18794345

  1. Terminal field specificity of forebrain efferent axons to the pontine parabrachial nucleus and medullary reticular formation

    PubMed Central

    Zhang, Chi; Kang, Yi; Lundy, Robert F.

    2010-01-01

    The pontine parabrachial nucleus (PBN) and medullary reticular formation (RF) are hindbrain regions that, respectively, process sensory input and coordinate motor output related to ingestive behavior. Neural processing in each hindbrain site is subject to modulation originating from several forebrain structures including the insular gustatory cortex (IC), bed nucleus of the stria terminalis (BNST), central nucleus of the amygdala (CeA), and lateral hypothalamus (LH). The present study combined electrophysiology and retrograde tracing techniques to determine the extent of overlap between neurons within the IC, BNST, CeA and LH that target both the PBN and RF. One fluorescent retrograde tracer, red (RFB) or green (GFB) latex microbeads, was injected into the gustatory PBN under electrophysiological guidance and a different retrograde tracer, GFB or fluorogold (FG), into the ipsilateral RF using the location of gustatory NST as a point of reference. Brain tissue containing each forebrain region was sectioned, scanned using a confocal microscope, and scored for the number of single and double labeled neurons. Neurons innervating the RF only, the PBN only, or both the medullary RF and PBN were observed, largely intermingled, in each forebrain region. The CeA contained the largest number of cells retrogradely labeled after tracer injection into either hindbrain region. For each forebrain area except the IC, the origin of descending input to the RF and PBN was almost entirely ipsilateral. Axons from a small percentage of hindbrain projecting forebrain neurons targeted both the PBN and RF. Target specific and non specific inputs from a variety of forebrain nuclei to the hindbrain likely reflect functional specialization in the control of ingestive behaviors. PMID:21040715

  2. Substitution of natural sensory input by artificial neurostimulation of an amputated trigeminal nerve does not prevent the degeneration of basal forebrain cholinergic circuits projecting to the somatosensory cortex

    PubMed Central

    Herrera-Rincon, Celia; Panetsos, Fivos

    2014-01-01

    Peripheral deafferentation downregulates acetylcholine (ACh) synthesis in sensory cortices. However, the responsible neural circuits and processes are not known. We irreversibly transected the rat infraorbital nerve and implanted neuroprosthetic microdevices for proximal stump stimulation, and assessed cytochrome-oxidase and choline- acetyl-transferase (ChAT) in somatosensory, auditory and visual cortices; estimated the number and density of ACh-neurons in the magnocellular basal nucleus (MBN); and localized down-regulated ACh-neurons in basal forebrain using retrograde labeling from deafferented cortices. Here we show that nerve transection, causes down regulation of MBN cholinergic neurons. Stimulation of the cut nerve reverses the metabolic decline but does not affect the decrease in cholinergic fibers in cortex or cholinergic neurons in basal forebrain. Artifical stimulation of the nerve also has no affect of ACh-innervation of other cortices. Cortical ChAT depletion is due to loss of corticopetal MBN ChAT-expressing neurons. MBN ChAT downregulation is not due to a decrease of afferent activity or to a failure of trophic support. Basalocortical ACh circuits are sensory specific, ACh is provided to each sensory cortex “on demand” by dedicated circuits. Our data support the existence of a modality-specific cortex-MBN-cortex circuit for cognitive information processing. PMID:25452715

  3. Effect of time period after boric acid injection on 10B absorption in different regions of adult male rat's brain.

    PubMed

    Khojasteh, Nasrin Baghban; Pazirandeh, Ali; Jameie, Behnam; Goodarzi, Samereh

    2012-06-01

    Distribution of (10)B in different regions of rat normal brain was studied. Two groups were chosen as control and trial. Trial group received 2 ml of neutral boron compound. 2, 4 and 6 h after the injection brain removed, coronal sections of forebrain, midbrain and hindbrain were sandwiched between two pieces of polycarbonate. Autoradiography plots of (10)B distribution showed significant differences in three regions with the highest (10)B concentration in the forebrain during 4 h after injection. PMID:22476013

  4. Age-dependent increase of brain copper levels and expressions of copper regulatory proteins in the subventricular zone and choroid plexus

    PubMed Central

    Fu, Sherleen; Jiang, Wendy; Zheng, Wei

    2015-01-01

    Our recent data suggest a high accumulation of copper (Cu) in the subventricular zone (SVZ) along the wall of brain ventricles. Anatomically, SVZ is in direct contact with cerebrospinal fluid (CSF), which is secreted by a neighboring tissue choroid plexus (CP). Changes in Cu regulatory gene expressions in the SVZ and CP as the function of aging may determine Cu levels in the CSF and SVZ. This study was designed to investigate the associations between age, Cu levels, and Cu regulatory genes in SVZ and plexus. The SVZ and CP were dissected from brains of 3-week, 10-week, or 9-month old male rats. Analyses by atomic absorption spectroscopy revealed that the SVZ of adult and old animals contained the highest Cu level compared with other tested brain regions. Significantly positive correlations between age and Cu levels in SVZ and plexus were observed; the SVZ Cu level of old animals was 7.5- and 5.8-fold higher than those of young and adult rats (p < 0.01), respectively. Quantitation by qPCR of the transcriptional expressions of Cu regulatory proteins showed that the SVZ expressed the highest level of Cu storage protein metallothioneins (MTs), while the CP expressed the high level of Cu transporter protein Ctr1. Noticeably, Cu levels in the SVZ were positively associated with type B slow proliferating cell marker Gfap (p < 0.05), but inversely associated with type A proliferating neuroblast marker Dcx (p < 0.05) and type C transit amplifying progenitor marker Nestin (p < 0.01). Dmt1 had significant positive correlations with age and Cu levels in the plexus (p < 0.01). These findings suggest that Cu levels in all tested brain regions are increased as the function of age. The SVZ shows a different expression pattern of Cu-regulatory genes from the CP. The age-related increase of MTs and decrease of Ctr1 may contribute to the high Cu level in this neurogenesis active brain region. PMID:26106293

  5. Increased Subventricular Zone Radiation Dose Correlates With Survival in Glioblastoma Patients After Gross Total Resection

    SciTech Connect

    Chen, Linda; Guerrero-Cazares, Hugo; Ye, Xiaobu; Ford, Eric; McNutt, Todd; Kleinberg, Lawrence; Lim, Michael; Chaichana, Kaisorn; Quinones-Hinojosa, Alfredo; Redmond, Kristin

    2013-07-15

    Purpose: Neural progenitor cells in the subventricular zone (SVZ) have a controversial role in glioblastoma multiforme (GBM) as potential tumor-initiating cells. The purpose of this study was to examine the relationship between radiation dose to the SVZ and survival in GBM patients. Methods and Materials: The study included 116 patients with primary GBM treated at the Johns Hopkins Hospital between 2006 and 2009. All patients underwent surgical resection followed by adjuvant radiation therapy with intensity modulated radiation therapy (60 Gy/30 fractions) and concomitant temozolomide. Ipsilateral, contralateral, and bilateral SVZs were contoured on treatment plans by use of coregistered magnetic resonance imaging and computed tomography. Multivariate Cox regression was used to examine the relationship between mean SVZ dose and progression-free survival (PFS), as well as overall survival (OS). Age, Karnofsky Performance Status score, and extent of resection were used as covariates. The median age was 58 years (range, 29-80 years). Results: Of the patients, 12% underwent biopsy, 53% had subtotal resection (STR), and 35% had gross total resection (GTR). The Karnofsky Performance Status score was less than 90 in 54 patients and was 90 or greater in 62 patients. The median ipsilateral, contralateral, and bilateral mean SVZ doses were 48.7 Gy, 34.4 Gy, and 41.5 Gy, respectively. Among patients who underwent GTR, a mean ipsilateral SVZ dose of 40 Gy or greater was associated with a significantly improved PFS compared with patients who received less than 40 Gy (15.1 months vs 10.3 months; P=.028; hazard ratio, 0.385 [95% confidence interval, 0.165-0.901]) but not in patients undergoing STR or biopsy. The subgroup of GTR patients who received an ipsilateral dose of 40 Gy or greater also had a significantly improved OS (17.5 months vs 15.6 months; P=.027; hazard ratio, 0.385 [95% confidence interval, 0.165-0.895]). No association was found between SVZ radiation dose and PFS

  6. [Method of Calculating the Distance Between the Classes of the Structural Components of the Forebrain Birds].

    PubMed

    Voronov, L N; Konstantinov, V Y

    2016-01-01

    The method of calculating the distance between the classes of the structural components of the brain of birds. Compared interclass distances of glia, neurons and neuroglial complexes in the forebrain hooded crow (Corvus cornix) (a bird with a highly rational activity) and common crossbill (Loxia curvirostra) (birds with a medium level of rational activity). PMID:27263281

  7. GABAergic Terminals Are a Source of Galanin to Modulate Cholinergic Neuron Development in the Neonatal Forebrain

    PubMed Central

    Keimpema, Erik; Zheng, Kang; Barde, Swapnali Shantaram; Berghuis, Paul; Dobszay, Márton B.; Schnell, Robert; Mulder, Jan; Luiten, Paul G. M.; Xu, Zhiqing David; Runesson, Johan; Langel, Ülo; Lu, Bai; Hökfelt, Tomas; Harkany, Tibor

    2014-01-01

    The distribution and (patho-)physiological role of neuropeptides in the adult and aging brain have been extensively studied. Galanin is an inhibitory neuropeptide that can coexist with γ-aminobutyric acid (GABA) in the adult forebrain. However, galanin's expression sites, mode of signaling, impact on neuronal morphology, and colocalization with amino acid neurotransmitters during brain development are less well understood. Here, we show that galaninergic innervation of cholinergic projection neurons, which preferentially express galanin receptor 2 (GalR2) in the neonatal mouse basal forebrain, develops by birth. Nerve growth factor (NGF), known to modulate cholinergic morphogenesis, increases GalR2 expression. GalR2 antagonism (M871) in neonates reduces the in vivo expression and axonal targeting of the vesicular acetylcholine transporter (VAChT), indispensable for cholinergic neurotransmission. During cholinergic neuritogenesis in vitro, GalR2 can recruit Rho-family GTPases to induce the extension of a VAChT-containing primary neurite, the prospective axon. In doing so, GalR2 signaling dose-dependently modulates directional filopodial growth and antagonizes NGF-induced growth cone differentiation. Galanin accumulates in GABA-containing nerve terminals in the neonatal basal forebrain, suggesting its contribution to activity-driven cholinergic development during the perinatal period. Overall, our data define the cellular specificity and molecular complexity of galanin action in the developing basal forebrain. PMID:23897649

  8. Basal forebrain moderates the magnitude of task-dependent amygdala functional connectivity

    PubMed Central

    Knodt, Annchen R.; Hariri, Ahmad R.

    2015-01-01

    Animal studies reveal that the amygdala promotes attention and emotional memory, in part, by driving activity in downstream target regions including the prefrontal cortex (PFC) and hippocampus. Prior work has demonstrated that the amygdala influences these regions directly through monosynaptic glutamatergic signaling, and indirectly by driving activity of the cholinergic basal forebrain and subsequent downstream acetylcholine release. Yet to date, no work has addressed the functional relevance of the cholinergic basal forebrain in facilitating signaling from the amygdala in humans. We set out to determine how blood oxygen level-dependent signal within the amygdala and cholinergic basal forebrain interact to predict neural responses within downstream targets. Here, we use functional connectivity analyses to demonstrate that the cholinergic basal forebrain moderates increased amygdala connectivity with both the PFC and the hippocampus during the processing of biologically salient stimuli in humans. We further demonstrate that functional variation within the choline transporter gene predicts the magnitude of this modulatory effect. Collectively, our results provide novel evidence for the importance of cholinergic signaling in modulating neural pathways supporting arousal, attention and memory in humans. Further, our results may shed light on prior association studies linking functional variation within the choline transporter gene and diagnoses of major depression and attention-deficit hyperactivity disorder. PMID:24847112

  9. Conserved Noncoding Sequences Regulate lhx5 Expression in the Zebrafish Forebrain

    PubMed Central

    Sun, Liu; Chen, Fengjiao; Peng, Gang

    2015-01-01

    The LIM homeobox family protein Lhx5 plays important roles in forebrain development in the vertebrates. The lhx5 gene exhibits complex temporal and spatial expression patterns during early development but its transcriptional regulation mechanisms are not well understood. Here, we have used transgenesis in zebrafish in order to define regulatory elements that drive lhx5 expression in the forebrain. Through comparative genomic analysis we identified 10 non-coding sequences conserved in five teleost species. We next examined the enhancer activities of these conserved non-coding sequences with Tol2 transposon mediated transgenesis. We found a proximately located enhancer gave rise to robust reporter EGFP expression in the forebrain regions. In addition, we identified an enhancer located at approximately 50 kb upstream of lhx5 coding region that is responsible for reporter gene expression in the hypothalamus. We also identify an enhancer located approximately 40 kb upstream of the lhx5 coding region that is required for expression in the prethalamus (ventral thalamus). Together our results suggest discrete enhancer elements control lhx5 expression in different regions of the forebrain. PMID:26147098

  10. Slow age-dependent decline of doublecortin expression and BrdU labeling in the forebrain from lesser hedgehog tenrecs.

    PubMed

    Alpár, Alán; Künzle, Heinz; Gärtner, Ulrich; Popkova, Yulia; Bauer, Ute; Grosche, Jens; Reichenbach, Andreas; Härtig, Wolfgang

    2010-05-12

    In addition to synaptic remodeling, formation of new neurons is increasingly acknowledged as an important cue for plastic changes in the central nervous system. Whereas all vertebrates retain a moderate neuroproliferative capacity, phylogenetically younger mammals become dramatically impaired in this potential during aging. The present study shows that the lesser hedgehog tenrec, an insectivore with a low encephalization index, preserves its neurogenic potential surprisingly well during aging. This was shown by quantitative analysis of 5-bromo-2'-deoxyuridine (BrdU) immunolabeling in the olfactory bulb, paleo-, archi-, and neocortices from 2- to 7-year-old animals. In addition to these newly born cells, a large number of previously formed immature neurons are present throughout adulthood as shown by doublecortin (DCX) immunostaining in various forebrain regions including archicortex, paleocortex, nucleus accumbens, and amygdala. Several ventricle-associated cells in olfactory bulb and hippocampus were double-labeled by BrdU and DCX immunoreactivity. However, most DCX cells in the paleocortex can be considered as persisting immature neurons that obviously do not enter a differentiation program since double fluorescence labeling does not reveal their co-occurrence with numerous neuronal markers, whereas only a small portion coexpresses the pan-neuronal marker HuC/D. Finally, the present study reveals tenrecs as suitable laboratory animals to study age-dependent brain alterations (e.g., of neurogenesis) or slow degenerative processes, particularly due to the at least doubled longevity of tenrecs in comparison to mice and rats. PMID:20298680

  11. Gamma-aminobutyric acid and benzodiazepine receptor changes induced by unilateral 6-hydroxydopamine lesions of the medial forebrain bundle.

    PubMed

    Pan, H S; Penney, J B; Young, A B

    1985-11-01

    Quantitative autoradiography was used to ascertain alterations in [3H]muscimol, [3H]flunitrazepam (FLU), [3H]naloxone, [3H]D-alanine-D-leucine-enkephalin (DADL), and [3H]spiroperidol binding in basal ganglia 1 week, 4 weeks, and 5 months after unilateral 6-hydroxydopamine lesions of the medial forebrain bundle (MFB) in the rat. At 1 and 4 weeks following lesions, [3H]spiroperidol binding increased 33% in striatum. At 5 months, [3H]spiroperidol was only nonsignificantly increased above control. At 1 week, [3H]muscimol binding decreased 39% in ipsilateral globus pallidus (GP), but increased 41% and 11% in entopeduncular nucleus (EPN) and substantia nigra pars reticulata (SNr), respectively. At 4 weeks, [3H]muscimol binding was reduced 19% in striatum and 44% in GP and remained enhanced by 32% in both EPN and SNr. These changes in [3H]muscimol binding persisted at 5 months. [3H]FLU binding was altered in the same direction as [3H]muscimol binding; however, changes were slower in onset and became significant (and remained so) only at 4 weeks after lesions. Decreases in [3H]naloxone and [3H]DADL binding were seen in striatum, GP, EPN, and SNr. Scatchard analyses revealed that only receptor numbers were altered. This study provides biochemical evidence for differential regulation of striatal GABAergic output to GP and EPN/SNr. PMID:2995585

  12. Presynaptic TRPV1 vanilloid receptor function is age- but not CB1 cannabinoid receptor-dependent in the rodent forebrain.

    PubMed

    Köles, László; Garção, Pedro; Zádori, Zoltán S; Ferreira, Samira G; Pinheiro, Bárbara S; da Silva-Santos, Carla S; Ledent, Catherine; Köfalvi, Attila

    2013-08-01

    Neocortical and striatal TRPV1 (vanilloid or capsaicin) receptors (TRPV1Rs) are excitatory ligand-gated ion channels, and are implicated in psychiatric disorders. However, the purported presynaptic neuromodulator role of TRPV1Rs in glutamatergic, serotonergic or dopaminergic terminals of the rodent forebrain remains little understood. With the help of patch-clamp electrophysiology and neurochemical approaches, we mapped the age-dependence of presynaptic TRPV1R function, and furthermore, we aimed at exploring whether the presence of CB1 cannabinoid receptors (CB1Rs) influences the function of the TRPV1Rs, as both receptor types share endogenous ligands. We found that the major factor which affects presynaptic TRPV1R function is age: by post-natal day 13, the amplitude of capsaicin-induced release of dopamine and glutamate is halved in the rat striatum, and two weeks later, capsaicin already loses its effect. However, TRPV1R receptor function is not enhanced by chemical or genetic ablation of the CB1Rs in dopaminergic, glutamatergic and serotonergic terminals of the mouse brain. Altogether, our data indicate a possible neurodevelopmental role for presynaptic TRPV1Rs in the rodent brain, but we found no cross-talk between TRPV1Rs and CB1Rs in the same nerve terminal. PMID:23831917

  13. Optogenetic Dissection of the Basal Forebrain Neuromodulatory Control of Cortical Activation, Plasticity, and Cognition

    PubMed Central

    Brown, Ritchie E.; Hussain Shuler, Marshall G.; Petersen, Carl C.H.; Kepecs, Adam

    2015-01-01

    The basal forebrain (BF) houses major ascending projections to the entire neocortex that have long been implicated in arousal, learning, and attention. The disruption of the BF has been linked with major neurological disorders, such as coma and Alzheimer's disease, as well as in normal cognitive aging. Although it is best known for its cholinergic neurons, the BF is in fact an anatomically and neurochemically complex structure. Recent studies using transgenic mouse lines to target specific BF cell types have led to a renaissance in the study of the BF and are beginning to yield new insights about cell-type-specific circuit mechanisms during behavior. These approaches enable us to determine the behavioral conditions under which cholinergic and noncholinergic BF neurons are activated and how they control cortical processing to influence behavior. Here we discuss recent advances that have expanded our knowledge about this poorly understood brain region and laid the foundation for future cell-type-specific manipulations to modulate arousal, attention, and cortical plasticity in neurological disorders. SIGNIFICANCE STATEMENT Although the basal forebrain is best known for, and often equated with, acetylcholine-containing neurons that provide most of the cholinergic innervation of the neocortex, it is in fact an anatomically and neurochemically complex structure. Recent studies using transgenic mouse lines to target specific cell types in the basal forebrain have led to a renaissance in this field and are beginning to dissect circuit mechanisms in the basal forebrain during behavior. This review discusses recent advances in the roles of basal forebrain cholinergic and noncholinergic neurons in cognition via their dynamic modulation of cortical activity. PMID:26468190

  14. Dopamine receptor activation modulates GABA neuron migration from the basal forebrain to the cerebral cortex.

    PubMed

    Crandall, James E; McCarthy, Deirdre M; Araki, Kiyomi Y; Sims, John R; Ren, Jia-Qian; Bhide, Pradeep G

    2007-04-01

    GABA neurons of the cerebral cortex and other telencephalic structures are produced in the basal forebrain and migrate to their final destinations during the embryonic period. The embryonic basal forebrain is enriched in dopamine and its receptors, creating a favorable environment for dopamine to influence GABA neuron migration. However, whether dopamine receptor activation can influence GABA neuron migration is not known. We show that dopamine D1 receptor activation promotes and D2 receptor activation decreases GABA neuron migration from the medial and caudal ganglionic eminences to the cerebral cortex in slice preparations of embryonic mouse forebrain. Slice preparations from D1 or D2 receptor knock-out mouse embryos confirm the findings. In addition, D1 receptor electroporation into cells of the basal forebrain and pharmacological activation of the receptor promote migration of the electroporated cells to the cerebral cortex. Analysis of GABA neuron numbers in the cerebral wall of the dopamine receptor knock-out mouse embryos further confirmed the effects of dopamine receptor activation on GABA neuron migration. Finally, dopamine receptor activation mobilizes striatal neuronal cytoskeleton in a manner consistent with the effects on neuronal migration. These data show that impairing the physiological balance between D1 and D2 receptors can alter GABA neuron migration from the basal forebrain to the cerebral cortex. The intimate relationship between dopamine and GABA neuron development revealed here may offer novel insights into developmental disorders such as schizophrenia, attention deficit or autism, and fetal cocaine exposure, all of which are associated with dopamine and GABA imbalance. PMID:17409246

  15. RhoE deficiency alters postnatal subventricular zone development and the number of calbindin-expressing neurons in the olfactory bulb of mouse.

    PubMed

    Ballester-Lurbe, Begoña; González-Granero, Susana; Mocholí, Enric; Poch, Enric; García-Manzanares, María; Dierssen, Mara; Pérez-Roger, Ignacio; García-Verdugo, José M; Guasch, Rosa M; Terrado, José

    2015-11-01

    The subventricular zone represents an important reservoir of progenitor cells in the adult brain. Cells from the subventricular zone migrate along the rostral migratory stream and reach the olfactory bulb, where they originate different types of interneurons. In this work, we have analyzed the role of the small GTPase RhoE/Rnd3 in subventricular zone cell development using mice-lacking RhoE expression. Our results show that RhoE null mice display a remarkable postnatal broadening of the subventricular zone and caudal rostral migratory stream. This broadening was caused by an increase in progenitor proliferation, observed in the second postnatal week but not before, and by an altered migration of the cells, which appeared in disorganized cell arrangements that impaired the appropriate contact between cells in the rostral migratory stream. In addition, the thickness of the granule cell layer in the olfactory bulb was reduced, although the density of granule cells did not differ between wild-type and RhoE null mice. Finally, the lack of RhoE expression affected the olfactory glomeruli inducing a severe reduction of calbindin-expressing interneurons in the periglomerular layer. This was already evident in the newborns and even more pronounced 15 days later when RhoE null mice displayed 89% less cells than control mice. Our results indicate that RhoE has pleiotropic functions on subventricular cells because of its role in proliferation and tangential migration, affecting mainly the development of calbindin-expressing cells in the olfactory bulb. PMID:25009316

  16. A restricted period for formation of outer subventricular zone defined by Cdh1 and Trnp1 levels

    PubMed Central

    Martínez-Martínez, Maria Ángeles; De Juan Romero, Camino; Fernández, Virginia; Cárdenas, Adrián; Götz, Magdalena; Borrell, Víctor

    2016-01-01

    The outer subventricular zone (OSVZ) is a germinal layer playing key roles in the development of the neocortex, with particular relevance in gyrencephalic species such as human and ferret, where it contains abundant basal radial glia cells (bRGCs) that promote cortical expansion. Here we identify a brief period in ferret embryonic development when apical RGCs generate a burst of bRGCs that become founders of the OSVZ. After this period, bRGCs in the OSVZ proliferate and self-renew exclusively locally, thereby forming a self-sustained lineage independent from the other germinal layers. The time window for the brief period of OSVZ bRGC production is delineated by the coincident downregulation of Cdh1 and Trnp1, and their upregulation reduces bRGC production and prevents OSVZ seeding. This mechanism in cortical development may have key relevance in brain evolution and disease. PMID:27264089

  17. A restricted period for formation of outer subventricular zone defined by Cdh1 and Trnp1 levels.

    PubMed

    Martínez-Martínez, Maria Ángeles; De Juan Romero, Camino; Fernández, Virginia; Cárdenas, Adrián; Götz, Magdalena; Borrell, Víctor

    2016-01-01

    The outer subventricular zone (OSVZ) is a germinal layer playing key roles in the development of the neocortex, with particular relevance in gyrencephalic species such as human and ferret, where it contains abundant basal radial glia cells (bRGCs) that promote cortical expansion. Here we identify a brief period in ferret embryonic development when apical RGCs generate a burst of bRGCs that become founders of the OSVZ. After this period, bRGCs in the OSVZ proliferate and self-renew exclusively locally, thereby forming a self-sustained lineage independent from the other germinal layers. The time window for the brief period of OSVZ bRGC production is delineated by the coincident downregulation of Cdh1 and Trnp1, and their upregulation reduces bRGC production and prevents OSVZ seeding. This mechanism in cortical development may have key relevance in brain evolution and disease. PMID:27264089

  18. Upregulated expression of Nogo-A and NgR in an experimental model of focal microgyria regulates the migration, proliferation and self-renewal of subventricular zone neural progenitors.

    PubMed

    Yu, Sixun; Shu, Haifeng; Yang, Tao; Huang, Haidong; Li, Song; Zhao, Ziyi; Kuang, Yongqin

    2016-04-29

    Nogo-A and its receptor (NgR) were first described as myelin-associated inhibitors of neuronal regeneration in response to injury. In recent years, knowledge about the important role of the Nogo-A protein in several neuronal pathologies has grown considerably. Here, we employed a neonatal cortex freeze-lesion (NFL) model in neonatal rats and measured the expression of Nogo-A and NgR in the resulting cerebrocortical microdysgenesis 5-75 days after freezing injury. We observed marked upregulation of Nogo-A and NgR in protein levels. Furthermore, the migration of neural precursor cells (NPCs) derived from the subventricular zone (SVZ) toward the sits of injury was perturbed by treatment of NgR antagonist peptide NEP1-40. In vitro analysis showed that the knockdown of NgR by lentivirus-delivered siRNA promoted in axonal regeneration and SVZ-derived neural stem cell/progenitor cell (SVZ-NPCs) adhesion and migration, findings which were similar to the effects of NEP1-40. Taken together, our results indicate an important role for NgR in regulating the physiological processes of SVZ-NPCs. The observation of upregulated Nogo-A/NgR in lesion sites in the NFL model suggest that the effects of the perturbed Nogo-A are a key feature during the development and/or the progression of cortical malformation. PMID:26987715

  19. Fezf2 promotes neuronal differentiation through localised activation of Wnt/β-catenin signalling during forebrain development

    PubMed Central

    Zhang, Siwei; Li, Jingjing; Lea, Robert; Vleminckx, Kris; Amaya, Enrique

    2014-01-01

    Brain regionalisation, neuronal subtype diversification and circuit connectivity are crucial events in the establishment of higher cognitive functions. Here we report the requirement for the transcriptional repressor Fezf2 for proper differentiation of neural progenitor cells during the development of the Xenopus forebrain. Depletion of Fezf2 induces apoptosis in postmitotic neural progenitors, with concomitant reduction in forebrain size and neuronal differentiation. Mechanistically, we found that Fezf2 stimulates neuronal differentiation by promoting Wnt/β-catenin signalling in the developing forebrain. In addition, we show that Fezf2 promotes activation of Wnt/β-catenin signalling by repressing the expression of two negative regulators of Wnt signalling, namely lhx2 and lhx9. Our findings suggest that Fezf2 plays an essential role in controlling when and where neuronal differentiation occurs within the developing forebrain and that it does so by promoting local Wnt/β-catenin signalling via a double-repressor model. PMID:25468942

  20. ADAR1 and ADAR2 Expression and Editing Activity during Forebrain Development

    PubMed Central

    Jacobs, Michelle M.; Fogg, Rachel L.; Emeson, Ronald B.; Stanwood, Gregg D.

    2009-01-01

    The conversion of adenosine-to-inosine within RNA transcripts is regulated by the ADAR family of enzymes. Little is known regarding the developmental expression of ADAR family members or the mechanisms responsible for the specific patterns of editing observed for ADAR substrates. We have examined the spatiotemporal expression patterns for ADAR1 and ADAR2 in mouse forebrain. ADAR1 and ADAR2 are broadly distributed in most regions of the mouse forebrain by P0, including the cerebral cortex, hippocampus, and diencephalon. High expression levels were maintained into adulthood. Co-localization studies demonstrated ADAR1 and ADAR2 expression in neurons but not astrocytes. Editing for specific ADAR mRNA targets precedes high expression of ADAR proteins, suggesting that region-specific differences in editing patterns may not be mediated solely by ADAR expression levels. PMID:19325227

  1. The ancestral role of nodal signalling in breaking L/R symmetry in the vertebrate forebrain.

    PubMed

    Lagadec, Ronan; Laguerre, Laurent; Menuet, Arnaud; Amara, Anis; Rocancourt, Claire; Péricard, Pierre; Godard, Benoît G; Rodicio, Maria Celina; Rodriguez-Moldes, Isabel; Mayeur, Hélène; Rougemont, Quentin; Mazan, Sylvie; Boutet, Agnès

    2015-01-01

    Left-right asymmetries in the epithalamic region of the brain are widespread across vertebrates, but their magnitude and laterality varies among species. Whether these differences reflect independent origins of forebrain asymmetries or taxa-specific diversifications of an ancient vertebrate feature remains unknown. Here we show that the catshark Scyliorhinus canicula and the lampreys Petromyzon marinus and Lampetra planeri exhibit conserved molecular asymmetries between the left and right developing habenulae. Long-term pharmacological treatments in these species show that nodal signalling is essential to their generation, rather than their directionality as in teleosts. Moreover, in contrast to zebrafish, habenular left-right differences are observed in the absence of overt asymmetry of the adjacent pineal field. These data support an ancient origin of epithalamic asymmetry, and suggest that a nodal-dependent asymmetry programme operated in the forebrain of ancestral vertebrates before evolving into a variable trait in bony fish. PMID:25819227

  2. Forebrain-Specific Loss of BMPRII in Mice Reduces Anxiety and Increases Object Exploration

    PubMed Central

    McBrayer, Zofeyah L.; Dimova, Jiva; Pisansky, Marc T.; Sun, Mu; Beppu, Hideyuki; Gewirtz, Jonathan C.; O’Connor, Michael B.

    2015-01-01

    To investigate the role of Bone Morphogenic Protein Receptor Type II (BMPRII) in learning, memory, and exploratory behavior in mice, a tissue-specific knockout of BMPRII in the post-natal hippocampus and forebrain was generated. We found that BMPRII mutant mice had normal spatial learning and memory in the Morris water maze, but showed significantly reduced swimming speeds with increased floating behavior. Further analysis using the Porsolt Swim Test to investigate behavioral despair did not reveal any differences in immobility between mutants and controls. In the Elevated Plus Maze, BMPRII mutants and Smad4 mutants showed reduced anxiety, while in exploratory tests, BMPRII mutants showed more interest in object exploration. These results suggest that loss of BMPRII in the mouse hippocampus and forebrain does not disrupt spatial learning and memory encoding, but instead impacts exploratory and anxiety-related behaviors. PMID:26444546

  3. Overexpression of the Type 1 Adenylyl Cyclase in the Forebrain Leads to Deficits of Behavioral Inhibition

    PubMed Central

    Cao, Hong; Saraf, Amit; Zweifel, Larry S.

    2015-01-01

    The type 1 adenylyl cyclase (AC1) is an activity-dependent, calcium-stimulated adenylyl cyclase expressed in the nervous system that is implicated in memory formation. We examined the locomotor activity, and impulsive and social behaviors of AC1+ mice, a transgenic mouse strain overexpressing AC1 in the forebrain. Here we report that AC1+ mice exhibit hyperactive behaviors and demonstrate increased impulsivity and reduced sociability. In contrast, AC1 and AC8 double knock-out mice are hypoactive, and exhibit increased sociability and reduced impulsivity. Interestingly, the hyperactivity of AC1+ mice can be corrected by valproate, a mood-stabilizing drug. These data indicate that increased expression of AC1 in the forebrain leads to deficits in behavioral inhibition. PMID:25568126

  4. Stereotaxic probabilistic maps of the magnocellular cell groups in human basal forebrain

    PubMed Central

    Zaborszky, L.; Hoemke, L.; Mohlberg, H.; Schleicher, A.; Amunts, K.; Zilles, K.

    2008-01-01

    The basal forebrain contains several interdigitating anatomical structures, including the diagonal band of Broca, the basal nucleus of Meynert, the ventral striatum, and also cell groups underneath the globus pallidus that bridge the centromedial amygdala to the bed nucleus of the stria terminalis. Among the cell populations, the magnocellular, cholinergic corticopetal projection neurons have received particular attention due to their loss in Alzheimer’s disease. In MRI images, the precise delineation of these structures is difficult due to limited spatial resolution and contrast. Here, using microscopic delineations in ten human postmortem brains, we present stereotaxic probabilistic maps of the basal forebrain areas containing the magnocellular cell groups. Cytoarchitectonic mapping was performed in silver stained histological serial sections. The positions and the extent of the magnocellular cell groups within the septum (Ch1-2), the horizontal limb of the diagonal band (Ch3), and in the sublenticular part of the basal forebrain (Ch4) were traced in high-resolution digitized histological sections, 3D reconstructed, and warped to the reference space of the MNI single subject brain. The superposition of the cytoarchitectonic maps in the MNI brain shows the intersubject variability of the various Ch compartments and their stereotaxic position relative to other brain structures. Both the right and left Ch4 regions showed significantly smaller volumes when age was considered as a covariate. Probabilistic maps of compartments of the basal forebrain magnocellular system are now available as an open source reference for correlation with fMRI, PET, and structural MRI data of the living human brain. PMID:18585468

  5. Brain-derived neurotrophic factor signaling is altered in the forebrain of Engrailed-2 knockout mice.

    PubMed

    Zunino, G; Messina, A; Sgadò, P; Baj, G; Casarosa, S; Bozzi, Y

    2016-06-01

    Engrailed-2 (En2), a homeodomain transcription factor involved in regionalization and patterning of the midbrain and hindbrain regions has been associated to autism spectrum disorders (ASDs). En2 knockout (En2(-/-)) mice show ASD-like features accompanied by a significant loss of GABAergic subpopulations in the hippocampus and neocortex. Brain-derived neurotrophic factor (BDNF) is a crucial factor for the postnatal development of forebrain GABAergic neurons, and altered GABA signaling has been hypothesized to underlie the symptoms of ASD. Here we sought to determine whether interneuron loss in the En2(-/-) forebrain might be related to altered expression of BDNF and its signaling receptors. We first evaluated the expression of different BDNF mRNA isoforms in the neocortex and hippocampus of wild-type (WT) and En2(-/-) mice. Quantitative RT-PCR showed a marked down-regulation of several splicing variants of BDNF mRNA in the neocortex but not hippocampus of adult En2(-/-) mice, as compared to WT controls. Accordingly, levels of mature BDNF protein were lower in the neocortex but not hippocampus of En2(-/-) mice, as compared to WT. Increased levels of phosphorylated TrkB and decreased levels of p75 receptor were also detected in the neocortex of mutant mice. Accordingly, the expression of low density lipoprotein receptor (LDLR) and RhoA, two genes regulated via p75 was significantly altered in forebrain areas of mutant mice. These data indicate that BDNF signaling alterations might be involved in the anatomical changes observed in the En2(-/-) forebrain and suggest a pathogenic role of altered BDNF signaling in this mouse model of ASD. PMID:26987954

  6. GPR30 is Positioned to Mediate Estrogen Effects on Basal Forebrain Cholinergic Neurons and Cognitive Performance

    PubMed Central

    Hammond, R.; Gibbs, R.B.

    2011-01-01

    Beneficial effects of estrogen therapy on cognitive performance diminish with age and time following the loss of ovarian function. This has led to the ‘Window of Opportunity’ hypothesis, which states that estrogen therapy must be administered within a limited period of time following menopause in order to be effective. Effects of estrogen therapy on cognitive performance are due, at least in part, to effects on cholinergic afferents innervating the hippocampus and cortex, and it has been suggested that the loss of estrogen effect with age and time following menopause is due to a substantial reduction in the function of these projections. The mechanisms that underlie the effects are not clear. GPR30 is a novel G-protein coupled estrogen receptor that is expressed in brain and other tissues. Our recent studies show that GPR30 is expressed in areas of the brain important for spatial learning, memory, and attention. In addition, GPR30 in expressed by the vast majority of cholinergic neurons in the basal forebrain, and appears to be an important regulator of basal forebrain cholinergic function. We hypothesize that GPR30 plays an important role in mediating direct effects of estradiol on basal forebrain cholinergic neurons, with corresponding effects on cognitive performance. Hence, GPR30 may be an important target for developing new therapies that can enhance or restore estrogen effects on cognitive performance in older women. Here we briefly review the cholinergic hypothesis and summarize our findings to date showing effects of a GPR30 agonist and antagonist on basal forebrain cholinergic function and cognitive performance. PMID:21138734

  7. Understanding the cognitive impact of the contraceptive estrogen Ethinyl Estradiol: tonic and cyclic administration impairs memory, and performance correlates with basal forebrain cholinergic system integrity

    PubMed Central

    Mennenga, Sarah E.; Gerson, Julia E.; Koebele, Stephanie V.; Kingston, Melissa L.; Tsang, Candy W.S.; Engler-Chiurazzi, Elizabeth B.; Baxter, Leslie C.; Bimonte-Nelson, Heather A.

    2015-01-01

    Ethinyl estradiol (EE), a synthetic, orally bio-available estrogen, is the most commonly prescribed form of estrogen in oral contraceptives, and is found in at least 30 different contraceptive formulations currently prescribed to women as well as hormone therapies prescribed to menopausal women. Thus, EE is prescribed clinically to women at ages ranging from puberty to reproductive senescence. Here, in two separate studies, the cognitive effects of cyclic or tonic EE administration following ovariectomy (Ovx) were evaluated in young female rats. Study I assessed the cognitive effects of low and high doses of EE, delivered tonically via a subcutaneous osmotic pump. Study II evaluated the cognitive effects of low, medium, and high doses of EE administered via a daily subcutaneous injection, modeling the daily rise and fall of serum EE levels with oral regimens. Study II also investigated the impact of low, medium and high doses of EE on the basal forebrain cholinergic system. The low and medium doses utilized here correspond to the range of doses currently used in clinical formulations, and the high dose corresponds to doses prescribed to a generation of women between 1960 and 1970, when oral contraceptives first became available. Here, we evaluate cognition using a battery of maze tasks tapping several domains of spatial learning and memory and basal forebrain cholinergic integrity by using immunohistochemistry and unbiased stereology to estimate the number of choline acetyltransferase (ChAT)-producing cells in the medial septum and vertical/diagonal bands. At the highest dose, EE treatment impaired multiple domains of spatial memory relative to vehicle treatment, regardless of administration method. When given cyclically at the low and medium doses, EE did not impact working memory, but transiently impaired reference memory during the learning phase of testing. Of the doses and regimens tested here, only EE at the highest dose impaired several domains of memory

  8. Understanding the cognitive impact of the contraceptive estrogen Ethinyl Estradiol: tonic and cyclic administration impairs memory, and performance correlates with basal forebrain cholinergic system integrity.

    PubMed

    Mennenga, Sarah E; Gerson, Julia E; Koebele, Stephanie V; Kingston, Melissa L; Tsang, Candy W S; Engler-Chiurazzi, Elizabeth B; Baxter, Leslie C; Bimonte-Nelson, Heather A

    2015-04-01

    Ethinyl Estradiol (EE), a synthetic, orally bio-available estrogen, is the most commonly prescribed form of estrogen in oral contraceptives, and is found in at least 30 different contraceptive formulations currently prescribed to women as well as hormone therapies prescribed to menopausal women. Thus, EE is prescribed clinically to women at ages ranging from puberty to reproductive senescence. Here, in two separate studies, the cognitive effects of cyclic or tonic EE administration following ovariectomy (Ovx) were evaluated in young female rats. Study I assessed the cognitive effects of low and high doses of EE, delivered tonically via a subcutaneous osmotic pump. Study II evaluated the cognitive effects of low, medium, and high doses of EE administered via a daily subcutaneous injection, modeling the daily rise and fall of serum EE levels with oral regimens. Study II also investigated the impact of low, medium and high doses of EE on the basal forebrain cholinergic system. The low and medium doses utilized here correspond to the range of doses currently used in clinical formulations, and the high dose corresponds to doses prescribed to a generation of women between 1960 and 1970, when oral contraceptives first became available. We evaluate cognition using a battery of maze tasks tapping several domains of spatial learning and memory as well as basal forebrain cholinergic integrity using immunohistochemistry and unbiased stereology to estimate the number of choline acetyltransferase (ChAT)-producing cells in the medial septum and vertical/diagonal bands. At the highest dose, EE treatment impaired multiple domains of spatial memory relative to vehicle treatment, regardless of administration method. When given cyclically at the low and medium doses, EE did not impact working memory, but transiently impaired reference memory during the learning phase of testing. Of the doses and regimens tested here, only EE at the highest dose impaired several domains of memory

  9. Heterogeneous patterns of oligodendroglial differentiation in the forebrain of the opossum Didelphis marsupialis.

    PubMed

    Barradas, P C; Gomes, S S; Cavalcante, L A

    1998-01-01

    The differentiation of oligodendrocytes in the forebrain of the opossum (Didelphis marsupialis) has been studied by the immunohistochemical identification of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) and by the autoradiographic detection of the uptake of 3H-thymidine. CNPase is expressed early in oligodendroglia somata and fibre sheaths (myelin) in the forebrain and its persistence in the cell bodies is regionally heterogeneous, being ephemeral in cells within the optic pathway, supraoptic decussation, and posterior commissure, of intermediate duration in the mamillo-thalamic fascicle, and stria medullaris, and long-lasting in other diencephalic and in telencephalic tracts. In the cerebral cortex, most CNPase+ cells have small somata and multiple processes (types I and II). CNPase-expressing oligodendrocytes are also regionally heterogeneous in terms of proliferative capability, which could not be detected in forebrain tracts or diencephalon, but has appeared in a small proportion of cells in the neocortical white matter and in the fimbria. Our findings provide additional evidence in favour of the heterogeneity of oligodendrocytes. PMID:9530996

  10. Altered cholesterol biosynthesis causes precocious neurogenesis in the developing mouse forebrain.

    PubMed

    Driver, Ashley M; Kratz, Lisa E; Kelley, Richard I; Stottmann, Rolf W

    2016-07-01

    We previously reported a mutation in the cholesterol biosynthesis gene, hydroxysteroid (17-beta) dehydrogenase 7 (Hsd17b7(rudolph)), that results in striking embryonic forebrain dysgenesis. Here we describe abnormal patterns of neuroprogenitor proliferation in the mutant forebrain, namely, a decrease in mitotic cells within the ventricular zone (VZ) and an increase through the remainder of the cortex by E11.5. Further evidence suggests mutant cells undergo abnormal interkinetic nuclear migration (IKNM). Furthermore, intermediate progenitors are increased at the expense of apical progenitors by E12.5, and post-mitotic neurons are expanded by E14.5. In vitro primary neuron culture further supports our model of accelerated cortical differentiation in the mutant. Combined administration of a statin and dietary cholesterol in utero achieved partial reversal of multiple developmental abnormalities in the Hsd17b7(rudolph) embryo, including the forebrain. These results suggest that abnormally increased levels of specific cholesterol precursors in the Hsd17b7(rudolph) embryo cause cortical dysgenesis by altering patterns of neurogenesis. PMID:26921468

  11. The neuroprotective mechanism of ampicillin in a mouse model of transient forebrain ischemia

    PubMed Central

    Lee, Kyung-Eon; Cho, Kyung-Ok; Choi, Yun-Sik

    2016-01-01

    Ampicillin, a β-lactam antibiotic, dose-dependently protects neurons against ischemic brain injury. The present study was performed to investigate the neuroprotective mechanism of ampicillin in a mouse model of transient global forebrain ischemia. Male C57BL/6 mice were anesthetized with halothane and subjected to bilateral common carotid artery occlusion for 40 min. Before transient forebrain ischemia, ampicillin (200 mg/kg, intraperitoneally [i.p.]) or penicillin G (6,000 U/kg or 20,000 U/kg, i.p.) was administered daily for 5 days. The pretreatment with ampicillin but not with penicillin G signifi cantly attenuated neuronal damage in the hippocampal CA1 subfield. Mechanistically, the increased activity of matrix metalloproteinases (MMPs) following forebrain ischemia was also attenuated by ampicillin treatment. In addition, the ampicillin treatment reversed increased immunoreactivities to glial fibrillary acidic protein and isolectin B4, markers of astrocytes and microglia, respectively. Furthermore, the ampicillin treatment significantly increased the level of glutamate transporter-1, and dihydrokainic acid (DHK, 10 mg/kg, i.p.), an inhibitor of glutamate transporter-1 (GLT-1), reversed the neuroprotective effect of ampicillin. Taken together, these data indicate that ampicillin provides neuroprotection against ischemia-reperfusion brain injury, possibly through inducing the GLT-1 protein and inhibiting the activity of MMP in the mouse hippocampus. PMID:26937215

  12. Cell Death Atlas of the Postnatal Mouse Ventral Forebrain and Hypothalamus: Effects of Age and Sex

    PubMed Central

    Ahern, Todd H.; Krug, Stefanie; Carr, Audrey V.; Murray, Elaine K.; Fitzpatrick, Emmett; Bengston, Lynn; McCutcheon, Jill; De Vries, Geert J.; Forger, Nancy G.

    2016-01-01

    Naturally occurring cell death is essential to the development of the mammalian nervous system. Although the importance of developmental cell death has been appreciated for decades, there is no comprehensive account of cell death across brain areas in the mouse. Moreover, several regional sex differences in cell death have been described for the ventral forebrain and hypothalamus, but it is not known how widespread the phenomenon is. We used immunohistochemical detection of activated caspase-3 to identify dying cells in the brains of male and female mice from postnatal day (P) 1 to P11. Cell death density, total number of dying cells, and regional volume were determined in 16 regions of the hypothalamus and ventral forebrain (the anterior hypothalamus, arcuate nucleus, anteroventral periventricular nucleus, medial preoptic nucleus, paraventricular nucleus, suprachiasmatic nucleus, and ventromedial nucleus of the hypothalamus; the basolateral, central, and medial amygdala; the lateral and principal nuclei of the bed nuclei of the stria terminalis; the caudate-putamen; the globus pallidus; the lateral septum; and the islands of Calleja). All regions showed a significant effect of age on cell death. The timing of peak cell death varied between P1 to P7, and the average rate of cell death varied tenfold among regions. Several significant sex differences in cell death and/or regional volume were detected. These data address large gaps in the developmental literature and suggest interesting region-specific differences in the prevalence and timing of cell death in the hypothalamus and ventral forebrain. PMID:23296992

  13. Forebrain neuroanatomy of the neonatal and juvenile dolphin (T. truncatus and S. coeruloalba).

    PubMed

    Parolisi, Roberta; Peruffo, Antonella; Messina, Silvia; Panin, Mattia; Montelli, Stefano; Giurisato, Maristella; Cozzi, Bruno; Bonfanti, Luca

    2015-01-01

    Knowledge of dolphin functional neuroanatomy mostly derives from post-mortem studies and non-invasive approaches (i.e., magnetic resonance imaging), due to limitations in experimentation on cetaceans. As a consequence the availability of well-preserved tissues for histology is scarce, and detailed histological analyses are referred mainly to adults. Here we studied the neonatal/juvenile brain in two species of dolphins, the bottlenose dolphin (Tursiops truncatus) and the striped dolphin (Stenella coeruleoalba), with special reference to forebrain regions. We analyzed cell density in subcortical nuclei, white/gray matter ratio, and myelination in selected regions at different anterior-posterior levels of the whole dolphin brain at different ages, to better define forebrain neuroanatomy and the developmental stage of the dolphin brain around birth. The analyses were extended to the periventricular germinal layer and the cerebellum, whose delayed genesis of the granule cell layer is a hallmark of postnatal development in the mammalian nervous system. Our results establish an atlas of the young dolphin forebrain and, on the basis of occurrence/absence of delayed neurogenic layers, confirm the stage of advanced brain maturation in these animals with respect to most terrestrial mammals. PMID:26594155

  14. Forebrain neuroanatomy of the neonatal and juvenile dolphin (T. truncatus and S. coeruloalba)

    PubMed Central

    Parolisi, Roberta; Peruffo, Antonella; Messina, Silvia; Panin, Mattia; Montelli, Stefano; Giurisato, Maristella; Cozzi, Bruno; Bonfanti, Luca

    2015-01-01

    Knowledge of dolphin functional neuroanatomy mostly derives from post-mortem studies and non-invasive approaches (i.e., magnetic resonance imaging), due to limitations in experimentation on cetaceans. As a consequence the availability of well-preserved tissues for histology is scarce, and detailed histological analyses are referred mainly to adults. Here we studied the neonatal/juvenile brain in two species of dolphins, the bottlenose dolphin (Tursiops truncatus) and the striped dolphin (Stenella coeruleoalba), with special reference to forebrain regions. We analyzed cell density in subcortical nuclei, white/gray matter ratio, and myelination in selected regions at different anterior–posterior levels of the whole dolphin brain at different ages, to better define forebrain neuroanatomy and the developmental stage of the dolphin brain around birth. The analyses were extended to the periventricular germinal layer and the cerebellum, whose delayed genesis of the granule cell layer is a hallmark of postnatal development in the mammalian nervous system. Our results establish an atlas of the young dolphin forebrain and, on the basis of occurrence/absence of delayed neurogenic layers, confirm the stage of advanced brain maturation in these animals with respect to most terrestrial mammals. PMID:26594155

  15. Salt Appetite: Interaction of Forebrain Angiotensinergic and Hindbrain Serotonergic Mechanisms

    NASA Technical Reports Server (NTRS)

    Menani, Jose Vanderlei; Colombari, Debora S. A.; Beltz, Terry G.; Thunhorst, Robert L.; Johnson, Alan Kim

    1998-01-01

    Methysergide injected into the lateral parabrachial nucleus (LPBN) increases the salt appetite of rats depleted of sodium by furosemide (FURO). The present study investigated the effects of angiotensin 2 (ANG 2) receptor blockade in the subfornical organ (SFO) on this increased salt appetite. The intake of 0.3 M NaCl and water was induced by combined administration of the diuretic, FURO, and the angiotensin-convertina, enzyme inhibitor, captopril (CAP). Pretreatment of the SFO with the anciotensin Type 1 (AT,) receptor antagonist, losartan (1 microgram/200 nl), reduced water intake but not 0.3 M NaCl intake induced by subcutaneous FURO+ CAP. Methysergide (4 microgram/200 nl) injected bilaterally into the LPBN increased 0.3 M NaCl intake after FURO + CAP. Losartan injected into the SFO prevented additional 0.3 M NaCl intake caused by methysergide injections into the LPBN. These results indicate that AT, receptors located in the SFO may have a role in mediatina the intake of sodium and water induced by sodium depletion. They also suggest that after treatment with FURO + CAP an LPBN-associated scrotonergic mechanism inhibits increased sodium intake.

  16. Glycoprotein M6a is present in glutamatergic axons in adult rat forebrain and cerebellum.

    PubMed

    Cooper, Ben; Werner, Hauke B; Flügge, Gabriele

    2008-03-01

    Glycoprotein M6a is a neuronally expressed member of the proteolipid protein (PLP) family of tetraspans. In vitro studies suggested a potential role in neurite outgrowth and spine formation and previous investigations have identified M6a as a stress-regulated gene. To investigate whether the distribution of M6a correlates with neuronal structures susceptible to alterations in response to stress, we localized M6a expression in neurons of hippocampal formation, prefrontal cortex and cerebellum using in situ hybridization and confocal immunofluorescence microscopy. In situ hybridization confirmed that M6a is expressed in dentate gyrus and cerebellar granule neurons and in hippocampal and cortical pyramidal neurons. Confocal microscopy localized M6a immunoreactivity to distinct sites within axonal membranes, but not in dendrites or neuronal somata. Moreover, M6a colocalized with synaptic markers of glutamatergic, but not GABAergic nerve terminals. M6a expression in the adult brain is particularly strong in unmyelinated axonal fibers, i.e. cerebellar parallel and hippocampal mossy fibers. In contrast, myelinated axons exhibit only minimal M6a immunoreactivity localized exclusively to terminal regions. The present neuroanatomical data demonstrate that M6a is an axonal component of glutamatergic neurons and that it is localized to distinct sites of the axonal plasma membrane of pyramidal and granule cells. PMID:18241840

  17. Functional Connectome Analysis of Dopamine Neuron Glutamatergic Connections in Forebrain Regions

    PubMed Central

    Mingote, Susana; Chuhma, Nao; Kusnoor, Sheila V.; Field, Bianca; Deutch, Ariel Y.

    2015-01-01

    In the ventral tegmental area (VTA), a subpopulation of dopamine neurons express vesicular glutamate transporter 2 and make glutamatergic connections to nucleus accumbens (NAc) and olfactory tubercle (OT) neurons. However, their glutamatergic connections across the forebrain have not been explored systematically. To visualize dopamine neuron forebrain projections and to enable photostimulation of their axons independent of transmitter status, we virally transfected VTA neurons with channelrhodopsin-2 fused to enhanced yellow fluorescent protein (ChR2-EYFP) and used DATIREScre mice to restrict expression to dopamine neurons. ChR2-EYFP-expressing neurons almost invariably stained for tyrosine hydroxylase, identifying them as dopaminergic. Dopamine neuron axons visualized by ChR2-EYFP fluorescence projected most densely to the striatum, moderately to the amygdala and entorhinal cortex (ERC), sparsely to prefrontal and cingulate cortices, and rarely to the hippocampus. Guided by ChR2-EYFP fluorescence, we recorded systematically from putative principal neurons in target areas and determined the incidence and strength of glutamatergic connections by activating all dopamine neuron terminals impinging on recorded neurons with wide-field photostimulation. This revealed strong glutamatergic connections in the NAc, OT, and ERC; moderate strength connections in the central amygdala; and weak connections in the cingulate cortex. No glutamatergic connections were found in the dorsal striatum, hippocampus, basolateral amygdala, or prefrontal cortex. These results indicate that VTA dopamine neurons elicit widespread, but regionally distinct, glutamatergic signals in the forebrain and begin to define the dopamine neuron excitatory functional connectome. SIGNIFICANCE STATEMENT Dopamine neurons are important for the control of motivated behavior and are involved in the pathophysiology of several major neuropsychiatric disorders. Recent studies have shown that some ventral midbrain

  18. Modulation of learning and memory by the targeted deletion of the circadian clock gene Bmal1 in forebrain circuits.

    PubMed

    Snider, Kaitlin H; Dziema, Heather; Aten, Sydney; Loeser, Jacob; Norona, Frances E; Hoyt, Kari; Obrietan, Karl

    2016-07-15

    A large body of literature has shown that the disruption of circadian clock timing has profound effects on mood, memory and complex thinking. Central to this time keeping process is the master circadian pacemaker located within the suprachiasmatic nucleus (SCN). Of note, within the central nervous system, clock timing is not exclusive to the SCN, but rather, ancillary oscillatory capacity has been detected in a wide range of cell types and brain regions, including forebrain circuits that underlie complex cognitive processes. These observations raise questions about the hierarchical and functional relationship between the SCN and forebrain oscillators, and, relatedly, about the underlying clock-gated synaptic circuitry that modulates cognition. Here, we utilized a clock knockout strategy in which the essential circadian timing gene Bmal1 was selectively deleted from excitatory forebrain neurons, whilst the SCN clock remained intact, to test the role of forebrain clock timing in learning, memory, anxiety, and behavioral despair. With this model system, we observed numerous effects on hippocampus-dependent measures of cognition. Mice lacking forebrain Bmal1 exhibited deficits in both acquisition and recall on the Barnes maze. Notably, loss of forebrain Bmal1 abrogated time-of-day dependent novel object location memory. However, the loss of Bmal1 did not alter performance on the elevated plus maze, open field assay, and tail suspension test, indicating that this phenotype specifically impairs cognition but not affect. Together, these data suggest that forebrain clock timing plays a critical role in shaping the efficiency of learning and memory retrieval over the circadian day. PMID:27091299

  19. Transposon Mediated Integration of Plasmid DNA into the Subventricular Zone of Neonatal Mice to Generate Novel Models of Glioblastoma

    PubMed Central

    Calinescu, Anda-Alexandra; Núñez, Felipe Javier; Koschmann, Carl; Kolb, Bradley L.; Lowenstein, Pedro R.; Castro, Maria G.

    2015-01-01

    An urgent need exists to test the contribution of new genes to the pathogenesis and progression of human glioblastomas (GBM), the most common primary brain tumor in adults with dismal prognosis. New potential therapies are rapidly emerging from the bench and require systematic testing in experimental models which closely reproduce the salient features of the human disease. Herein we describe in detail a method to induce new models of GBM with transposon-mediated integration of plasmid DNA into cells of the subventricular zone of neonatal mice. We present a simple way to clone new transposons amenable for genomic integration using the Sleeping Beauty transposon system and illustrate how to monitor plasmid uptake and disease progression using bioluminescence, histology and immuno-histochemistry. We also describe a method to create new primary GBM cell lines. Ideally, this report will allow further dissemination of the Sleeping Beauty transposon system among brain tumor researchers, leading to an in depth understanding of GBM pathogenesis and progression and to the timely design and testing of effective therapies for patients. PMID:25741859

  20. NMDA receptors activated by subventricular zone astrocytic glutamate are critical for neuroblast survival prior to entering a synaptic network

    PubMed Central

    Platel, Jean-Claude; Dave, Kathleen A.; Gordon, Valerie; Lacar, Benjamin; Rubio, Maria E.; Bordey, Angélique

    2010-01-01

    SUMMARY Even before integrating into existing circuitry, adult-born neurons express receptors for neurotransmitters, but the intercellular mechanisms and their impact on neurogenesis remain largely unexplored. Here, we show that neuroblasts born in the postnatal subventricular zone (SVZ) acquire NMDA receptors (NMDARs) during their migration to the olfactory bulb. Along their route, neuroblasts are ensheathed by astrocyte-like cells expressing vesicular glutamate release machinery. Increasing calcium in these specialized astrocytes induced NMDAR-activity in neuroblasts and blocking astrocytic vesicular release eliminated spontaneous NMDAR-activity. Single-cell knockout of NMDARs using neonatal electroporation resulted in neuroblast apoptosis at the time of NMDAR acquisition. This cumulated in a 40% loss of neuroblasts along their migratory route demonstrating that NMDAR acquisition is critical for neuroblast survival, prior to entering a synaptic network. In addition, our findings suggest an unexpected mechanism where SVZ astrocytes use glutamate signaling through NMDARs to control the number of adult-born neurons reaching their final destination. PMID:20346761

  1. Prox1 Is Required for Oligodendrocyte Cell Identity in Adult Neural Stem Cells of the Subventricular Zone.

    PubMed

    Bunk, Eva C; Ertaylan, Gökhan; Ortega, Felipe; Pavlou, Maria A; Gonzalez Cano, Laura; Stergiopoulos, Athanasios; Safaiyan, Shima; Völs, Sandra; van Cann, Marianne; Politis, Panagiotis K; Simons, Mikael; Berninger, Benedikt; Del Sol, Antonio; Schwamborn, Jens C

    2016-08-01

    Adult neural stem cells with the ability to generate neurons and glia cells are active throughout life in both the dentate gyrus (DG) and the subventricular zone (SVZ). Differentiation of adult neural stem cells is induced by cell fate determinants like the transcription factor Prox1. Evidence has been provided for a function of Prox1 as an inducer of neuronal differentiation within the DG. We now show that within the SVZ Prox1 induces differentiation into oligodendrocytes. Moreover, we find that loss of Prox1 expression in vivo reduces cell migration into the corpus callosum, where the few Prox1 deficient SVZ-derived remaining cells fail to differentiate into oligodendrocytes. Thus, our work uncovers a novel function of Prox1 as a fate determinant for oligodendrocytes in the adult mammalian brain. These data indicate that the neurogenic and oligodendrogliogenic lineages in the two adult neurogenic niches exhibit a distinct requirement for Prox1, being important for neurogenesis in the DG but being indispensable for oligodendrogliogenesis in the SVZ. Stem Cells 2016;34:2115-2129. PMID:27068685

  2. The multifaceted subventricular zone astrocyte: From a metabolic and pro-neurogenic role to acting as a neural stem cell.

    PubMed

    Platel, J C; Bordey, A

    2016-05-26

    A few decades ago it was discovered that two regions of the adult brain retain the ability to generate new neurons. These regions include the subgranular zone of the hippocampal dentate gyrus and the ventricular-subventricular zone (V-SVZ) located at the border of the lateral ventricle. In the V-SVZ, it was discovered that neural progenitor cells (NPCs) share many features of mature astrocytes and are often referred as V-SVZ astrocytes. We will first describe the markers, the morphology, and the neurophysiological characteristics of the mouse V-SVZ astrocytes. We will then discuss the fact that V-SVZ astrocytes constitute a mixed population with respect to their neurogenic properties, e.g., quiescent versus activated state, neurogenic fate, and transcription factors expression. Finally, we will describe two functions of V-SVZ astrocytes, their metabolic coupling to blood vessels and their neurogenic-supportive role consisting of providing guidance and survival cues to migrating newborn neurons. PMID:26546469

  3. Anosmin-1 over-expression increases adult neurogenesis in the subventricular zone and neuroblast migration to the olfactory bulb.

    PubMed

    García-González, Diego; Murcia-Belmonte, Verónica; Esteban, Pedro F; Ortega, Felipe; Díaz, David; Sánchez-Vera, Irene; Lebrón-Galán, Rafael; Escobar-Castañondo, Laura; Martínez-Millán, Luis; Weruaga, Eduardo; García-Verdugo, José Manuel; Berninger, Benedikt; de Castro, Fernando

    2016-01-01

    New subventricular zone (SVZ)-derived neuroblasts that migrate via the rostral migratory stream are continuously added to the olfactory bulb (OB) of the adult rodent brain. Anosmin-1 (A1) is an extracellular matrix protein that binds to FGF receptor 1 (FGFR1) to exert its biological effects. When mutated as in Kallmann syndrome patients, A1 is associated with severe OB morphogenesis defects leading to anosmia and hypogonadotropic hypogonadism. Here, we show that A1 over-expression in adult mice strongly increases proliferation in the SVZ, mainly with symmetrical divisions, and produces substantial morphological changes in the normal SVZ architecture, where we also report the presence of FGFR1 in almost all SVZ cells. Interestingly, for the first time we show FGFR1 expression in the basal body of primary cilia in neural progenitor cells. Additionally, we have found that A1 over-expression also enhances neuroblast motility, mainly through FGFR1 activity. Together, these changes lead to a selective increase in several GABAergic interneuron populations in different OB layers. These specific alterations in the OB would be sufficient to disrupt the normal processing of sensory information and consequently alter olfactory memory. In summary, this work shows that FGFR1-mediated A1 activity plays a crucial role in the continuous remodelling of the adult OB. PMID:25300351

  4. A comparative study of the structural organization of spheres derived from the adult human subventricular zone and glioblastoma biopsies

    SciTech Connect

    Vik-Mo, Einar Osland; Sandberg, Cecilie; Joel, Mrinal; Stangeland, Biljana; Watanabe, Yasuhiro; Mackay-Sim, Alan; Moe, Morten Carstens; Murrell, Wayne; Langmoen, Iver Arne

    2011-04-15

    Sphere forming assays have been useful to enrich for stem like cells in a range of tumors. The robustness of this system contrasts the difficulties in defining a stem cell population based on cell surface markers. We have undertaken a study to describe the cellular and organizational composition of tumorspheres, directly comparing these to neurospheres derived from the adult human subventricular zone (SVZ). Primary cell cultures from brain tumors were found to contain variable fractions of cells positive for tumor stem cell markers (CD133 (2-93%)/SSEA1 (3-15%)/CXCR4 (1-72%)). All cultures produced tumors upon xenografting. Tumorspheres contained a heterogeneous population of cells, but were structurally organized with stem cell markers present at the core of spheres, with markers of more mature glial progenitors and astrocytes at more peripheral location. Ultrastructural studies showed that tumorspheres contained a higher fraction of electron dense cells in the core than the periphery (36% and 19%, respectively). Neurospheres also contained a heterogeneous cell population, but did not have an organization similar to tumorspheres. Although tumorspheres clearly display irregular and neoplastic cells, they establish an organized structure with an outward gradient of differentiation. We suggest that this organization is central in maintaining the tumor stem cell pool.

  5. Altered speeds and trajectories of neurons migrating in the ventricular and subventricular zones of the reeler neocortex.

    PubMed

    Britto, Joanne M; Tait, Karen J; Johnston, Leigh A; Hammond, Vicki E; Kalloniatis, Michael; Tan, Seong-Seng

    2011-05-01

    The Reelin signaling pathway is essential for proper cortical development, but it is unclear to whether Reelin function is primarily important for cortical layering or neuron migration. It has been proposed that Reelin is perhaps required only for somal translocation but not glial-dependent locomotion. This implies that the location of neurons responding to Reelin is restricted to the outer regions of the cortical plate (CP). To determine whether Reelin is required for migration outside of the CP, we used time-lapse imaging to track the behavior of cells undergoing locomotion in the germinal zones. We focused on the migratory activity in the ventricular/subventricular zones where the first transition of bipolar to multipolar migration occurs and where functional Reelin receptors are known to be expressed. Despite Reelin loss, neurons had no difficulty in undergoing radial migration and indeed displayed greater migratory speed. Additionally, compared with the wild-type, reeler neurons displayed altered trajectories with greater deviation from a radial path. These results suggest that Reelin loss has early consequences for migration in the germinal zones that are portrayed as defective radial trajectories and migratory speeds. Together, these abnormalities can give rise to the increased cell dispersion observed in the reeler cortex. PMID:20847150

  6. Dissociation of feeding and hoarding after bilateral destruction of lateral septal nuclei in rats.

    PubMed

    Gogate, M G; Salgar, D C; Brid, S V; Wingkar, K C

    1989-01-01

    The interrelationship between Feeding and Hoarding of food pellets was observed to be disrupted following bilateral destruction of lateral septal nuclei in adult male albino rats. The significance of forebrain areas and neuro-endocrinal connection to hypothalamus is discussed. PMID:2737748

  7. Vocal matching and intensity of begging calls are associated with a forebrain song circuit in a generalist brood parasite.

    PubMed

    Liu, Wan-Chun; Rivers, James W; White, David J

    2016-06-01

    Vocalizations produced by developing young early in life have simple acoustic features and are thought to be innate. Complex forms of early vocal learning are less likely to evolve in young altricial songbirds because the forebrain vocal-learning circuit is underdeveloped during the period when early vocalizations are produced. However, selective pressure experienced in early postnatal life may lead to early vocal learning that is likely controlled by a simpler brain circuit. We found the food begging calls produced by fledglings of the brown-headed cowbird (Molothrus ater), a generalist avian brood parasite, induced the expression of several immediate early genes and early circuit innervation in a forebrain vocal-motor pathway that is later used for vocal imitation. The forebrain neural activity was correlated with vocal intensity and variability of begging calls that appears to allow cowbirds to vocally match host nestmates. The begging-induced forebrain circuits we observed in fledgling cowbirds were not detected in nonparasitic passerines, including species that are close relatives to the cowbird. The involvement of forebrain vocal circuits during fledgling begging and its association with vocal learning plasticity may be an adaptation that provides young generalist brood parasites with a flexible signaling strategy to procure food from a wide range of heterospecific host parents. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 615-625, 2016. PMID:26335154

  8. HESX1- and TCF3-mediated repression of Wnt/β-catenin targets is required for normal development of the anterior forebrain

    PubMed Central

    Andoniadou, Cynthia L.; Signore, Massimo; Young, Rodrigo M.; Gaston-Massuet, Carles; Wilson, Stephen W.; Fuchs, Elaine; Martinez-Barbera, Juan Pedro

    2011-01-01

    The Wnt/β-catenin pathway plays an essential role during regionalisation of the vertebrate neural plate and its inhibition in the most anterior neural ectoderm is required for normal forebrain development. Hesx1 is a conserved vertebrate-specific transcription factor that is required for forebrain development in Xenopus, mice and humans. Mouse embryos deficient for Hesx1 exhibit a variable degree of forebrain defects, but the molecular mechanisms underlying these defects are not fully understood. Here, we show that injection of a hesx1 morpholino into a ‘sensitised’ zygotic headless (tcf3) mutant background leads to severe forebrain and eye defects, suggesting an interaction between Hesx1 and the Wnt pathway during zebrafish forebrain development. Consistent with a requirement for Wnt signalling repression, we highlight a synergistic gene dosage-dependent interaction between Hesx1 and Tcf3, a transcriptional repressor of Wnt target genes, to maintain anterior forebrain identity during mouse embryogenesis. In addition, we reveal that Tcf3 is essential within the neural ectoderm to maintain anterior character and that its interaction with Hesx1 ensures the repression of Wnt targets in the developing forebrain. By employing a conditional loss-of-function approach in mouse, we demonstrate that deletion of β-catenin, and concomitant reduction of Wnt signalling in the developing anterior forebrain of Hesx1-deficient embryos, leads to a significant rescue of the forebrain defects. Finally, transcriptional profiling of anterior forebrain precursors from mouse embryos expressing eGFP from the Hesx1 locus provides molecular evidence supporting a novel function of Hesx1 in mediating repression of Wnt/β-catenin target activation in the developing forebrain. PMID:22007134

  9. Delta opioid receptors expressed in forebrain GABAergic neurons are responsible for SNC80-induced seizures

    PubMed Central

    CHUNG, Paul CHU SIN; BOEHRER, Annie; STEPHAN, Aline; MATIFAS, Audrey; SCHERRER, Gregory; DARCQ, Emmanuel; BEFORT, Katia; KIEFFER, Brigitte L.

    2014-01-01

    The delta opioid receptor (DOR) has raised much interest for the development of new therapeutic drugs, particularly to treat patients suffering from mood disorders and chronic pain. Unfortunately, the prototypal DOR agonist SNC80 induces mild epileptic seizures in rodents. Although recently developed agonists do not seem to show convulsant properties, mechanisms and neuronal circuits that support DOR-mediated epileptic seizures remain to be clarified. DORs are expressed throughout the nervous system. In this study we tested the hypothesis that SNC80-evoked seizures stem from DOR activity at the level of forebrain GABAergic transmission, whose inhibition is known to facilitate the development of epileptic seizures. We generated a conditional DOR knockout mouse line, targeting the receptor gene specifically in GABAergic neurons of the forebrain (Dlx-DOR). We measured effects of SNC80 (4.5, 9, 13.5 and 32 mg/kg), ARM390 (10, 30 and 60 mg/kg) or ADL5859 (30, 100 and 300 mg/kg) administration on electroencephalograms (EEGs) recorded in Dlx-DOR mice and their control littermates (Ctrl mice). SNC80 produced dose-dependent seizure events in Ctrl mice, but these effects were not detected in Dlx-DOR mice. As expected, ARM390 and ADL5859 did not trigger any detectable change in mice from both genotypes. These results demonstrate for the first time that SNC80-induced DOR activation induces epileptic seizures via direct inhibition of GABAergic forebrain neurons, and supports the notion of differential activities between first and second-generation DOR agonists. PMID:25447299

  10. Adjustable frequency selectivity of auditory forebrain neurons recorded in a freely moving songbird via radiotelemetry.

    PubMed

    Nieder, A; Klump, G M

    1999-01-01

    One of the hearing system's basic properties that determines the detection of signals is its frequency selectivity. In the natural environment, a songbird may achieve an improved detection ability if the neuronal filters of its auditory system could be sharpened to adapt to the spectrum of the background noise. To address this issue, we studied 35 multi-unit clusters in the input layer of the primary auditory forebrain of nine European starlings (Sturnus vulgaris). Microelectrodes were chronically implanted in this songbird's cortex analogue and the neuronal activity was transmitted from unrestrained birds via a miniature FM transmitter. Frequency tuning curves (FTCs) and inhibitory sidebands were determined by presenting a matrix of frequency-level combinations of pure tones. From each FTC, the characteristic frequency (CF) and several parameters describing the neurons' filter characteristics were derived and compared to the same recording site's filter function while simultaneously stimulating with a continuous CF tone 20 dB above the response threshold. Our results show a significant improvement of frequency selectivity during two-tone stimulation, indicating that spectral filtering in the starling's auditory forebrain depends on the acoustic background in which a signal is presented. Moreover, frequency selectivity was found to be a function of the time over which the stimulus persisted, since FTCs were much sharper and inhibitory sidebands were largely expanded several milliseconds after response onset. Neuronal filter bandwidths during two-tone stimulation in the auditory forebrain are in good agreement with psychoacoustically measured critical bandwidths in the same species. Radiotelemetry proved to be a powerful tool in studying neuronal activity in freely behaving birds. PMID:9925015

  11. CBP regulates the differentiation of interneurons from ventral forebrain neural precursors during murine development.

    PubMed

    Tsui, David; Voronova, Anastassia; Gallagher, Denis; Kaplan, David R; Miller, Freda D; Wang, Jing

    2014-01-15

    The mechanisms that regulate appropriate genesis and differentiation of interneurons in the developing mammalian brain are of significant interest not only because interneurons play key roles in the establishment of neural circuitry, but also because when they are deficient, this can cause epilepsy. In this regard, one genetic syndrome that is associated with deficits in neural development and epilepsy is Rubinstein-Taybi Syndrome (RTS), where the transcriptional activator and histone acetyltransferase CBP is mutated and haploinsufficient. Here, we have asked whether CBP is necessary for the appropriate genesis and differentiation of interneurons in the murine forebrain, since this could provide an explanation for the epilepsy that is associated with RTS. We show that CBP is expressed in neural precursors within the embryonic medial ganglionic eminence (MGE), an area that generates the vast majority of interneurons for the cortex. Using primary cultures of MGE precursors, we show that knockdown of CBP causes deficits in differentiation of these precursors into interneurons and oligodendrocytes, and that overexpression of CBP is by itself sufficient to enhance interneuron genesis. Moreover, we show that levels of the neurotransmitter synthesis enzyme GAD67, which is expressed in inhibitory interneurons, are decreased in the dorsal and ventral forebrain of neonatal CBP(+/-) mice, indicating that CBP plays a role in regulating interneuron development in vivo. Thus, CBP normally acts to ensure the differentiation of appropriate numbers of forebrain interneurons, and when its levels are decreased, this causes deficits in interneuron development, providing a potential explanation for the epilepsy seen in individuals with RTS. PMID:24247009

  12. Overexpression of Forebrain CRH During Early Life Increases Trauma Susceptibility in Adulthood.

    PubMed

    Toth, Mate; Flandreau, Elizabeth I; Deslauriers, Jessica; Geyer, Mark A; Mansuy, Isabelle M; Merlo Pich, Emilio; Risbrough, Victoria B

    2016-05-01

    Although early-life stress is a significant risk factor for developing anxiety disorders, including posttraumatic stress disorder (PTSD), the underlying mechanisms are unclear. Corticotropin releasing hormone (CRH) is disrupted in individuals with PTSD and early-life stress and hence may mediate the effects of early-life stress on PTSD risk. We hypothesized that CRH hyper-signaling in the forebrain during early development is sufficient to increase response to trauma in adulthood. To test this hypothesis, we induced transient, forebrain-specific, CRH overexpression during early-life (pre-puberty, CRHOEdev) in double-mutant mice (Camk2a-rtta2 × tetO-Crh) and tested their behavioral and gene expression responses to the predator stress model of PTSD in adulthood. In one cohort of CRHOEdev exposed and unexposed mice, avoidance and arousal behaviors were examined 7-15 days after exposure to predator stress. In another cohort, gene expression changes in Crhr1, Crhr2, and Fkbp51 in forebrain of CRHOEdev exposed and unexposed mice were examined 7 days after predator stress. CRHOEdev induced robust increases in startle reactivity and reductions in startle inhibition independently of predator stress in both male and female mice. Avoidance behaviors after predator stress were highly dependent on sex and CRHOEdev exposure. Whereas stressed females exhibited robust avoidance responses that were not altered by CRHOEdev, males developed significant avoidance only when exposed to both CRHOEdev and stress. Quantitative real-time-PCR analysis indicated that CRHOEdev unexposed males exhibit significant changes in Crhr2 expression in the amygdala and bed nucleus stria terminalis in response to stress, whereas males exposed to CRHOEdev did not. Similar to CRHOEdev males, females exhibited no significant Crhr2 gene expression changes in response to stress. Cortical Fkbp51 expression was also significantly reduced by stress and CRHOEdev exposure in males, but not in females. These

  13. The forebrain of the blind cave fish Astyanax hubbsi (Characidae). I. General anatomy of the telencephalon.

    PubMed

    Riedel, G

    1997-01-01

    This paper presents a survey of the cell groups in the telencephalon of the teleost Astyanax hubbsi, based on series of transverse sections stained with the Nissl-Klüver-Barrera and Bodian procedures. The work was conducted for two reasons. Firstly, it was intended to determine the contribution of the forebrain of blind cave fish to certain forms of behavior. An understanding of the anatomy of the telencephalic organization is essential for such a neuroethological approach. The second purpose was to provide the cytoarchitectural basis for the experimental analysis of the fiber connectivity of the telencephalon of A. hubbsi. Furthermore, information about the forebrain of characids is widely lacking, and this study may thus provide important knowledge about the cellular organization of characid forebrains for comparative anatomists. The brain of A. hubbsi is slender and elongated. Both optic nerves and optic tectum are reduced. Three longitudinal sulci-s. ypsiliformis, s. externus and s. limitans telencephali-can be distinguished in the telencephalon. A fiber lamina reaching from the s. externus to the s. limitans telencephali separates the area dorsalis (D) from the area ventralis telencephali (V). The two hemispheres are connected by fibers decussating in the anterior commissure. Although cross sections revealed no distinct fiber laminae between cytoarchitectonic components, 17 cell masses could be delineated: ten of these belong to D, seven to V. The topological analysis yielded the following results. The dorsal telencephalon D consists of three longitudinal columns, termed pars medialis (Dm), pars dorsalis and centralis (Dd and Dc) considered together, and par lateralis (Dl), which converge into a uniform posterior part (Dp). The columns can be divided into several subregions: Dm1 and Dm2, as well as Dlv and Dld, precommissurally, Dm3 and Dm4 postcommisurally. At polus posterior levels nucleus tenia can be identified. The ventral telencephalon (V) is arranged

  14. Homologs of genes expressed in Caenorhabditis elegans GABAergic neurons are also found in the developing mouse forebrain

    PubMed Central

    2010-01-01

    Background In an effort to identify genes that specify the mammalian forebrain, we used a comparative approach to identify mouse homologs of transcription factors expressed in developing Caenorhabditis elegans GABAergic neurons. A cell-specific microarray profiling study revealed a set of transcription factors that are highly expressed in embryonic C. elegans GABAergic neurons. Results Bioinformatic analyses identified mouse protein homologs of these selected transcripts and their expression pattern was mapped in the mouse embryonic forebrain by in situ hybridization. A review of human homologs indicates several of these genes are potential candidates in neurodevelopmental disorders. Conclusions Our comparative approach has revealed several novel candidates that may serve as future targets for studies of mammalian forebrain development. PMID:21122108

  15. Choline Acetyltransferase Activity in Striatum of Neonatal Rats Increased by Nerve Growth Factor

    NASA Astrophysics Data System (ADS)

    Mobley, William C.; Rutkowski, J. Lynn; Tennekoon, Gihan I.; Buchanan, Karen; Johnston, Michael V.

    1985-07-01

    Some neurodegenerative disorders may be caused by abnormal synthesis or utilization of trophic molecules required to support neuronal survival. A test of this hypothesis requires that trophic agents specific for the affected neurons be identified. Cholinergic neurons in the corpus striatum of neonatal rats were found to respond to intracerebroventricular administration of nerve growth factor with prominent, dose-dependent, selective increases in choline acetyltransferase activity. Cholinergic neurons in the basal forebrain also respond to nerve growth factor in this way. These actions of nerve growth factor may indicate its involvement in the normal function of forebrain cholinergic neurons as well as in neurodegenerative disorders involving such cells.

  16. Sleep-waking states develop independently in the isolated forebrain and brain stem following early postnatal midbrain transection in cats.

    PubMed

    Villablanca, J R; de Andrés, I; Olmstead, C E

    2001-01-01

    We report the effects of permanently separating the immature forebrain from the brain stem upon sleeping and waking development. Kittens ranging from postnatal 9 to 27 days of age sustained a mesencephalic transection and were maintained for up to 135 days. Prior to postnatal day 40, the electroencephalogram of the isolated forebrain and behavioral sleep-wakefulness of the decerebrate animal showed the immature patterns of normal young kittens. Thereafter, the isolated forebrain showed alternating sleep-wakefulness electrocortical rhythms similar to the corresponding normal patterns of intact, mature cats. Olfactory stimuli generally changed forebrain sleeping into waking activity, and in cats with the section behind the third nerve nuclei, normal correlates of eye movements-pupillary activity with electrocortical rhythms were present. Behind the transection, decerebrate animals showed wakefulness, and after 20 days of age displayed typical behavioral episodes of rapid eye movements sleep and, during these periods, the pontine recordings showed ponto-geniculo-occipital waves, which are markers for this sleep stage, together with muscle atonia and rapid lateral eye movements. Typically, but with remarkable exceptions suggesting humoral interactions, the sleep-waking patterns of the isolated forebrain were dissociated from those of the decerebrate animal. These results were very similar to our previous findings in midbrain-transected adult cats. However, subtle differences suggested greater functional plasticity in the developing versus the adult isolated forebrain. We conclude that behavioral and electroencephalographic patterns of non-rapid eye movement sleep and of rapid eye movement sleep states mature independently in the forebrain and the brain stem, respectively, after these structures are separated early postnatally. In terms of waking, the findings strengthen our concept that in higher mammals the rostral brain can independently support wakefulness

  17. The cholinergic basal forebrain in the ferret and its inputs to the auditory cortex

    PubMed Central

    Bajo, Victoria M; Leach, Nicholas D; Cordery, Patricia M; Nodal, Fernando R; King, Andrew J

    2014-01-01

    Cholinergic inputs to the auditory cortex can modulate sensory processing and regulate stimulus-specific plasticity according to the behavioural state of the subject. In order to understand how acetylcholine achieves this, it is essential to elucidate the circuitry by which cholinergic inputs influence the cortex. In this study, we described the distribution of cholinergic neurons in the basal forebrain and their inputs to the auditory cortex of the ferret, a species used increasingly in studies of auditory learning and plasticity. Cholinergic neurons in the basal forebrain, visualized by choline acetyltransferase and p75 neurotrophin receptor immunocytochemistry, were distributed through the medial septum, diagonal band of Broca, and nucleus basalis magnocellularis. Epipial tracer deposits and injections of the immunotoxin ME20.4-SAP (monoclonal antibody specific for the p75 neurotrophin receptor conjugated to saporin) in the auditory cortex showed that cholinergic inputs originate almost exclusively in the ipsilateral nucleus basalis. Moreover, tracer injections in the nucleus basalis revealed a pattern of labelled fibres and terminal fields that resembled acetylcholinesterase fibre staining in the auditory cortex, with the heaviest labelling in layers II/III and in the infragranular layers. Labelled fibres with small en-passant varicosities and simple terminal swellings were observed throughout all auditory cortical regions. The widespread distribution of cholinergic inputs from the nucleus basalis to both primary and higher level areas of the auditory cortex suggests that acetylcholine is likely to be involved in modulating many aspects of auditory processing. PMID:24945075

  18. [REM sleep modulation by non-GABAergic neurons of the hypothalamus and basal forebrain].

    PubMed

    Reinoso Suárez, Fernando

    2010-01-01

    The ventral part of the oral pontine reticular nucleus (vRPO) is a demonstrated site of brainstem REM-sleep generation and maintenance. The vRPO has reciprocal connections with structures that control other states of the sleep-wakefulness cycle, many situated in the basal forebrain and the diencephalon. The aim of the present revision is to map, using the results described in previous publications of our group, the local origin of the basal forebrain and hypothalamus non-GABAergic projections to the vRPO, and specially the contribution of the hypothalamic neurons positive to hypocretin/orexin (H/O) peptides. I summarize non-GABAergic projections to the vRPO from the: ipsilateral central amygdaline nucleus and the stria terminalis bed nuclei, bilateral projections, but most abundant in the ipsilateral side, from the median preoptic nucleus, medial and lateral preoptic areas, abundant from the zona incerta and dorsal, lateral, posterior and perifornical hypothalamic areas. Very abundant bilateral projections of H/O neurons to the vRPO are described, expressive of the important modulation exerted by these neurons on the vRPO nucleus. I discuss the functional significance of the above results and the corresponding mechanisms, supported by physiological and ultrastructural results of our group. Based on the connections and action mechanisms of H/O neurons on the vRPO, which produce the decreased activity of neurons in this nucleus and, therefore, inhibition of REM sleep, I reflect briefly on narcolepsy pathophysiology. PMID:21877412

  19. GABAA Receptor Expression in the Forebrain of Ataxic Rolling Nagoya Mice.

    PubMed

    Nielsen, Elsebet Østergaard; Kaja, Simon

    2014-01-01

    The human CACNA1A gene encodes the pore-forming α1 subunit of CaV2.1 (P/Q-type) calcium channels and is the locus for several neurological disorders, including episodic ataxia type 2 (EA2), spinocerebellar ataxia type 6 (SCA6) and Familial Hemiplegic Migraine type 1 (FHM1). Several spontaneous mouse Cacna1a mutant strains exist, among them Rolling Nagoya (tg (rol)), carrying the R1262G point mutation in the mouse Cacna1a gene. tg (rol) mice display a phenotype of severe gait ataxia and motor dysfunction of the hind limbs. At the functional level, the R1262G mutation results in a positive shift of the activation voltage of the CaV2.1 channel and reduced current density. γ-Aminobutyric acid type A (GABAA) receptor subunit expression depends critically on neuronal calcium influx, and GABAA receptor dysfunction has previously been described for the cerebellum of tg (rol) and other ataxic Cacna1a mutant mice. Given the expression pattern of CaV2.1, it was hypothesized that calcium dysregulation in tg (rol) might affect GABAA receptor expression in the forebrain. Herein, functional GABAA receptors in the forebrain of tg (rol) mice were quantified and pharmacologically dissociated using [(3)H] radioligand binding. No gross changes to functional GABAA receptors were identified. Future cell type-specific analyses are required to identify possible cortical contributions to the psychomotor phenotype of tg (rol) mice. PMID:25309056

  20. Expression of neuron specific phosphatase, striatal enriched phosphatase (STEP) in reactive astrocytes after transient forebrain ischemia.

    PubMed

    Hasegawa, S; Morioka, M; Goto, S; Korematsu, K; Okamura, A; Yano, S; Kai, Y; Hamada, J I; Ushio, Y

    2000-02-15

    We studied the distribution and change of striatal enriched phosphatase (STEP) in the gerbil hippocampus after transient forebrain ischemia. STEP was expressed in the perikarya and in neuronal processes; it was not detected in non-neuronal cells of control animals. After 5-min forebrain ischemia, STEP immunoreactivity (STEP-IR) was preserved for 2 days; it disappeared 4 and more days after ischemia with completion of delayed neuronal death (DND) in the CA1 subfield. Furthermore, only in the CA1 after ischemia, STEP was expressed in reactive astrocytes for 4 to 28 days, showing different patterns of glial fibrillary acidic protein (GFAP)-positive reactive astrocytes. After non-or less-than lethal ischemia, STEP expression in reactive astrocytes corresponded with the degree of neuronal degeneration. Immunoblot analysis of the CA1 subfield revealed the expression of three isoforms, STEP45, -56 and -61; their expression patterns changed with time after ischemia. These data suggest that neuronal STEP is preserved until cell degeneration after ischemia and that STEP is expressed in reactive astrocytes only after lethal ischemia, with different expression patterns for its isoforms. Of STEP45, -56 and -61, STEP61 was the most strongly expressed in the reactive astrocytes; both STEP45 and -61 were expressed in neurons and the expression of STEP56 was weak. STEP may play an important role not only in neurons but also in reactive astrocytes after ischemia, depending on neuronal degeneration. PMID:10652442

  1. Representation of binaural spatial cues in field L of the barn owl forebrain.

    PubMed

    Cohen, Y E; Knudsen, E I

    1998-02-01

    This study examined the representation of spatial information in the barn owl Field L, the first telencephalic processing stage of the classical auditory pathway. Field L units were recorded extracellularly, and their responses to dichotically presented interaural time differences (ITD) and interaural level differences (ILD) were tested. We observed a variety of tuning profiles in Field L. Some sites were not sensitive to ITD or ILD. Other sites, especially those in the high-frequency region, were highly selective for values of ITD and ILD. These sites had multipeaked (commonly called "phase ambiguous") ITD tuning profiles and were tuned for a single value of ILD. The tuning properties of these sites are similar to those seen in the lateral shell of the central nucleus of the inferior colliculus. Although the tuning properties of Field L sites were similar to those observed in the inferior colliculus, the functional organization of this spatial information was fundamentally different. Whereas in the inferior colliculus spatial information is organized into global topographics maps, in Field L spatial information is organized into local clusters, with sites having similar binaural tuning properties grouped together. The representation of binaural cues in Field L suggests that it is involved in auditory space processing but at a lower level of information processing than the auditory archistriatum, a forebrain area that is specialized for processing spatial information, and that the levels of information processing in the forebrain space processing pathway are remarkably similar to those in the well-known midbrain space processing pathway. PMID:9463449

  2. Loss of MeCP2 From Forebrain Excitatory Neurons Leads to Cortical Hyperexcitation and Seizures

    PubMed Central

    Zhang, Wen; Peterson, Matthew; Beyer, Barbara; Frankel, Wayne N.

    2014-01-01

    Mutations of MECP2 cause Rett syndrome (RTT), a neurodevelopmental disorder leading to loss of motor and cognitive functions, impaired social interactions, and seizure at young ages. Defects of neuronal circuit development and function are thought to be responsible for the symptoms of RTT. The majority of RTT patients show recurrent seizures, indicating that neuronal hyperexcitation is a common feature of RTT. However, mechanisms underlying hyperexcitation in RTT are poorly understood. Here we show that deletion of Mecp2 from cortical excitatory neurons but not forebrain inhibitory neurons in the mouse leads to spontaneous seizures. Selective deletion of Mecp2 from excitatory but not inhibitory neurons in the forebrain reduces GABAergic transmission in layer 5 pyramidal neurons in the prefrontal and somatosensory cortices. Loss of MeCP2 from cortical excitatory neurons reduces the number of GABAergic synapses in the cortex, and enhances the excitability of layer 5 pyramidal neurons. Using single-cell deletion of Mecp2 in layer 2/3 pyramidal neurons, we show that GABAergic transmission is reduced in neurons without MeCP2, but is normal in neighboring neurons with MeCP2. Together, these results suggest that MeCP2 in cortical excitatory neurons plays a critical role in the regulation of GABAergic transmission and cortical excitability. PMID:24523563

  3. A method of basal forebrain anatomical standardization for functional image analysis.

    PubMed

    Buchsbaum, M S; Fallon, J H; Wei, T C; Guich, S; Spiegel-Cohen, J; Hamilton, M; Tang, C

    1998-12-14

    Functional as well as structural assessment of the basal forebrain has mostly focused on the dorsal caudate and putamen in axial slices where they are easily outlined or their centers located with stereotaxic methods. The more ventral extent of the basal forebrain, where the irregular form and indistinct boundaries of the nucleus accumbens and substantia innominata are difficult to trace and where the brain's ventral surface may contribute partial volume artifacts to measurement, has been less studied. We present a method based on coronal sections, landmarks placed on clearly visible anchor points, and the computational technique of thin-plate spline warping which allows the alignment of groups of individuals to common coordinates for pixel-by-pixel statistical mapping. The reliability of the landmarks across independent raters yields a median absolute difference of 1.3-1.6 mm. The validity of the method is confirmed by variance maps which reveal significant decreases in variance over spindle and bounding box alignment. PMID:10710168

  4. The Impact of Hippocampal Lesions on Trace Eyeblink Conditioning and Forebrain-Cerebellar Interactions

    PubMed Central

    Weiss, Craig; Disterhoft, John F.

    2015-01-01

    Twenty-five years ago Behavioral Neuroscience published a pivotal paper by Moyer, Deyo and Disterhoft (1990) that described the impaired acquisition of trace eyeblink conditioning in rabbits with complete removal of the hippocampus. As part of the Behavioral Neuroscience celebration commemorating the 30th anniversary of the Journal, we reflect upon the impact of that study on understanding the role of the hippocampus, forebrain, and forebrain-cerebellar interactions that mediate acquisition and retention of trace conditioned responses, and of declarative memory more globally. We discuss the expansion of the conditioning paradigm to species other than the rabbit, the heterogeneity of responses among hippocampal neurons during trace conditioning, the responsivity of hippocampal neurons following consolidation of conditioning, the role of awareness in conditioning, how blink conditioning can be used as a translational tool by assaying potential therapeutics for cognitive enhancement, how trace and delay classical conditioning may be used to investigate neurological disorders including Alzheimer's Disease and schizophrenia, and how the two paradigms may be used to understand the relationship between declarative and nondeclarative memory systems. PMID:26214216

  5. Central thalamic deep brain stimulation to support anterior forebrain mesocircuit function in the severely injured brain.

    PubMed

    Schiff, Nicholas D

    2016-07-01

    This integrative review frames a general rationale for the use of central thalamic deep brain stimulation (CT-DBS) to support arousal regulation mechanisms in the severely injured brain. The organizing role of the anterior forebrain mesocircuit in recovery mechanisms following widespread deafferentation produced by multi-focal structural brain injuries is emphasized. The mesocircuit model provides the conceptual foundation for the key role of the central thalamus as a privileged node for neuromodulation to support forebrain arousal regulation. In this context, cellular mechanisms arising at the neocortical, striatal, and thalamic population level are considered in the assessment of an individual patient's capacity for harboring underlying reserve that could be recruited for further recovery. Recent preclinical studies and pilot clinical results are compared to frame the detailed rationale for CT-DBS. Application of CT-DBS across the range of outcomes following severe-to-moderate brain injuries is discussed with the aim of improving consciousness and cognition in patients with non-progressive brain injuries. PMID:27113938

  6. Defects in subventricular zone pigmented epithelium-derived factor niche signaling in the senescence-accelerated mouse prone-8.

    PubMed

    Castro-Garcia, Paola; Díaz-Moreno, María; Gil-Gas, Carmen; Fernández-Gómez, Francisco J; Honrubia-Gómez, Paloma; Álvarez-Simón, Carmen Belén; Sánchez-Sánchez, Francisco; Cano, Juan Carlos Castillo; Almeida, Francisco; Blanco, Vicente; Jordán, Joaquín; Mira, Helena; Ramírez-Castillejo, Carmen

    2015-04-01

    We studied potential changes in the subventricular zone (SVZ) stem cell niche of the senescence-accelerated mouse prone-8 (SAM-P8) aging model. Bromodeoxyuridine (BrdU) assays with longtime survival revealed a lower number of label-retaining stem cells in the SAM-P8 SVZ compared with the SAM-Resistant 1 (SAM-R1) control strain. We also found that in SAM-P8 niche signaling is attenuated and the stem cell pool is less responsive to the self-renewal niche factor pigmented epithelium-derived factor (PEDF). Protein analysis demonstrated stable amounts of the PEDF ligand in the SAM-P8 SVZ niche; however, SAM-P8 stem cells present a significant expression decrease of patatin-like phospholipase domain containing 2, a receptor for PEDF (PNPLA2-PEDF) receptor, but not of laminin receptor (LR), a receptor for PEDF (LR-PEDF) receptor. We observed changes in self-renewal related genes (hairy and enhancer of split 1 (Hes1), hairy and enhancer of split 1 (Hes5), Sox2] and report that although these genes are down-regulated in SAM-P8, differentiation genes (Pax6) are up-regulated and neurogenesis is increased. Finally, sheltering mammalian telomere complexes might be also involved given a down-regulation of telomeric repeat binding factor 1 (Terf1) expression was observed in SAM-P8 at young age periods. Differences between these 2 models, SAM-P8 and SAM-R1 controls, have been previously detected at more advanced ages. We now describe alterations in the PEDF signaling pathway and stem cell self-renewal at a very young age, which could be involved in the premature senescence observed in the SAM-P8 model. PMID:25636741

  7. PPARβ/δ and PPARγ maintain undifferentiated phenotypes of mouse adult neural precursor cells from the subventricular zone

    PubMed Central

    Bernal, Carolina; Araya, Claudia; Palma, Verónica; Bronfman, Miguel

    2015-01-01

    The subventricular zone (SVZ) is one of the main niches of neural stem cells in the adult mammalian brain. Stem and precursor cells in this region are the source for neurogenesis and oligodendrogesis, mainly in the olfactory bulb and corpus callosum, respectively. The identification of the molecular components regulating the decision of these cells to differentiate or maintain an undifferentiated state is important in order to understand the modulation of neurogenic processes in physiological and pathological conditions. PPARs are a group of transcription factors, activated by lipid ligands, with important functions in cellular differentiation and proliferation in several tissues. In this work, we demonstrate that mouse adult neural precursor cells (NPCs), in situ and in vitro, express PPARβ/δ and PPARγ. Pharmacological activation of both PPARs isoforms induces proliferation and maintenance of the undifferentiated phenotype. Congruently, inhibition of PPARβ/δ and PPARγ results in a decrease of proliferation and loss of the undifferentiated phenotype. Interestingly, PPARγ regulates the level of EGFR in adult NPCs, concurrent with it is function described in embryonic NPCs. Furthermore, we describe for the first time that PPARβ/δ regulates SOX2 level in adult NPCs, probably through a direct transcriptional regulation, as we identified two putative PPAR response elements in the promoter region of Sox2. EGFR and SOX2 are key players in neural stem/precursor cells self-renewal. Finally, rosiglitazone, a PPARγ ligand, increases PPARβ/δ level, suggesting a possible cooperation between these two PPARs in the control of cell fate behavior. Our work contributes to the understanding of the molecular mechanisms associated to neural cell fate decision and places PPARβ/δ and PPARγ as interesting new targets of modulation of mammalian brain homeostasis. PMID:25852474

  8. PPARβ/δ and PPARγ maintain undifferentiated phenotypes of mouse adult neural precursor cells from the subventricular zone.

    PubMed

    Bernal, Carolina; Araya, Claudia; Palma, Verónica; Bronfman, Miguel

    2015-01-01

    The subventricular zone (SVZ) is one of the main niches of neural stem cells in the adult mammalian brain. Stem and precursor cells in this region are the source for neurogenesis and oligodendrogesis, mainly in the olfactory bulb and corpus callosum, respectively. The identification of the molecular components regulating the decision of these cells to differentiate or maintain an undifferentiated state is important in order to understand the modulation of neurogenic processes in physiological and pathological conditions. PPARs are a group of transcription factors, activated by lipid ligands, with important functions in cellular differentiation and proliferation in several tissues. In this work, we demonstrate that mouse adult neural precursor cells (NPCs), in situ and in vitro, express PPARβ/δ and PPARγ. Pharmacological activation of both PPARs isoforms induces proliferation and maintenance of the undifferentiated phenotype. Congruently, inhibition of PPARβ/δ and PPARγ results in a decrease of proliferation and loss of the undifferentiated phenotype. Interestingly, PPARγ regulates the level of EGFR in adult NPCs, concurrent with it is function described in embryonic NPCs. Furthermore, we describe for the first time that PPARβ/δ regulates SOX2 level in adult NPCs, probably through a direct transcriptional regulation, as we identified two putative PPAR response elements in the promoter region of Sox2. EGFR and SOX2 are key players in neural stem/precursor cells self-renewal. Finally, rosiglitazone, a PPARγ ligand, increases PPARβ/δ level, suggesting a possible cooperation between these two PPARs in the control of cell fate behavior. Our work contributes to the understanding of the molecular mechanisms associated to neural cell fate decision and places PPARβ/δ and PPARγ as interesting new targets of modulation of mammalian brain homeostasis. PMID:25852474

  9. Evidence for a subventricular zone neural stem cell phagocytic activity stimulated by the vitamin K-dependent factor protein S.

    PubMed

    Ginisty, Aurélie; Gély-Pernot, Aurore; Abaamrane, Loubna; Morel, Franck; Arnault, Patricia; Coronas, Valérie; Benzakour, Omar

    2015-02-01

    Neural stem cells, whose major reservoir in the adult mammalian brain is the subventricular zone (SVZ), ensure neuropoiesis, a process during which many generated cells die. Removal of dead cells and debris by phagocytes is necessary for tissue homeostasis. Using confocal and electron microscopy, we demonstrate that cultured SVZ cells phagocytose both 1 and 2 µm latex beads and apoptotic cell-derived fragments. We determine by flow cytometry that phagocytic cells represent more than 10% of SVZ cultured cells. Phenotyping of SVZ cells using nestin, GFAP, Sox2, or LeX/SSEA and quantification of aldehyde dehydrogenase (ALDH) activity, reveals that cells with neural stem-cell features phagocytose and represent more than 30% of SVZ phagocytic cells. In vivo, nestin-, Sox2-, and ALDH-expressing neural stem-like cells engulfed latex beads or apoptotic cell-derived fragments that were injected into mice lateral brain ventricles. We show also that SVZ cell phagocytic activity is an active process, which depends both on cytoskeleton dynamic and on recognition of phosphatidylserine eat-me signal, and is stimulated by the vitamin K-dependent factor protein S (ProS). ProS neutralizing antibodies inhibit SVZ cell phagocytic activity and exposure of SVZ cells to apoptotic cell-derived fragments induces a transient Mer tyrosine kinase receptor (MerTK) phosphorylation. Conversely, MerTK blocking antibodies impair both basal and ProS-stimulated SVZ cell phagocytic activity. By revealing that neural stem-like cells act within the SVZ neurogenic niche as phagocytes and that the ProS/MerTK path represents an endogenous regulatory mechanism for SVZ cell phagocytic activity, the present report opens-up new perspectives for both stem cell biology and brain physiopathology. PMID:25308179

  10. Neural progenitor cells isolated from the subventricular zone present hemichannel activity and form functional gap junctions with glial cells

    PubMed Central

    Talaverón, Rocío; Fernández, Paola; Escamilla, Rosalba; Pastor, Angel M.; Matarredona, Esperanza R.; Sáez, Juan C.

    2015-01-01

    The postnatal subventricular zone (SVZ) lining the walls of the lateral ventricles contains neural progenitor cells (NPCs) that generate new olfactory bulb interneurons. Communication via gap junctions between cells in the SVZ is involved in NPC proliferation and in neuroblast migration towards the olfactory bulb. SVZ NPCs can be expanded in vitro in the form of neurospheres that can be used for transplantation purposes after brain injury. We have previously reported that neurosphere-derived NPCs form heterocellular gap junctions with host glial cells when they are implanted after mechanical injury. To analyze functionality of NPC-glial cell gap junctions we performed dye coupling experiments in co-cultures of SVZ NPCs with astrocytes or microglia. Neurosphere-derived cells expressed mRNA for at least the hemichannel/gap junction channel proteins connexin 26 (Cx26), Cx43, Cx45 and pannexin 1 (Panx1). Dye coupling experiments revealed that gap junctional communication occurred among neurosphere cells (incidence of coupling: 100%). Moreover, hemichannel activity was also detected in neurosphere cells as evaluated in time-lapse measurements of ethidium bromide uptake. Heterocellular coupling between NPCs and glial cells was evidenced in co-cultures of neurospheres with astrocytes (incidence of coupling: 91.0 ± 4.7%) or with microglia (incidence of coupling: 71.9 ± 6.7%). Dye coupling in neurospheres and in co-cultures was inhibited by octanol, a gap junction blocker. Altogether, these results suggest the existence of functional hemichannels and gap junction channels in postnatal SVZ neurospheres. In addition, they demonstrate that SVZ-derived NPCs can establish functional gap junctions with astrocytes or microglia. Therefore, cell-cell communication via gap junctions and hemichannels with host glial cells might subserve a role in the functional integration of NPCs after implantation in the damaged brain. PMID:26528139

  11. A quantitative cytochrome oxidase mapping study, cross-regional and neurobehavioural correlations in the anterior forebrain of an animal model of Attention Deficit Hyperactivity Disorder.

    PubMed

    Papa, M; Berger, D F; Sagvolden, T; Sergeant, J A; Sadile, A G

    1998-07-01

    The aim of this study was to trace by molecular imaging techniques the neural substrates of attention deficit hyperactivity disorder (ADHD) using the spontaneously hypertensive rat (SHR) as animal model. Adult SHR and Wistar-Kyoto (WKY) controls were used throughout this study. In experiment 1, naive male SHR and WKY were used, whereas in experiment 2 SHR and WKY rats of both genders were trained on a multiple fixed interval (FI (120 s for water, 5-min extinction)) paradigm and sacrificed 6 months later. In both experiments coronal sections of the anterior forebrain were processed for quantitative cytochrome oxidase (COase) histochemistry by the method of Gonzalez-Lima. Optical density values were transformed into actual enzyme activity units by using tissue-calibrated standards. In experiment 1, non-trained male rats of the SHR line showed lower COase activity in the medial and lateral prefrontal cortices, compared with WKY controls. In experiment 2, there was a line x treatment interaction effect in the pole of the nucleus accumbens (ACB). Regional correlative analyses revealed that: (i) under basal conditions, SHR are more synchronized than WKY rats in the COase level of different brain regions; and (ii) the training desynchronizes COase activity in the WKY, further synchronizes it and increases the cross-talk between hemispheres in male SHR only. Neurobehavioral covariations between behavioural scores and metabolic capacity in the medial and lateral prefrontal/frontal cortices, the caudate-putamen complex (CPU), the pole, core, and shell of the accumbal complex (ACB), and the ventral pallidum (VP), indicated that, in the WKY rats, the frequency of lever pressing covaried positively with the COase activity in the CPU, whereas in the SHR covaried with both medial and lateral prefrontal/frontal cortices. The bursts of activity during the 1-1.33-s segment was positively correlated, in the WKY rats only, with the core and shell of the ACB, and with the VP. Finally

  12. Repeated preconditioning with hyperbaric oxygen induces neuroprotection against forebrain ischemia via suppression of p38 mitogen activated protein kinase.

    PubMed

    Yamashita, Satoshi; Hirata, Takao; Mizukami, Yoichi; Cui, Ying Jun; Fukuda, Shiro; Ishida, Kazuyoshi; Matsumoto, Mishiya; Sakabe, Takefumi

    2009-12-01

    We previously reported in rats that preconditioning with hyperbaric oxygen (HBO; 100% O(2) 3.5-atomsphere absolute (ATA), 1 h/day for 5 days) provided neuroprotection against transient (8 min) forebrain ischemia possibly through protein synthesis relevant to neurotrophin receptor and inflammatory-immune system. A recent report suggested that HBO-induced neuroprotection is relevant to brain derived neurotrophic factor and its downstream event involving suppression of p38 mitogen activated protein kinase (p38) activation. In the present study, we first performed a dose comparison (1, 2, and 3.5 ATA) of HBO-induced neuroprotection and then investigated pharmacological modification by 10 mg/kg anisomycin (a protein synthesis inhibitor and potent activator for p38) and 200 microg/kg SB203580 (a p38 inhibitor), which were given intraperitoneally 60 and 30 min before every 3.5 ATA-HBO treatment, respectively. Most prominent protective effect on hippocampal CA1 neurons was observed with 3.5 ATA-HBO (survived neurons: 69% [62-73%] vs. untreated: 3.9% [2-8%], 1 ATA: 8.8% [0-26%], 2 ATA-HBO: 46% [22-62%] (median [range]) (7 days after ischemia). Anisomycin abolished a neuroprotective effect (survived neuron: 1.2% [0-7%]). SB203580, when given between administration of anisomycin and HBO treatment, resumed a neuroprotective effect (survived neuron: 52% [37-62%]). The level of phosphorylated p38 at 10-min reperfusion was significantly decreased in 3.5 ATA-HBO group (32% [12-53%] of sham). Single pretreatment with 100 and 200 microg/kg of SB203580 exerted a similar neuroprotective effect (39% [25-51%] and 59% [50-72%]) to 2 and 3.5 ATA-HBO preconditioning, respectively. It is concluded that suppression of p38 phosphorylation plays a key role in HBO-induced neuroprotection and that pretreatment with a p38 inhibitor (SB203580) can provide similar neuroprotection. PMID:19747454

  13. Lhx2 and Lhx9 determine neuronal differentiation and compartition in the caudal forebrain by regulating Wnt signaling.

    PubMed

    Peukert, Daniela; Weber, Sabrina; Lumsden, Andrew; Scholpp, Steffen

    2011-12-01

    Initial axial patterning of the neural tube into forebrain, midbrain, and hindbrain primordia occurs during gastrulation. After this patterning phase, further diversification within the brain is thought to proceed largely independently in the different primordia. However, mechanisms that maintain the demarcation of brain subdivisions at later stages are poorly understood. In the alar plate of the caudal forebrain there are two principal units, the thalamus and the pretectum, each of which is a developmental compartment. Here we show that proper neuronal differentiation of the thalamus requires Lhx2 and Lhx9 function. In Lhx2/Lhx9-deficient zebrafish embryos the differentiation process is blocked and the dorsally adjacent Wnt positive epithalamus expands into the thalamus. This leads to an upregulation of Wnt signaling in the caudal forebrain. Lack of Lhx2/Lhx9 function as well as increased Wnt signaling alter the expression of the thalamus specific cell adhesion factor pcdh10b and lead subsequently to a striking anterior-posterior disorganization of the caudal forebrain. We therefore suggest that after initial neural tube patterning, neurogenesis within a brain compartment influences the integrity of the neuronal progenitor pool and border formation of a neuromeric compartment. PMID:22180728

  14. Lhx2 and Lhx9 Determine Neuronal Differentiation and Compartition in the Caudal Forebrain by Regulating Wnt Signaling

    PubMed Central

    Peukert, Daniela; Weber, Sabrina; Lumsden, Andrew; Scholpp, Steffen

    2011-01-01

    Initial axial patterning of the neural tube into forebrain, midbrain, and hindbrain primordia occurs during gastrulation. After this patterning phase, further diversification within the brain is thought to proceed largely independently in the different primordia. However, mechanisms that maintain the demarcation of brain subdivisions at later stages are poorly understood. In the alar plate of the caudal forebrain there are two principal units, the thalamus and the pretectum, each of which is a developmental compartment. Here we show that proper neuronal differentiation of the thalamus requires Lhx2 and Lhx9 function. In Lhx2/Lhx9-deficient zebrafish embryos the differentiation process is blocked and the dorsally adjacent Wnt positive epithalamus expands into the thalamus. This leads to an upregulation of Wnt signaling in the caudal forebrain. Lack of Lhx2/Lhx9 function as well as increased Wnt signaling alter the expression of the thalamus specific cell adhesion factor pcdh10b and lead subsequently to a striking anterior-posterior disorganization of the caudal forebrain. We therefore suggest that after initial neural tube patterning, neurogenesis within a brain compartment influences the integrity of the neuronal progenitor pool and border formation of a neuromeric compartment. PMID:22180728

  15. Early visual experience shapes the representation of auditory space in the forebrain gaze fields of the barn owl.

    PubMed

    Miller, G L; Knudsen, E I

    1999-03-15

    Auditory spatial information is processed in parallel forebrain and midbrain pathways. Sensory experience early in life has been shown to exert a powerful influence on the representation of auditory space in the midbrain space-processing pathway. The goal of this study was to determine whether early experience also shapes the representation of auditory space in the forebrain. Owls were raised wearing prismatic spectacles that shifted the visual field in the horizontal plane. This manipulation altered the relationship between interaural time differences (ITDs), the principal cue used for azimuthal localization, and locations of auditory stimuli in the visual field. Extracellular recordings were used to characterize ITD tuning in the auditory archistriatum (AAr), a subdivision of the forebrain gaze fields, in normal and prism-reared owls. Prism rearing altered the representation of ITD in the AAr. In prism-reared owls, unit tuning for ITD was shifted in the adaptive direction, according to the direction of the optical displacement imposed by the spectacles. Changes in ITD tuning involved the acquisition of unit responses to adaptive ITD values and, to a lesser extent, the elimination of responses to nonadaptive (previously normal) ITD values. Shifts in ITD tuning in the AAr were similar to shifts in ITD tuning observed in the optic tectum of the same owls. This experience-based adjustment of binaural tuning in the AAr helps to maintain mutual registry between the forebrain and midbrain representations of auditory space and may help to ensure consistent behavioral responses to auditory stimuli. PMID:10066282

  16. Differential effects of light and feeding on circadian organization of peripheral clocks in a forebrain Bmal1 mutant

    PubMed Central

    Izumo, Mariko; Pejchal, Martina; Schook, Andrew C; Lange, Ryan P; Walisser, Jacqueline A; Sato, Takashi R; Wang, Xiaozhong; Bradfield, Christopher A; Takahashi, Joseph S

    2014-01-01

    In order to assess the contribution of a central clock in the hypothalamic suprachiasmatic nucleus (SCN) to circadian behavior and the organization of peripheral clocks, we generated forebrain/SCN-specific Bmal1 knockout mice by using floxed Bmal1 and pan-neuronal Cre lines. The forebrain knockout mice showed >90% deletion of BMAL1 in the SCN and exhibited an immediate and complete loss of circadian behavior in constant conditions. Circadian rhythms in peripheral tissues persisted but became desynchronized and damped in constant darkness. The loss of synchrony was rescued by light/dark cycles and partially by restricted feeding (only in the liver and kidney but not in the other tissues) in a distinct manner. These results suggest that the forebrain/SCN is essential for internal temporal order of robust circadian programs in peripheral clocks, and that individual peripheral clocks are affected differently by light and feeding in the absence of a functional oscillator in the forebrain. DOI: http://dx.doi.org/10.7554/eLife.04617.001 PMID:25525750

  17. Regional expression of c-fos antigen in the basal forebrain following intraventricular infusions of angiotensin and its modulation by drinking either water or saline.

    PubMed

    Herbert, J; Forsling, M L; Howes, S R; Stacey, P M; Shiers, H M

    1992-12-01

    The expression of c-fos protein was examined in the basal forebrains of male rats 60 min following intracerebroventricular infusions of 250 pmol angiotensin II. Levels of corticosterone and vasopressin were also measured at the same time point. In animals not allowed access to water after infusion, angiotensin II induced intense c-fos expression in a band of neurons extending throughout the anterior region of the third ventricle region, including the organum vasculosum of the lamina terminalis, the median preoptic nucleus (nucleus medianus) and the subfornical organ. There were also high levels of expression in the hypothalamic supraoptic nucleus and the paraventricular nucleus, particularly its lateral (magnocellular) region, though other, parvicellular areas were also affected. No other area of the hypothalamus was altered. There was increased c-fos expression in the central nucleus of the amygdala and the bed nucleus of the stria terminalis. Allowing rats to drink during the 60-min survival period modified this pattern of response. c-fos was markedly reduced in the supraoptic nucleus and the paraventricular nucleus but not in the other areas examined, including the anterior region of the third ventricle and the amygdala. When water was withheld for 15 min, but then allowed, rats drank the same total volume but c-fos expression was no longer inhibited in either the supraoptic nucleus or paraventricular nucleus. When rats were given 0.9% saline to drink, they ingested about three times as much as water, but angiotensin II-induced c-fos expression was similar to that in rats denied access to water. The pattern was similar following access to 1.8% saline, though levels in the organum vasculosum of the lamina terminalis were reduced. There was a marked correlation between the number of c-fos-positive neurons in the supraoptic nucleus or paraventricular nucleus and plasma levels of corticosterone 60 min after infusion, but not with arginine-vasopressin levels. These

  18. Melanin-concentrating hormone (MCH) immunoreactivity in non-neuronal cells within the raphe nuclei and subventricular region of the brainstem of the cat.

    PubMed

    Torterolo, Pablo; Lagos, Patricia; Sampogna, Sharon; Chase, Michael H

    2008-05-19

    Neurons that utilize melanin-concentrating hormone (MCH) as a neuromodulator are localized within the postero-lateral hypothalamus and zona incerta. These neurons project diffusely throughout the central nervous system and have been implicated in critical physiological processes such as energy homeostasis and sleep. In the present report, we examined the distribution of MCH immunoreactivity in the brainstem of the cat. In addition to MCH+ axons, we found MCH-immunoreactive cells that have not been previously described either in the midbrain raphe nuclei or in the periaqueductal and periventricular areas. These MCH+ cells constituted: 1. ependymal cells that lined the fourth ventricle and aqueduct, 2. ependymal cells with long basal processes that projected deeply into the subventricular (subaqueductal) parenchyma, and, 3. cells in subventricular regions and the midbrain raphe nuclei. The MCH+ cells in the midbrain raphe nuclei were closely related to neuronal processes of serotonergic neurons. Utilizing Neu-N and GFAP immunohistochemistry we determined that the preceding MCH+ cells were neither neurons nor astrocytes. However, we found that vimentin, an intermediate-filament protein that is used as a marker for tanycytes, was specifically co-localized with MCH in these cells. We conclude that MCH is present in tanycytes whose processes innervate the midbrain raphe nuclei and adjacent subependymal regions. Because tanycytes are specialized cells that transport substances from the cerebrospinal fluid (CSF) to neural parenchyma, we suggest that MCH is absorbed from the CSF by tanycytes and subsequently liberate to act upon neurons of brainstem nuclei. PMID:18410908

  19. Age-related neurogenesis decline in the subventricular zone is associated with specific cell cycle regulation changes in activated neural stem cells

    PubMed Central

    Daynac, Mathieu; Morizur, Lise; Chicheportiche, Alexandra; Mouthon, Marc-André; Boussin, François D.

    2016-01-01

    Although neural stem cells (NSCs) sustain continuous neurogenesis throughout the adult lifespan of mammals, they progressively exhibit proliferation defects that contribute to a sharp reduction in subventricular neurogenesis during aging. However, little is known regarding the early age-related events in neurogenic niches. Using a fluorescence-activated cell sorting technique that allows for the prospective purification of the main neurogenic populations from the subventricular zone (SVZ), we demonstrated an early decline in adult neurogenesis with a dramatic loss of progenitor cells in 4 month-old young adult mice. Whereas the activated and quiescent NSC pools remained stable up to 12 months, the proliferative status of activated NSCs was already altered by 6 months, with an overall extension of the cell cycle resulting from a specific lengthening of G1. Whole genome analysis of activated NSCs from 2- and 6-month-old mice further revealed distinct transcriptomic and molecular signatures, as well as a modulation of the TGFβ signalling pathway. Our microarray study constitutes a cogent identification of new molecular players and signalling pathways regulating adult neurogenesis and its early modifications. PMID:26893147

  20. Optimizing Culture Medium Composition to Improve Oligodendrocyte Progenitor Cell Yields In Vitro from Subventricular Zone-Derived Neural Progenitor Cell Neurospheres

    PubMed Central

    Franco, Paula G.; Pasquini, Juana M.; Silvestroff, Lucas

    2015-01-01

    Neural Stem and Progenitor Cells (NSC/NPC) are gathering tangible recognition for their uses in cell therapy and cell replacement therapies for human disease, as well as a model system to continue research on overall neural developmental processes in vitro. The Subventricular Zone is one of the largest NSC/NPC niches in the developing mammalian Central Nervous System, and persists through to adulthood. Oligodendrocyte progenitor cell (OPC) enriched cultures are usefull tools for in vitro studies as well as for cell replacement therapies for treating demyelination diseases. We used Subventricular Zone-derived NSC/NPC primary cultures from newborn mice and compared the effects of different growth factor combinations on cell proliferation and OPC yield. The Platelet Derived Growth Factor-AA and BB homodimers had a positive and significant impact on OPC generation. Furthermore, heparin addition to the culture media contributed to further increase overall culture yields. The OPC generated by this protocol were able to mature into Myelin Basic Protein-expressing cells and to interact with neurons in an in vitro co-culture system. As a whole, we describe an optimized in vitro method for increasing OPC. PMID:25837625

  1. Age-related neurogenesis decline in the subventricular zone is associated with specific cell cycle regulation changes in activated neural stem cells.

    PubMed

    Daynac, Mathieu; Morizur, Lise; Chicheportiche, Alexandra; Mouthon, Marc-André; Boussin, François D

    2016-01-01

    Although neural stem cells (NSCs) sustain continuous neurogenesis throughout the adult lifespan of mammals, they progressively exhibit proliferation defects that contribute to a sharp reduction in subventricular neurogenesis during aging. However, little is known regarding the early age-related events in neurogenic niches. Using a fluorescence-activated cell sorting technique that allows for the prospective purification of the main neurogenic populations from the subventricular zone (SVZ), we demonstrated an early decline in adult neurogenesis with a dramatic loss of progenitor cells in 4 month-old young adult mice. Whereas the activated and quiescent NSC pools remained stable up to 12 months, the proliferative status of activated NSCs was already altered by 6 months, with an overall extension of the cell cycle resulting from a specific lengthening of G1. Whole genome analysis of activated NSCs from 2- and 6-month-old mice further revealed distinct transcriptomic and molecular signatures, as well as a modulation of the TGFβ signalling pathway. Our microarray study constitutes a cogent identification of new molecular players and signalling pathways regulating adult neurogenesis and its early modifications. PMID:26893147

  2. Attentive, Affective, and Adaptive Behavior in the Cat: Sensory deprivation of the forebrain by lesions in the brain stem results in striking behavioral abnormalities.

    PubMed

    Sprague, J M; Chambers, W W; Stellar, E

    1961-01-20

    Lesions of the lateral portion of the upper midbrain, involving medial, lateral, spinal, and trigeminal lemnisci primarily, result in a consistent syndrome of symptoms in the cat. (i) There is a marked sensory deficit, characterized mainly by sensory inattention and poor localization in the tactile, proprioceptive, auditory, gustatory, and nociceptive modalities, where direct pathways are interrupted. Similar defectsappear in vision and olfaction where no known direct or primary paths are interrupted. (ii) These cats are characterized by a lack of affect, showing little or no defensive and aggressive reaction to noxious and aversive situations and no response to pleasurable stimulation or solicitation of affection or petting. The animals are mute, lack facial expression, and show minimal autonomic responses. (iii) They show a hyperexploratory activity characterized by incessant, stereotyped wandering, sniffing, and visual searching, as though hallucinating. This behavior appears to be centrally directed and is very difficult to interrupt with environmental stimuli. (iv) They also demonstrate exaggerated oral activities: they snap in response to tactile stimulation of the lips, seizing and swallowing small objects even if inedible; they overeat; they hold objects too large to swallow (a mouse, a catnip ball) firmly clamped in the mouth for long periods of time; they mount and seize other animals (rat, cat, dog, monkey) by the back or the neck; they lick and chew the hair and skin of the back or tail incessantly when confined in a cage. In interpreting these results we emphasize the view that the syndrome is due chiefly to the extensive, specific, sensory deprivation produced by interruption of the lemnisci at the rostral midbrain. The relation of these findings to the effects of sensory isolation in man and animals, to the effects of midbrain lesions and neodecortication, to parietal lobe syndrome in primates, and to the behavior of autistic children is discussed

  3. Motor Origin of Precise Synaptic Inputs onto Forebrain Neurons Driving a Skilled Behavior

    PubMed Central

    Vallentin, Daniela

    2015-01-01

    Sensory feedback is crucial for learning and performing many behaviors, but its role in the execution of complex motor sequences is poorly understood. To address this, we consider the forebrain nucleus HVC in the songbird, which contains the premotor circuitry for song production and receives multiple convergent sensory inputs. During singing, projection neurons within HVC exhibit precisely timed synaptic events that may represent the ongoing motor program or song-related sensory feedback. To distinguish between these possibilities, we recorded the membrane potential from identified HVC projection neurons in singing zebra finches. External auditory perturbations during song production did not affect synaptic inputs in these neurons. Furthermore, the systematic removal of three sensory feedback streams (auditory, proprioceptive, and vagal) did not alter the frequency or temporal precision of synaptic activity observed. These findings support a motor origin for song-related synaptic events and suggest an updated circuit model for generating behavioral sequences. PMID:25568122

  4. Calcium Imaging of Basal Forebrain Activity during Innate and Learned Behaviors

    PubMed Central

    Harrison, Thomas C.; Pinto, Lucas; Brock, Julien R.; Dan, Yang

    2016-01-01

    The basal forebrain (BF) plays crucial roles in arousal, attention, and memory, and its impairment is associated with a variety of cognitive deficits. The BF consists of cholinergic, GABAergic, and glutamatergic neurons. Electrical or optogenetic stimulation of BF cholinergic neurons enhances cortical processing and behavioral performance, but the natural activity of these cells during behavior is only beginning to be characterized. Even less is known about GABAergic and glutamatergic neurons. Here, we performed microendoscopic calcium imaging of BF neurons as mice engaged in spontaneous behaviors in their home cages (innate) or performed a go/no-go auditory discrimination task (learned). Cholinergic neurons were consistently excited during movement, including running and licking, but GABAergic and glutamatergic neurons exhibited diverse responses. All cell types were activated by overt punishment, either inside or outside of the discrimination task. These findings reveal functional similarities and distinctions between BF cell types during both spontaneous and task-related behaviors. PMID:27242444

  5. Distribution of SNAP-25 in transient neuronal circuitries of the developing human forebrain.

    PubMed

    Ulfig, N; Setzer, M; Neudörfer, F; Bohl, J

    2000-04-27

    The distribution of SNAP-25 is demonstrated within prominent transient structures in the developing human forebrain. During early fetal development SNAP-25 is mainly expressed in axons of the intermediate zone and the internal capsule. The fibers appear directed towards the mantle zone of the ganglionic eminence and the perireticular nucleus located within the internal capsule. Cells of these two areas are shown to interact with SNAP-25 immunoreactive structures with the aid of double-labellings. The SNAP-25 immunoreactive fibers may represent corticofugal axons which contact the perireticular nucleus and ganglionic eminence which are regarded as intermediate targets providing a scaffold for growing axons. Anti-SNAP-25, thus, is an appropriate marker of intermediate targets which are involved in brain injuries of preterm infants. PMID:10817603

  6. GRK5 Deficiency Leads to Selective Basal Forebrain Cholinergic Neuronal Vulnerability

    PubMed Central

    He, Minchao; Singh, Prabhakar; Cheng, Shaowu; Zhang, Qiang; Peng, Wei; Ding, XueFeng; Li, Longxuan; Liu, Jun; Premont, Richard T.; Morgan, Dave; Burns, Jeffery M.; Swerdlow, Russell H.; Suo, William Z.

    2016-01-01

    Why certain diseases primarily affect one specific neuronal subtype rather than another is a puzzle whose solution underlies the development of specific therapies. Selective basal forebrain cholinergic (BFC) neurodegeneration participates in cognitive impairment in Alzheimer’s disease (AD), yet the underlying mechanism remains elusive. Here, we report the first recapitulation of the selective BFC neuronal loss that is typical of human AD in a mouse model termed GAP. We created GAP mice by crossing Tg2576 mice that over-express the Swedish mutant human β-amyloid precursor protein gene with G protein-coupled receptor kinase-5 (GRK5) knockout mice. This doubly defective mouse displayed significant BFC neuronal loss at 18 months of age, which was not observed in either of the singly defective parent strains or in the wild type. Along with other supporting evidence, we propose that GRK5 deficiency selectively renders BFC neurons more vulnerable to degeneration. PMID:27193825

  7. Adult mouse basal forebrain harbors two distinct cholinergic populations defined by their electrophysiology

    PubMed Central

    Unal, Cagri T.; Golowasch, Jorge P.; Zaborszky, Laszlo

    2012-01-01

    We performed whole-cell recordings from basal forebrain (BF) cholinergic neurons in transgenic mice expressing enhanced green fluorescent protein (eGFP) under the control of the choline acetyltransferase promoter. BF cholinergic neurons can be differentiated into two electrophysiologically identifiable subtypes: early and late firing neurons. Early firing neurons (∼70%) are more excitable, show prominent spike frequency adaptation and are more susceptible to depolarization blockade, a phenomenon characterized by complete silencing of the neuron following initial action potentials. Late firing neurons (∼30%), albeit being less excitable, could maintain a tonic discharge at low frequencies. In voltage clamp analysis, we have shown that early firing neurons have a higher density of low voltage activated (LVA) calcium currents. These two cholinergic cell populations might be involved in distinct functions: the early firing group being more suitable for phasic changes in cortical acetylcholine release associated with attention while the late firing neurons could support general arousal by maintaining tonic acetylcholine levels. PMID:22586380

  8. [Qualitative features of confabulation in a case with basal forebrain amnesia].

    PubMed

    Abe, M; Ohtake, H; Suzuki, K; Suzuki, M; Fujii, T; Yamadori, A

    2001-12-01

    We investigated qualitative features of confabulation in a case with basal forebrain amnesia. A 66-year-old, right-handed woman with a 8th-grade education, was admitted to the Rehabilitation Department of Tohoku University Hospital, Japan, for evaluation and therapy of amnesia. Her previous medical history included hypertension. Nine months before admission, she went to a hospital because of headache and blurred vision. She was diagnosed as suffering from a suprasellar arachnoid cyst and unruptured aneurysm at the anterior communicating artery. Five months later, resection of the cyst and clipping of the aneurysm was performed. After the operation, she became disoriented and amnesic with marked confabulation. On admission to our hospital 3 months later, she was alert and cooperative. Detailed neuropsychological assessment was performed during the next two months. She remained clinically stable throughout her hospitalization. Neurological examination showed no abnormalities. Brain magnetic resonance images revealed lesions in the bilateral orbito-frontal cortices and basal forebrain. Measurement of blood flow with 123I-IMP single photon emission computed tomography showed hypoperfusion in the bilateral frontotemporal regions. We performed systematic investigations to clarify the qualitative features of her confabulations. Her confabulations included many facts she had experienced before, but they were out of context. Each fact was recalled in isolation or associated with erroneous places, persons or times. Her confabulations were never fantastic or momentary in nature, but were consisted with isolated facts. Experimental investigation revealed that she could recognize individual facts (a person, a place, a task and time) in each episode. However, she could not integrate individual facts into an episode. We propose calling this type of confabulation "mosaic confabulation". PMID:11806121

  9. Paravertebral fascial massage promotes brain development of neonatal rats via the insulin-like growth factor 1 pathway☆

    PubMed Central

    Wen, Zhongqiu; Zeng, Wenqin; Dai, Jingxing; Zhou, Xin; Yang, Chun; Duan, Fuhua; Liu, Yufeng; Yang, Huiying; Yuan, Lin

    2012-01-01

    Massage in traditional Chinese medicine can promote body and brain development of premature and normal newborn infants. In the present study, neonatal rats (1 day old) underwent paravertebral fascial massage (15 consecutive days), followed by subcutaneous injection of insulin-like growth factor 1 receptor antagonist, JB1 (9 consecutive days). Paravertebral fascial massage significantly increased insulin-like growth factor 1 expression and cell proliferation in the subventricular zone of the lateral ventricle and dentate gyrus of the hippocampus. However, JB1 inhibited this increase. Results suggest that paravertebral fascial massage can promote brain development of neonatal rats via the insulin-like growth factor 1 pathway. PMID:25722713

  10. The subventricular zone in the immature piglet brain: anatomy and exodus of neuroblasts into white matter after traumatic brain injury

    PubMed Central

    Costine, Beth A.; Missios, Symeon; Taylor, Sabrina R.; McGuone, Declan; Smith, Colin M.; Dodge, Carter P.; Harris, Brent T.; Duhaime, Ann-Christine

    2015-01-01

    Stimulation of postnatal neurogenesis in the subventricular zone (SVZ) and robust migration of neuroblasts to the lesion site in response to traumatic brain injury (TBI) is well-established in rodent species; however, it is not yet known if postnatal neurogenesis plays a role in repair after TBI in gyrencephalic species. Here we describe the anatomy of the SVZ in the piglet for the first time and initiate investigation into the effect of TBI on the SVZ architecture and the number of neuroblasts in the white matter. Among all ages of immaturity examined the SVZ contained a dense mesh network of neurogenic precursor cells (doublecortin+; DCX) positioned directly adjacent to the ependymal cells (ventricular SVZ; Vsvz) and neuroblasts organized into chains that were distinct from the ventricular SVZ (abventricular SVZ; Asvz). Though the architecture of the SVZ was similar among ages, the areas of Vsvz and Asvz neuroblast chains declined with age. At PND 14 the white matter tracts have a tremendous number of individual neuroblasts. In our scaled cortical impact model, lesion size increases with age. Similarly, the response of the SVZ to injury was also age-dependent. The younger age groups that sustained the proportionately smallest lesions had the largest SVZ areas that further increased in response to injury. In piglets that were injured at 4 months of age and had the largest lesions, the SVZ did not increase in response to injury. Similar to humans, swine have abundant gyri and gyral white matter providing a unique platform to study neuroblasts potentially migrating from the SVZ to the lesioned cortex along these white matter tracts. In piglets injured at PND7, TBI did not increase the total number of neuroblasts in the white matter compared to uninjured piglets, but redistribution occurred with a greater number of neuroblasts in the white matter of the hemisphere ipsilateral to the injury compared to the contralateral hemisphere. At 7 days post-injury, less than 1

  11. The subventricular zone in the immature piglet brain: anatomy and exodus of neuroblasts into white matter after traumatic brain injury.

    PubMed

    Costine, Beth A; Missios, Symeon; Taylor, Sabrina R; McGuone, Declan; Smith, Colin M; Dodge, Carter P; Harris, Brent T; Duhaime, Ann-Christine

    2015-01-01

    Stimulation of postnatal neurogenesis in the subventricular zone (SVZ) and robust migration of neuroblasts to the lesion site in response to traumatic brain injury (TBI) is well established in rodent species; however, it is not yet known whether postnatal neurogenesis plays a role in repair after TBI in gyrencephalic species. Here we describe the anatomy of the SVZ in the piglet for the first time and initiate an investigation into the effect of TBI on the SVZ architecture and the number of neuroblasts in the white matter. Among all ages of immaturity examined the SVZ contained a dense mesh network of neurogenic precursor cells (doublecortin+) positioned directly adjacent to the ependymal cells (ventricular SVZ, Vsvz) and neuroblasts organized into chains that were distinct from the Vsvz (abventricular SVZ, Asvz). Though the architecture of the SVZ was similar among ages, the areas of Vsvz and Asvz neuroblast chains declined with age. At postnatal day (PND) 14 the white matter tracts have a tremendous number of individual neuroblasts. In our scaled cortical impact model, lesion size increased with age. Similarly, the response of the SVZ to injury was also age dependent. The younger age groups that sustained the proportionately smallest lesions had the largest SVZ areas, which further increased in response to injury. In piglets that were injured at 4 months of age and had the largest lesions, the SVZ did not increase in response to injury. Similar to humans, swine have abundant gyri and gyral white matter, providing a unique platform to study neuroblasts potentially migrating from the SVZ to the lesioned cortex along these white matter tracts. In piglets injured at PND 7, TBI did not increase the total number of neuroblasts in the white matter compared to uninjured piglets, but redistribution occurred with a greater number of neuroblasts in the white matter of the hemisphere ipsilateral to the injury compared to the contralateral hemisphere. At 7 days after injury

  12. Type 3 Adenylyl Cyclase and Somatostatin Receptor 3 Expression Persists in Aged Rat Neocortical and Hippocampal Neuronal Cilia

    PubMed Central

    Guadiana, Sarah M.; Parker, Alexander K.; Filho, Gileno F.; Sequeira, Ashton; Semple-Rowland, Susan; Shaw, Gerry; Mandel, Ronald J.; Foster, Thomas C.; Kumar, Ashok; Sarkisian, Matthew R.

    2016-01-01

    The primary cilia of forebrain neurons assemble around birth and become enriched with neuromodulatory receptors. Our understanding of the permanence of these structures and their associated signaling pathways in the aging brain is poor, but they are worthy of investigation because disruptions in neuronal cilia signaling have been implicated in changes in learning and memory, depression-like symptoms, and sleep anomalies. Here, we asked whether neurons in aged forebrain retain primary cilia and whether the staining characteristics of aged cilia for type 3 adenylyl cyclase (ACIII), somatostatin receptor 3 (SSTR3), and pericentrin resemble those of cilia in younger forebrain. To test this, we analyzed immunostained sections of forebrain tissues taken from young and aged male Fischer 344 (F344) and F344 × Brown Norway (F344 × BN) rats. Analyses of ACIII and SSTR3 in young and aged cortices of both strains of rats revealed that the staining patterns in the neocortex and hippocampus were comparable. Virtually every NeuN positive cell examined possessed an ACIII positive cilium. The lengths of ACIII positive cilia in neocortex were similar between young and aged for both strains, whereas in F344 × BN hippocampus, the cilia lengths increased with age in CA1 and CA3, but not in dentate gyrus (DG). Additionally, the percentages of ACIII positive cilia that were also SSTR3 positive did not differ between young and aged tissues in either strain. We also found that pericentrin, a protein that localizes to the basal bodies of neuronal cilia and functions in primary cilia assembly, persisted in aged cortical neurons of both rat strains. Collectively, our data show that neurons in aged rat forebrain possess primary cilia and that these cilia, like those present in younger brain, continue to localize ACIII, SSTR3, and pericentrin. Further studies will be required to determine if the function and signaling pathways regulated by cilia are similar in aged compared to young brain

  13. Synaptic dysfunction, memory deficits and hippocampal atrophy due to ablation of mitochondrial fission in adult forebrain neurons

    PubMed Central

    Oettinghaus, B; Schulz, J M; Restelli, L M; Licci, M; Savoia, C; Schmidt, A; Schmitt, K; Grimm, A; Morè, L; Hench, J; Tolnay, M; Eckert, A; D'Adamo, P; Franken, P; Ishihara, N; Mihara, K; Bischofberger, J; Scorrano, L; Frank, S

    2016-01-01

    Well-balanced mitochondrial fission and fusion processes are essential for nervous system development. Loss of function of the main mitochondrial fission mediator, dynamin-related protein 1 (Drp1), is lethal early during embryonic development or around birth, but the role of mitochondrial fission in adult neurons remains unclear. Here we show that inducible Drp1 ablation in neurons of the adult mouse forebrain results in progressive, neuronal subtype-specific alterations of mitochondrial morphology in the hippocampus that are marginally responsive to antioxidant treatment. Furthermore, DRP1 loss affects synaptic transmission and memory function. Although these changes culminate in hippocampal atrophy, they are not sufficient to cause neuronal cell death within 10 weeks of genetic Drp1 ablation. Collectively, our in vivo observations clarify the role of mitochondrial fission in neurons, demonstrating that Drp1 ablation in adult forebrain neurons compromises critical neuronal functions without causing overt neurodegeneration. PMID:25909888

  14. Pregnenolone sulfate and its enantiomer: differential modulation of memory in a spatial discrimination task using forebrain NMDA receptor deficient mice

    PubMed Central

    Petit, Géraldine H.; Tobin, Christine; Krishnan, Kathiresan; Moricard, Yves; Covey, Douglas F.; Rondi-Reig, Laure; Akwa, Yvette

    2010-01-01

    This study examined the role of forebrain N-methyl-D-aspartate receptors (NMDA-Rs) in the promnesiant effects of natural (+) pregnenolone sulfate (PREGS) and its synthetic (−) enantiomer ent-PREGS in young adult mice. Using the two-trial arm discrimination task in a Y-maze, PREGS and ent-PREGS administration to control mice increased memory performances. In mice with a knock-out of the NR1 subunit of NMDA-Rs in the forebrain, the promnesiant effect of ent-PREGS was maintained whereas the activity of PREGS was lost. Memory enhancement by PREGS involves the NMDA-R activity in the hippocampal CA1 area and possibly in some locations of the cortical layers, whereas ent-PREGS acts independently of NMDA-R function. PMID:21036556

  15. Absence of Prenatal Forebrain Defects in the Dp(16)1Yey/+ Mouse Model of Down Syndrome

    PubMed Central

    Goodliffe, Joseph W.; Olmos-Serrano, Jose Luis; Aziz, Nadine M.; Pennings, Jeroen L.A.; Guedj, Faycal; Bianchi, Diana W.

    2016-01-01

    Studies in humans with Down syndrome (DS) show that alterations in fetal brain development are followed by postnatal deficits in neuronal numbers, synaptic plasticity, and cognitive and motor function. This same progression is replicated in several mouse models of DS. Dp(16)1Yey/+ (hereafter called Dp16) is a recently developed mouse model of DS in which the entire region of mouse chromosome 16 that is homologous to human chromosome 21 has been triplicated. As such, Dp16 mice may more closely reproduce neurodevelopmental changes occurring in humans with DS. Here, we present the first comprehensive cellular and behavioral study of the Dp16 forebrain from embryonic to adult stages. Unexpectedly, our results demonstrate that Dp16 mice do not have prenatal brain defects previously reported in human fetal neocortex and in the developing forebrains of other mouse models, including microcephaly, reduced neurogenesis, and abnormal cell proliferation. Nevertheless, we found impairments in postnatal developmental milestones, fewer inhibitory forebrain neurons, and deficits in motor and cognitive performance in Dp16 mice. Therefore, although this new model does not express prenatal morphological phenotypes associated with DS, abnormalities in the postnatal period appear sufficient to produce significant cognitive deficits in Dp16. SIGNIFICANCE STATEMENT Down syndrome (DS) leads to intellectual disability. Several mouse models have increased our understanding of the neuropathology of DS and are currently being used to test therapeutic strategies. A new mouse model that contains an expanded number of DS-related genes, known as Dp(16)1Yey/+ (Dp16), has been generated recently. We sought to determine whether the extended triplication creates a better phenocopy of DS-related brain pathologies. We measured embryonic development, forebrain maturation, and perinatal/adult behavior and revealed an absence of prenatal phenotypes in Dp16 fetal brain, but specific cellular and behavioral

  16. Forebrain-specific CRF overproduction during development is sufficient to induce enduring anxiety and startle abnormalities in adult mice.

    PubMed

    Toth, Mate; Gresack, Jodi E; Bangasser, Debra A; Plona, Zach; Valentino, Rita J; Flandreau, Elizabeth I; Mansuy, Isabelle M; Merlo-Pich, Emilio; Geyer, Mark A; Risbrough, Victoria B

    2014-05-01

    Corticotropin releasing factor (CRF) regulates physiological and behavioral responses to stress. Trauma in early life or adulthood is associated with increased CRF in the cerebrospinal fluid and heightened anxiety. Genetic variance in CRF receptors is linked to altered risk for stress disorders. Thus, both heritable differences and environmentally induced changes in CRF neurotransmission across the lifespan may modulate anxiety traits. To test the hypothesis that CRF hypersignaling is sufficient to modify anxiety-related phenotypes (avoidance, startle, and conditioned fear), we induced transient forebrain-specific overexpression of CRF (CRFOE) in mice (1) during development to model early-life stress, (2) in adulthood to model adult-onset stress, or (3) across the entire postnatal lifespan to model heritable increases in CRF signaling. The consequences of these manipulations on CRF peptide levels and behavioral responses were examined in adulthood. We found that transient CRFOE during development decreased startle habituation and prepulse inhibition, and increased avoidance (particularly in females) recapitulating the behavioral effects of lifetime CRFOE despite lower CRF peptide levels at testing. In contrast, CRFOE limited to adulthood reduced contextual fear learning in females and increased startle reactivity in males but did not change avoidance or startle plasticity. These findings suggest that forebrain CRFOE limited to development is sufficient to induce enduring alterations in startle plasticity and anxiety, while forebrain CRFOE during adulthood results in a different phenotype profile. These findings suggest that startle circuits are particularly sensitive to forebrain CRFOE, and that the impact of CRFOE may be dependent on the time of exposure. PMID:24326400

  17. Forebrain-Specific CRF Overproduction During Development is Sufficient to Induce Enduring Anxiety and Startle Abnormalities in Adult Mice

    PubMed Central

    Toth, Mate; Gresack, Jodi E; Bangasser, Debra A; Plona, Zach; Valentino, Rita J; Flandreau, Elizabeth I; Mansuy, Isabelle M; Merlo-Pich, Emilio; Geyer, Mark A; Risbrough, Victoria B

    2014-01-01

    Corticotropin releasing factor (CRF) regulates physiological and behavioral responses to stress. Trauma in early life or adulthood is associated with increased CRF in the cerebrospinal fluid and heightened anxiety. Genetic variance in CRF receptors is linked to altered risk for stress disorders. Thus, both heritable differences and environmentally induced changes in CRF neurotransmission across the lifespan may modulate anxiety traits. To test the hypothesis that CRF hypersignaling is sufficient to modify anxiety-related phenotypes (avoidance, startle, and conditioned fear), we induced transient forebrain-specific overexpression of CRF (CRFOE) in mice (1) during development to model early-life stress, (2) in adulthood to model adult-onset stress, or (3) across the entire postnatal lifespan to model heritable increases in CRF signaling. The consequences of these manipulations on CRF peptide levels and behavioral responses were examined in adulthood. We found that transient CRFOE during development decreased startle habituation and prepulse inhibition, and increased avoidance (particularly in females) recapitulating the behavioral effects of lifetime CRFOE despite lower CRF peptide levels at testing. In contrast, CRFOE limited to adulthood reduced contextual fear learning in females and increased startle reactivity in males but did not change avoidance or startle plasticity. These findings suggest that forebrain CRFOE limited to development is sufficient to induce enduring alterations in startle plasticity and anxiety, while forebrain CRFOE during adulthood results in a different phenotype profile. These findings suggest that startle circuits are particularly sensitive to forebrain CRFOE, and that the impact of CRFOE may be dependent on the time of exposure. PMID:24326400

  18. Gsx2 controls region-specific activation of neural stem cells and injury-induced neurogenesis in the adult subventricular zone

    PubMed Central

    López-Juárez, Alejandro; Howard, Jennifer; Ullom, Kristy; Howard, Lindsey; Grande, Andrew; Pardo, Andrea; Waclaw, Ronald; Sun, Yu-Yo; Yang, Dianer; Kuan, Chia-Yi; Campbell, Kenneth; Nakafuku, Masato

    2013-01-01

    Neural stem cells (NSCs) reside in widespread regions along the lateral ventricle and generate diverse olfactory bulb (OB) interneuron subtypes in the adult mouse brain. Molecular mechanisms underlying their regional diversity, however, are not well understood. Here we show that the homeodomain transcription factor Gsx2 plays a crucial role in the region-specific control of adult NSCs in both persistent and injury-induced neurogenesis. In the intact brain, Gsx2 is expressed in a regionally restricted subset of NSCs and promotes the activation and lineage progression of stem cells, thereby controlling the production of selective OB neuron subtypes. Moreover, Gsx2 is ectopically induced in damaged brains outside its normal expression domains and is required for injury-induced neurogenesis in the subventricular zone (SVZ). These results demonstrate that mobilization of adult NSCs is controlled in a region-specific manner and that distinct mechanisms operate in continuous and injury-induced neurogenesis in the adult brain. PMID:23723414

  19. ESC-Derived Basal Forebrain Cholinergic Neurons Ameliorate the Cognitive Symptoms Associated with Alzheimer's Disease in Mouse Models.

    PubMed

    Yue, Wei; Li, Yuanyuan; Zhang, Ting; Jiang, Man; Qian, Yun; Zhang, Min; Sheng, Nengyin; Feng, Su; Tang, Ke; Yu, Xiang; Shu, Yousheng; Yue, Chunmei; Jing, Naihe

    2015-11-10

    Degeneration of basal forebrain cholinergic neurons (BFCNs) is associated with cognitive impairments of Alzheimer's disease (AD), implying that BFCNs hold potentials in exploring stem cell-based replacement therapy for AD. However, studies on derivation of BFCNs from embryonic stem cells (ESCs) are limited, and the application of ESC-derived BFCNs remains to be determined. Here, we report on differentiation approaches for directing both mouse and human ESCs into mature BFCNs. These ESC-derived BFCNs exhibit features similar to those of their in vivo counterparts and acquire appropriate functional properties. After transplantation into the basal forebrain of AD model mice, ESC-derived BFCN progenitors predominantly differentiate into mature cholinergic neurons that functionally integrate into the endogenous basal forebrain cholinergic projection system. The AD mice grafted with mouse or human BFCNs exhibit improvements in learning and memory performances. Our findings suggest a promising perspective of ESC-derived BFCNs in the development of stem cell-based therapies for treatment of AD. PMID:26489896

  20. Targeted electroporation of defined lateral ventricular walls: a novel and rapid method to study fate specification during postnatal forebrain neurogenesis

    PubMed Central

    2011-01-01

    Background Postnatal olfactory bulb (OB) neurogenesis involves the generation of granule and periglomerular cells by neural stem cells (NSCs) located in the walls of the lateral ventricle (LV). Recent studies show that NSCs located in different regions of the LV give rise to different types of OB neurons. However, the molecular mechanisms governing neuronal specification remain largely unknown and new methods to approach these questions are needed. Results In this study, we refine electroporation of the postnatal forebrain as a technique to perform precise and accurate delivery of transgenes to NSCs located in distinct walls of the LV in the mouse. Using this method, we confirm and expand previous studies showing that NSCs in distinct walls of the LV produce neurons that invade different layers of the OB. Fate mapping of the progeny of radial glial cells located in these distinct LV walls reveals their specification into defined subtypes of granule and periglomerular neurons. Conclusions Our results provide a baseline with which future studies aiming at investigating the role of factors in postnatal forebrain neuronal specification can be compared. Targeted electroporation of defined LV NSC populations will prove valuable to study the genetic factors involved in forebrain neuronal specification. PMID:21466691

  1. Slit-Robo Signals Regulate Pioneer Axon Pathfinding of the Tract of the Postoptic Commissure in the Mammalian Forebrain

    PubMed Central

    Ricaño-Cornejo, Itzel; Altick, Amy L.; García-Peña, Claudia M.; Nural, Hikmet Feyza; Echevarría, Diego; Miquelajáuregui, Amaya; Mastick, Grant S.; Varela-Echavarría, Alfredo

    2014-01-01

    During early vertebrate forebrain development, pioneer axons establish a symmetrical scaffold descending longitudinally through the rostral forebrain, thus forming the tract of the postoptic commissure (TPOC). In mouse embryos, this tract begins to appear at embryonic day 9.5 (E9.5) as a bundle of axons tightly constrained at a specific dorsoventral level. We have characterized the participation of the Slit chemorepellants and their Robo receptors in the control of TPOC axon projection. In E9.5–E11.5 mouse embryos, Robo1 and Robo2 are expressed in the nucleus origin of the TPOC (nTPOC), and Slit expression domains flank the TPOC trajectory. These findings suggested that these proteins are important factors in the dorsoventral positioning of the TPOC axons. Consistently with this role, Slit2 inhibited TPOC axon growth in collagen gel cultures, and interfering with Robo function in cultured embryos induced projection errors in TPOC axons. Moreover, absence of both Slit1 and Slit2 or Robo1 and Robo2 in mutant mouse embryos revealed aberrant TPOC trajectories, resulting in abnormal spreading of the tract and misprojections into both ventral and dorsal tissues. These results reveal that Slit-Robo signaling regulates the dorsoventral position of this pioneer tract in the developing forebrain. PMID:21688288

  2. Post-Weaning, Forebrain-Specific Perturbation of the Oxytocin System Impairs Fear Conditioning

    PubMed Central

    Pagani, Jerome H.; Lee, Heon-Jin; Young, W. Scott

    2011-01-01

    Oxytocin (Oxt) and vasopressin (Avp) are important for a wide variety of behaviors and the use of transgenic mice lacking the peptides or their receptors, particularly when their loss is spatially and temporally manipulated, offers an opportunity to closely examine their role in a particular behavior. We used a cued fear conditioning paradigm to examine associative learning in three lines of transgenic mice: mice that constitutively lack vasopressin 1a (Avpr1a−/−) or Oxt receptors (Oxtr−/−) and mice that have oxytocin receptor loss restricted to the forebrain that begins post-weaning (OxtrFB/FB). Oxtr−/− and Avpr1a−/− mice have normal conditioned freezing. OxtrFB/FB mice have a reduction in freezing behavior during acquisition, as well as during context and cue retention. In addition to reduction of Oxtr in the central nucleus of the amygdala, in vitro receptor autoradiography revealed that the OxtrFB/FB mice have significantly reduced levels of Avpr1a only in that structure. Our results show that post-weaning alteration of the distribution of Oxtr receptors is critically important for fear behavior, an effect mirrored in the neural structures that mediate it. While constitutive knockouts of Oxtr and Avpr1a are useful for identifying the neural underpinnings of some behaviors, compensatory mechanisms within some circuits may obscure other behavioral roles. PMID:21668734

  3. Male song quality modulates c-Fos expression in the auditory forebrain of the female canary.

    PubMed

    Monbureau, Marie; Barker, Jennifer M; Leboucher, Gérard; Balthazart, Jacques

    2015-08-01

    In canaries, specific phrases of male song (sexy songs, SS) that are difficult to produce are especially attractive for females. Females exposed to SS produce more copulation displays and deposit more testosterone into their eggs than females exposed to non-sexy songs (NS). Increased expression of the immediate early genes c-Fos or zenk (a.k.a. egr-1) has been observed in the auditory forebrain of female songbirds hearing attractive songs. C-Fos immunoreactive (Fos-ir) cell numbers were quantified here in the brain of female canaries that had been collected 30min after they had been exposed for 60min to the playback of SS or NS or control white noise. Fos-ir cell numbers increased in the caudomedial mesopallium (CMM) and caudomedial nidopallium (NCM) of SS birds as compared to controls. Song playback (pooled SS and NS) also tended to increase average Fos-ir cell numbers in the mediobasal hypothalamus (MBH) but this effect did not reach full statistical significance. At the individual level, Fos expression in CMM was correlated with its expression in NCM and in MBH but also with the frequency of calls that females produced in response to the playbacks. These data thus indicate that male songs of different qualities induce a differential metabolic activation of NCM and CMM. The correlation between activation of auditory regions and of the MBH might reflect the link between auditory stimulation and changes in behavior and reproductive physiology. PMID:25846435

  4. Agonist mediated conformational changes of solubilized calf forebrain muscarinic acetylcholine receptors.

    PubMed

    Vanderheyden, P; Andre, C; de Backer, J P; Vauquelin, G

    1984-10-01

    Muscarinic receptors in calf forebrain membranes can be identified by the specific binding of the radiolabelled antagonist [3H]dexetimide. These receptors (2.8 pM/mg protein) comprise two non-interconvertible subpopulations with respectively high and low agonist affinity but with the same antagonist affinity. For all the agonists tested the low affinity sites represent 85 +/- 5% of the total receptor population. 0.5% Digitonin solubilized extracts contain 0.8 pM muscarinic receptor/mg protein. In contrast with the membranes, these extracts contain only sites with low agonist affinity. The alkylating reagent N-ethylmaleimide causes an increase of the acetylcholine affinity for the low affinity sites in membranes as well as for the solubilized sites. This effect is time dependent until a maximal 3-fold increase in affinity is attained. The rate of N-ethylmaleimide action is enhanced by the concomitant presence of agonists. In contrast, N-ethylmaleimide does not affect antagonist binding. This suggests that agonists mediate a conformational change of both the membrane bound low affinity muscarinic sites and of the solubilized sites, resulting in their increased susceptibility towards NEM alkylation. PMID:6487351

  5. Quantitative autoradiography of muscarinic and benzodiazepine receptors in the forebrain of the turtle, Pseudemys scripta

    SciTech Connect

    Schlegel, J.R.; Kriegstein, A.R.

    1987-11-22

    The distribution of muscarinic and benzodiazepine receptors was investigated in the turtle forebrain by the technique of in vitro receptor autoradiography. Muscarinic binding sites were labeled with 1 nM /sup 3/H-quinuclidinyl benzilate (/sup 3/H-QNB), and benzodiazepine sites were demonstrated with the aid of 1 nM /sup 3/H-flunitrazepam (/sup 3/H-FLU). Autoradiograms generated on /sup 3/H-Ultrofilm apposed to tissue slices revealed regionally specific distributions of muscarinic and benzodiazepine binding sites that are comparable with those for mammalian brain. Dense benzodiazepine binding was found in the anterior olfactory nucleus, the lateral and dorsal cortices, and the dorsal ventricular ridge (DVR), a structure with no clear mammalian homologue. Muscarinic binding sites were most dense in the striatum, accumbens, DVR, lateral geniculate, and the anterior olfactory nucleus. Cortical binding sites were studied in greater detail by quantitative analysis of autoradiograms generated by using emulsion-coated coverslips. Laminar gradients of binding were observed that were specific for each radioligand; /sup 3/H-QNB sites were most dense in the inner molecular layer in all cortical regions, whereas /sup 3/H-FLU binding was generally most concentrated in the outer molecular layer and was least dense through all layers in the dorsomedial cortex. Because pyramidal cells are arranged in register in turtle cortex, the laminar patterns of receptor binding may reflect different receptor density gradients along pyramidal cell dendrites.

  6. The Forebrain Song System Mediates Predictive Call Timing in Female and Male Zebra Finches.

    PubMed

    Benichov, Jonathan I; Benezra, Sam E; Vallentin, Daniela; Globerson, Eitan; Long, Michael A; Tchernichovski, Ofer

    2016-02-01

    The dichotomy between vocal learners and non-learners is a fundamental distinction in the study of animal communication. Male zebra finches (Taeniopygia guttata) are vocal learners that acquire a song resembling their tutors', whereas females can only produce innate calls. The acoustic structure of short calls, produced by both males and females, is not learned. However, these calls can be precisely coordinated across individuals. To examine how birds learn to synchronize their calls, we developed a vocal robot that exchanges calls with a partner bird. Because birds answer the robot with stereotyped latencies, we could program it to disrupt each bird's responses by producing calls that are likely to coincide with the bird's. Within minutes, the birds learned to avoid this disruptive masking (jamming) by adjusting the timing of their responses. Notably, females exhibited greater adaptive timing plasticity than males. Further, when challenged with complex rhythms containing jamming elements, birds dynamically adjusted the timing of their calls in anticipation of jamming. Blocking the song system cortical output dramatically reduced the precision of birds' response timing and abolished their ability to avoid jamming. Surprisingly, we observed this effect in both males and females, indicating that the female song system is functional rather than vestigial. We suggest that descending forebrain projections, including the song-production pathway, function as a general-purpose sensorimotor communication system. In the case of calls, it enables plasticity in vocal timing to facilitate social interactions, whereas in the case of songs, plasticity extends to developmental changes in vocal structure. PMID:26774786

  7. Disruption of auditory spatial working memory by inactivation of the forebrain archistriatum in barn owls.

    PubMed

    Knudsen, E I; Knudsen, P F

    1996-10-01

    Barn owls not only localize auditory stimuli with great accuracy, they also remember the locations of auditory stimuli and can use this remembered spatial information to guide their flight and strike. Although the mechanisms of sound localization have been studied extensively, the neurobiological basis of auditory spatial memory has not. Here we show that the ability of barn owls to orient their gaze towards and fly to the remembered location of auditory targets is lost during pharmacological inactivation of a small region in the forebrain, the anterior archistriatum. In contrast, archistriatal inactivation has no effect on stimulus-guided responses to auditory targets. The memory-dependent deficit is evident only for acoustic events that occur in the hemifield contralateral to the side that is inactivated. The data demonstrate that in the avian archistriatum, as in the mammalian frontal cortex, there exists a region that is essential for the expression of spatial working memory and that, in the barn owl, this region encodes auditory spatial memory. PMID:8837773

  8. Statistical learning of recurring sound patterns encodes auditory objects in songbird forebrain

    PubMed Central

    Lu, Kai; Vicario, David S.

    2014-01-01

    Auditory neurophysiology has demonstrated how basic acoustic features are mapped in the brain, but it is still not clear how multiple sound components are integrated over time and recognized as an object. We investigated the role of statistical learning in encoding the sequential features of complex sounds by recording neuronal responses bilaterally in the auditory forebrain of awake songbirds that were passively exposed to long sound streams. These streams contained sequential regularities, and were similar to streams used in human infants to demonstrate statistical learning for speech sounds. For stimulus patterns with contiguous transitions and with nonadjacent elements, single and multiunit responses reflected neuronal discrimination of the familiar patterns from novel patterns. In addition, discrimination of nonadjacent patterns was stronger in the right hemisphere than in the left, and may reflect an effect of top-down modulation that is lateralized. Responses to recurring patterns showed stimulus-specific adaptation, a sparsening of neural activity that may contribute to encoding invariants in the sound stream and that appears to increase coding efficiency for the familiar stimuli across the population of neurons recorded. As auditory information about the world must be received serially over time, recognition of complex auditory objects may depend on this type of mnemonic process to create and differentiate representations of recently heard sounds. PMID:25246563

  9. Characterization of the ubiquitin-modified proteome regulated by transient forebrain ischemia

    PubMed Central

    Iwabuchi, Masahiro; Sheng, Huaxin; Thompson, JWill; Wang, Liangli; Dubois, Laura G; Gooden, David; Moseley, MArthur; Paschen, Wulf; Yang, Wei

    2014-01-01

    Ubiquitylation is a posttranslational protein modification that modulates various cellular processes of key significance, including protein degradation and DNA damage repair. In animals subjected to transient cerebral ischemia, ubiquitin-conjugated proteins accumulate in Triton-insoluble aggregates. Although this process is widely considered to modulate the fate of postischemic neurons, few attempts have been made to characterize the ubiquitin-modified proteome in these aggregates. We performed proteomics analyses to identify ubiquitylated proteins in postischemic aggregates. Mice were subjected to 10 minutes of forebrain ischemia and 4 hours of reperfusion. The hippocampi were dissected, aggregates were isolated, and trypsin-digested after spiking with GG-BSA as internal standard. K-ɛ-GG-containing peptides were immunoprecipitated and analyzed by label-free quantitative liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis. We identified 1,664 peptides to 520 proteins containing at least one K-ɛ-GG. Sixty-six proteins were highly ubiquitylated, with 10 or more K-ɛ-GG peptides. Based on selection criteria of greater than fivefold increase and P<0.001, 763 peptides to 272 proteins were highly enriched in postischemic aggregates. These included proteins involved in important neuronal functions and signaling pathways that are impaired after ischemia. Results of this study could serve as an important platform to uncover the mechanisms linking insoluble ubiquitin aggregates to the functions of postischemic neurons. PMID:24301296

  10. Mitochondrial DNA Toxicity in Forebrain Neurons Causes Apoptosis, Neurodegeneration, and Impaired Behavior ▿

    PubMed Central

    Lauritzen, Knut H.; Moldestad, Olve; Eide, Lars; Carlsen, Harald; Nesse, Gaute; Storm, Johan F.; Mansuy, Isabelle M.; Bergersen, Linda H.; Klungland, Arne

    2010-01-01

    Mitochondrial dysfunction underlying changes in neurodegenerative diseases is often associated with apoptosis and a progressive loss of neurons, and damage to the mitochondrial genome is proposed to be involved in such pathologies. In the present study we designed a mouse model that allows us to specifically induce mitochondrial DNA toxicity in the forebrain neurons of adult mice. This is achieved by CaMKIIα-regulated inducible expression of a mutated version of the mitochondrial UNG DNA repair enzyme (mutUNG1). This enzyme is capable of removing thymine from the mitochondrial genome. We demonstrate that a continual generation of apyrimidinic sites causes apoptosis and neuronal death. These defects are associated with behavioral alterations characterized by increased locomotor activity, impaired cognitive abilities, and lack of anxietylike responses. In summary, whereas mitochondrial base substitution and deletions previously have been shown to correlate with premature and natural aging, respectively, we show that a high level of apyrimidinic sites lead to mitochondrial DNA cytotoxicity, which causes apoptosis, followed by neurodegeneration. PMID:20065039

  11. Age-related deficits in a forebrain-dependent task, trace-eyeblink conditioning

    PubMed Central

    Galvez, Roberto; Cua, Sabrina; Disterhoft, John F.

    2009-01-01

    Trace-eyeblink conditioning is a forebrain-dependent learning paradigm that has assisted in our understanding of age-related hippocampal neuronal plasticity; however, the hippocampus is not believed to be the permanent site for most long-term-memory storage. Studies in adult subjects have suggested the neocortex as one such site. Whisker plucking studies have further suggested that the ability for plasticity in the neocortex declines with age. Mice were trained in trace- and delay-eyeblink conditioning with whisker or auditory stimulation as the conditioned stimulus to examine possible age-related behavioral and neocortical abnormalities. Whisker stimulation was determined to be a more effective stimulus for examining age-related behavioral abnormalities in C57 mice. Additionally, neocortical barrel expansion, observed in trace conditioned adult mice and rabbits, does not occur in mice conditioned on a delay paradigm or in old mice unable to learn the whisker trace association. Abnormalities in neocortical memory storage in the elderly could contribute to normal age-dependent declines in associative learning abilities. PMID:20018411

  12. Statistical learning of recurring sound patterns encodes auditory objects in songbird forebrain.

    PubMed

    Lu, Kai; Vicario, David S

    2014-10-01

    Auditory neurophysiology has demonstrated how basic acoustic features are mapped in the brain, but it is still not clear how multiple sound components are integrated over time and recognized as an object. We investigated the role of statistical learning in encoding the sequential features of complex sounds by recording neuronal responses bilaterally in the auditory forebrain of awake songbirds that were passively exposed to long sound streams. These streams contained sequential regularities, and were similar to streams used in human infants to demonstrate statistical learning for speech sounds. For stimulus patterns with contiguous transitions and with nonadjacent elements, single and multiunit responses reflected neuronal discrimination of the familiar patterns from novel patterns. In addition, discrimination of nonadjacent patterns was stronger in the right hemisphere than in the left, and may reflect an effect of top-down modulation that is lateralized. Responses to recurring patterns showed stimulus-specific adaptation, a sparsening of neural activity that may contribute to encoding invariants in the sound stream and that appears to increase coding efficiency for the familiar stimuli across the population of neurons recorded. As auditory information about the world must be received serially over time, recognition of complex auditory objects may depend on this type of mnemonic process to create and differentiate representations of recently heard sounds. PMID:25246563

  13. Regulation of GABA and benzodiazepine receptors following neurotoxin-induced striatal and medial forebrain bundle lesions

    SciTech Connect

    Pan, H.S.I.

    1985-01-01

    GABA, a major inhibitory transmitter, is used by many projection neurons of the striatum. To investigate the role of GABA in striatal function, the GABA receptor complex was studied after lesions of the striatum or the nigrostriatal neurons. Quantitative receptor autoradiography using thaw-mounted tissue slices was developed for the study of GABA and benzodiazepine (BDZ) receptors. With the technique established, binding to GABA and BDZ receptors after unilateral striatal kainate lesions was examined. Subsequently, changes in GABA and BDZ receptors were studied following the destruction of dopaminergic nigrostriatal cells by unilateral 6-hydroxydopamine lesion of the medial forebrain bundle. In summary, quantitative receptor autoradiography allowed the detection of GABA and BDZ receptor changes in multiple small areas in each lesioned brain. This technique made it feasible to carry out kinetic saturation, and competition studies using less than 1 mg of tissue. The data suggest that dopamine is functionally inhibitory on striatopallidal neurons but is functionally excitatory on striatoentopeduncular and striatonigral cells which in turn inhibit the thalamus. This quantitative autoradiographic technique can be generalized to study other transmitter receptors and can be combined with 2-deoxyglucose uptake studies.

  14. Selective activation of cholinergic basal forebrain neurons induces immediate sleep-wake transitions.

    PubMed

    Han, Yong; Shi, Yu-feng; Xi, Wang; Zhou, Rui; Tan, Zhi-bing; Wang, Hao; Li, Xiao-ming; Chen, Zhong; Feng, Guoping; Luo, Minmin; Huang, Zhi-li; Duan, Shumin; Yu, Yan-qin

    2014-03-17

    The basal forebrain (BF) plays a crucial role in cortical activation [1, 2]. However, the exact role of cholinergic BF (ch-BF) neurons in the sleep-wake cycle remains unclear [3, 4]. We demonstrated that photostimulation of ch-BF neurons genetically targeted with channelrhodopsin 2 (ChR2) was sufficient to induce an immediate transition to waking or rapid eye movement (REM) sleep from slow-wave sleep (SWS). Light stimulation was most likely to induce behavioral arousal during SWS, but not during REM sleep, a result in contrast to the previously reported photostimulation of noradrenergic or hypocretin neurons that induces wake transitions from both SWS and REM sleep. Furthermore, the ratio of light-induced transitions from SWS to wakefulness or to REM sleep did not significantly differ from that of natural transitions, suggesting that activation of ch-BF neurons facilitates the transition from SWS but does not change the direction of the transition. Excitation of ch-BF neurons during wakefulness or REM sleep sustained the cortical activation. Stimulation of these neurons for 1 hr induced a delayed increase in the duration of wakefulness in the subsequent inactive period. Our results suggest that activation of ch-BF neurons alone is sufficient to suppress SWS and promote wakefulness and REM sleep. PMID:24613308

  15. Birds have primate-like numbers of neurons in the forebrain

    PubMed Central

    Olkowicz, Seweryn; Kocourek, Martin; Lučan, Radek K.; Porteš, Michal; Fitch, W. Tecumseh; Herculano-Houzel, Suzana; Němec, Pavel

    2016-01-01

    Some birds achieve primate-like levels of cognition, even though their brains tend to be much smaller in absolute size. This poses a fundamental problem in comparative and computational neuroscience, because small brains are expected to have a lower information-processing capacity. Using the isotropic fractionator to determine numbers of neurons in specific brain regions, here we show that the brains of parrots and songbirds contain on average twice as many neurons as primate brains of the same mass, indicating that avian brains have higher neuron packing densities than mammalian brains. Additionally, corvids and parrots have much higher proportions of brain neurons located in the pallial telencephalon compared with primates or other mammals and birds. Thus, large-brained parrots and corvids have forebrain neuron counts equal to or greater than primates with much larger brains. We suggest that the large numbers of neurons concentrated in high densities in the telencephalon substantially contribute to the neural basis of avian intelligence. PMID:27298365

  16. Birds have primate-like numbers of neurons in the forebrain.

    PubMed

    Olkowicz, Seweryn; Kocourek, Martin; Lučan, Radek K; Porteš, Michal; Fitch, W Tecumseh; Herculano-Houzel, Suzana; Němec, Pavel

    2016-06-28

    Some birds achieve primate-like levels of cognition, even though their brains tend to be much smaller in absolute size. This poses a fundamental problem in comparative and computational neuroscience, because small brains are expected to have a lower information-processing capacity. Using the isotropic fractionator to determine numbers of neurons in specific brain regions, here we show that the brains of parrots and songbirds contain on average twice as many neurons as primate brains of the same mass, indicating that avian brains have higher neuron packing densities than mammalian brains. Additionally, corvids and parrots have much higher proportions of brain neurons located in the pallial telencephalon compared with primates or other mammals and birds. Thus, large-brained parrots and corvids have forebrain neuron counts equal to or greater than primates with much larger brains. We suggest that the large numbers of neurons concentrated in high densities in the telencephalon substantially contribute to the neural basis of avian intelligence. PMID:27298365

  17. Distinct roles of basal forebrain cholinergic neurons in spatial and object recognition memory

    PubMed Central

    Okada, Kana; Nishizawa, Kayo; Kobayashi, Tomoko; Sakata, Shogo; Kobayashi, Kazuto

    2015-01-01

    Recognition memory requires processing of various types of information such as objects and locations. Impairment in recognition memory is a prominent feature of amnesia and a symptom of Alzheimer’s disease (AD). Basal forebrain cholinergic neurons contain two major groups, one localized in the medial septum (MS)/vertical diagonal band of Broca (vDB), and the other in the nucleus basalis magnocellularis (NBM). The roles of these cell groups in recognition memory have been debated, and it remains unclear how they contribute to it. We use a genetic cell targeting technique to selectively eliminate cholinergic cell groups and then test spatial and object recognition memory through different behavioural tasks. Eliminating MS/vDB neurons impairs spatial but not object recognition memory in the reference and working memory tasks, whereas NBM elimination undermines only object recognition memory in the working memory task. These impairments are restored by treatment with acetylcholinesterase inhibitors, anti-dementia drugs for AD. Our results highlight that MS/vDB and NBM cholinergic neurons are not only implicated in recognition memory but also have essential roles in different types of recognition memory. PMID:26246157

  18. Cognitive Correlates of Basal Forebrain Atrophy and Associated Cortical Hypometabolism in Mild Cognitive Impairment.

    PubMed

    Grothe, Michel J; Heinsen, Helmut; Amaro, Edson; Grinberg, Lea T; Teipel, Stefan J

    2016-06-01

    Degeneration of basal forebrain (BF) cholinergic nuclei is associated with cognitive decline, and this effect is believed to be mediated by neuronal dysfunction in the denervated cortical areas. MRI-based measurements of BF atrophy are increasingly being used as in vivo surrogate markers for cholinergic degeneration, but the functional implications of reductions in BF volume are not well understood. We used high-resolution MRI, fluorodeoxyglucose-positron emission tomography (PET), and neuropsychological test data of 132 subjects with mild cognitive impairment (MCI) and 177 cognitively normal controls to determine associations between BF atrophy, cortical hypometabolism, and cognitive deficits. BF atrophy in MCI correlated with both impaired memory function and attentional control deficits, whereas hippocampus volume was more specifically associated with memory deficits. BF atrophy was also associated with widespread cortical hypometabolism, and path analytic models indicated that hypometabolism in domain-specific cortical networks mediated the association between BF volume and cognitive dysfunction. The presence of cortical amyloid pathology, as assessed using AV45-PET, did not significantly interact with the observed associations. These data underline the potential of multimodal imaging markers to study structure-function-cognition relationships in the living human brain and provide important in vivo evidence for an involvement of the human BF in cortical activity and cognitive function. PMID:25840425

  19. Basal forebrain motivational salience signal enhances cortical processing and decision speed.

    PubMed

    Raver, Sylvina M; Lin, Shih-Chieh

    2015-01-01

    The basal forebrain (BF) contains major projections to the cerebral cortex, and plays a well-documented role in arousal, attention, decision-making, and in modulating cortical activity. BF neuronal degeneration is an early event in Alzheimer's disease (AD) and dementias, and occurs in normal cognitive aging. While the BF is best known for its population of cortically projecting cholinergic neurons, the region is anatomically and neurochemically diverse, and also contains prominent populations of non-cholinergic projection neurons. In recent years, increasing attention has been dedicated to these non-cholinergic BF neurons in order to better understand how non-cholinergic BF circuits control cortical processing and behavioral performance. In this review, we focus on a unique population of putative non-cholinergic BF neurons that encodes the motivational salience of stimuli with a robust ensemble bursting response. We review recent studies that describe the specific physiological and functional characteristics of these BF salience-encoding neurons in behaving animals. These studies support the unifying hypothesis whereby BF salience-encoding neurons act as a gain modulation mechanism of the decision-making process to enhance cortical processing of behaviorally relevant stimuli, and thereby facilitate faster and more precise behavioral responses. This function of BF salience-encoding neurons represents a critical component in determining which incoming stimuli warrant an animal's attention, and is therefore a fundamental and early requirement of behavioral flexibility. PMID:26528157

  20. Basal forebrain motivational salience signal enhances cortical processing and decision speed

    PubMed Central

    Raver, Sylvina M.; Lin, Shih-Chieh

    2015-01-01

    The basal forebrain (BF) contains major projections to the cerebral cortex, and plays a well-documented role in arousal, attention, decision-making, and in modulating cortical activity. BF neuronal degeneration is an early event in Alzheimer’s disease (AD) and dementias, and occurs in normal cognitive aging. While the BF is best known for its population of cortically projecting cholinergic neurons, the region is anatomically and neurochemically diverse, and also contains prominent populations of non-cholinergic projection neurons. In recent years, increasing attention has been dedicated to these non-cholinergic BF neurons in order to better understand how non-cholinergic BF circuits control cortical processing and behavioral performance. In this review, we focus on a unique population of putative non-cholinergic BF neurons that encodes the motivational salience of stimuli with a robust ensemble bursting response. We review recent studies that describe the specific physiological and functional characteristics of these BF salience-encoding neurons in behaving animals. These studies support the unifying hypothesis whereby BF salience-encoding neurons act as a gain modulation mechanism of the decision-making process to enhance cortical processing of behaviorally relevant stimuli, and thereby facilitate faster and more precise behavioral responses. This function of BF salience-encoding neurons represents a critical component in determining which incoming stimuli warrant an animal’s attention, and is therefore a fundamental and early requirement of behavioral flexibility. PMID:26528157

  1. Overexpression of SIRT1 in Mouse Forebrain Impairs Lipid/Glucose Metabolism and Motor Function

    PubMed Central

    Wu, Dongmei; Qiu, Yifu; Gao, Xiang; Yuan, Xiao-Bing; Zhai, Qiwei

    2011-01-01

    SIRT1 plays crucial roles in glucose and lipid metabolism, and has various functions in different tissues including brain. The brain-specific SIRT1 knockout mice display defects in somatotropic signaling, memory and synaptic plasticity. And the female mice without SIRT1 in POMC neuron are more sensitive to diet-induced obesity. Here we created transgenic mice overexpressing SIRT1 in striatum and hippocampus under the control of CaMKIIα promoter. These mice, especially females, exhibited increased fat accumulation accompanied by significant upregulation of adipogenic genes in white adipose tissue. Glucose tolerance of the mice was also impaired with decreased Glut4 mRNA levels in muscle. Moreover, the SIRT1 overexpressing mice showed decreased energy expenditure, and concomitantly mitochondria-related genes were decreased in muscle. In addition, these mice showed unusual spontaneous physical activity pattern, decreased activity in open field and rotarod performance. Further studies demonstrated that SIRT1 deacetylated IRS-2, and upregulated phosphorylation level of IRS-2 and ERK1/2 in striatum. Meanwhile, the neurotransmitter signaling in striatum and the expression of endocrine hormones in hypothalamus and serum T3, T4 levels were altered. Taken together, our findings demonstrate that SIRT1 in forebrain regulates lipid/glucose metabolism and motor function. PMID:21738790

  2. Inter-tissue networks between the basal forebrain, hippocampus, and prefrontal cortex in a model for depression caused by disturbed sleep.

    PubMed

    Lagus, Markus; Gass, Natalia; Saharinen, Juha; Savelyev, Sergey; Porkka-Heiskanen, Tarja; Paunio, Tiina

    2012-09-01

    Disturbances in sleep are encountered in the majority of patients with depressive disorder. To elucidate the molecular mechanisms behind this relationship, we examined gene expression changes in a rodent model for disturbed sleep and depression. The animals were treated with daily injections of clomipramine to affect their sleep during early infancy. This early interference with sleep is known to induce depression-like behavior in adult animals. After 2 weeks of treatment, the change in gene expression was examined using the Affymetrix Rat 230.2 chip. We studied the gene expression in the basal forebrain, hippocampus, and frontal cortex and combined the results to reveal the otherwise indissectible networks between and around the tissues. The major disrupted pathways between the three brain areas were related to synaptic transmission, regulation of translation, and ubiquitinylation. The involved pathways were within the cellular components of the axons, growth cones, melanosomes, and pigment granules. A network analysis allowing for additional interactors, in the form of chemicals or gene products, revealed a disturbed communicational network between the different brain areas. This disturbed network is centered around serotonin, Mn(II), and Rhoa. The findings elucidate inter-tissue pathways and networks in the brain that are involved in sleep and mood regulation. The findings are of uttermost interest, some are quite predictable and obvious, but some are novel or have only been proposed by rare theoretical speculations (such as the melanosome and Mn(II) involvement). Equally important as the findings are the methods described in this article. In this study, we present two novel simple ways to perform system biological analysis based on gene expression array data. We used two already existing tools in a new way, and by careful planning of the input data, managed to extrapolate intricate hidden inter-tissue networks to build a molecular picture of disease. PMID

  3. The 6-OHDA mouse model of Parkinson's disease - Terminal striatal lesions provide a superior measure of neuronal loss and replacement than median forebrain bundle lesions.

    PubMed

    Bagga, V; Dunnett, S B; Fricker, R A

    2015-07-15

    Unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway produce side-biased motor impairments that reflect the motor deficits seen in Parkinson's disease (PD). This toxin-induced model in the rat has been used widely, to evaluate possible therapeutic strategies, but has not been well established in mice. With the advancements in mouse stem cell research we believe the requirement for a mouse model is essential for the therapeutic potential of these and other mouse-derived cells to be efficiently assessed. This aim of this study focused on developing a mouse model of PD using the 129 P2/OLA Hsd mouse strain as this is widely used in the generation of mouse embryonic stem cells. Both unilateral 6-OHDA medial forebrain bundle (MFB) and striatal lesion protocols were compared, with mice analysed for appropriate drug-induced rotational bias. Results demonstrated that lesioned mice responded to d-amphetamine with peak rotation dose at 5mg/kg and 10mg/kg for MFB and striatal lesions respectively. Apomorphine stimulation produced no significant rotational responses, at any dose, in either the MFB or striatal 6-OHDA lesioned mice. Analysis of dopamine neuron loss revealed that the MFB lesion was unreliable with little correlation between dopamine neuron loss and rotational asymmetry. Striatal lesions however were more reliable, with a strong correlation between dopamine neuron loss and rotational asymmetry. Functional recovery of d-amphetamine-induced rotational bias was shown following transplantation of E13 mouse VM tissue into the lesioned striatum; confirming the validity of this mouse model. PMID:25841616

  4. Leptin acts in the forebrain to differentially influence baroreflex control of lumbar, renal, and splanchnic sympathetic nerve activity and heart rate.

    PubMed

    Li, Baoxin; Shi, Zhigang; Cassaglia, Priscila A; Brooks, Virginia L

    2013-04-01

    Although leptin is known to increase sympathetic nerve activity (SNA), we tested the hypothesis that leptin also enhances baroreflex control of SNA and heart rate (HR). Using α-chloralose anesthetized male rats, mean arterial pressure (MAP), HR, lumbar SNA (LSNA), splanchnic SNA (SSNA), and renal SNA (RSNA) were recorded before and for 2 hours after lateral cerebroventricular leptin or artificial cerebrospinal fluid administration. Baroreflex function was assessed using a 4-parameter sigmoidal fit of HR and SNA responses to slow ramp (3-5 minutes) changes in MAP, induced by intravenous infusion of nitroprusside and phenylephrine. Leptin (3 μg) increased (P<0.05) basal LSNA, SSNA, RSNA, HR, and MAP, and the LSNA, SSNA, RSNA, and HR baroreflex maxima. Leptin also increased gain of baroreflex control of LSNA and RSNA, but not of SSNA or HR. The elevations in HR were eliminated by pretreatment with methscopalamine, to block parasympathetic nerve activity; however, after cardiac sympathetic blockade with atenolol, leptin still increased basal HR and MAP and the HR baroreflex maximum and minimum. Leptin (1.5 μg) also increased LSNA and enhanced LSNA baroreflex gain and maximum, but did not alter MAP, HR, or the HR baroreflex. Lateral cerebroventricular artificial cerebrospinal fluid had no effects. Finally, to test whether leptin acts in the brain stem, leptin (3 μg) was infused into the 4th ventricle; however, no significant changes were observed. In conclusion, leptin acts in the forebrain to differentially influence baroreflex control of LSNA, RSNA, SSNA, and HR, with the latter action mediated via suppression of parasympathetic nerve activity. PMID:23424232

  5. The role of basal forebrain cholinergic neurons in fear and extinction memory.

    PubMed

    Knox, Dayan

    2016-09-01

    Cholinergic input to the neocortex, dorsal hippocampus (dHipp), and basolateral amygdala (BLA) is critical for neural function and synaptic plasticity in these brain regions. Synaptic plasticity in the neocortex, dHipp, ventral Hipp (vHipp), and BLA has also been implicated in fear and extinction memory. This finding raises the possibility that basal forebrain (BF) cholinergic neurons, the predominant source of acetylcholine in these brain regions, have an important role in mediating fear and extinction memory. While empirical studies support this hypothesis, there are interesting inconsistencies among these studies that raise questions about how best to define the role of BF cholinergic neurons in fear and extinction memory. Nucleus basalis magnocellularis (NBM) cholinergic neurons that project to the BLA are critical for fear memory and contextual fear extinction memory. NBM cholinergic neurons that project to the neocortex are critical for cued and contextual fear conditioned suppression, but are not critical for fear memory in other behavioral paradigms and in the inhibitory avoidance paradigm may even inhibit contextual fear memory formation. Medial septum and diagonal band of Broca cholinergic neurons are critical for contextual fear memory and acquisition of cued fear extinction. Thus, even though the results of previous studies suggest BF cholinergic neurons modulate fear and extinction memory, inconsistent findings among these studies necessitates more research to better define the neural circuits and molecular processes through which BF cholinergic neurons modulate fear and extinction memory. Furthermore, studies determining if BF cholinergic neurons can be manipulated in such a manner so as to treat excessive fear in anxiety disorders are needed. PMID:27264248

  6. Higher sensitivity to cadmium induced cell death of basal forebrain cholinergic neurons: a cholinesterase dependent mechanism.

    PubMed

    Del Pino, Javier; Zeballos, Garbriela; Anadon, María José; Capo, Miguel Andrés; Díaz, María Jesús; García, Jimena; Frejo, María Teresa

    2014-11-01

    Cadmium is an environmental pollutant, which is a cause of concern because it can be greatly concentrated in the organism causing severe damage to a variety of organs including the nervous system which is one of the most affected. Cadmium has been reported to produce learning and memory dysfunctions and Alzheimer like symptoms, though the mechanism is unknown. On the other hand, cholinergic system in central nervous system (CNS) is implicated on learning and memory regulation, and it has been reported that cadmium can affect cholinergic transmission and it can also induce selective toxicity on cholinergic system at peripheral level, producing cholinergic neurons loss, which may explain cadmium effects on learning and memory processes if produced on central level. The present study is aimed at researching the selective neurotoxicity induced by cadmium on cholinergic system in CNS. For this purpose we evaluated, in basal forebrain region, the cadmium toxic effects on neuronal viability and the cholinergic mechanisms related to it on NS56 cholinergic mourine septal cell line. This study proves that cadmium induces a more pronounced, but not selective, cell death on acetylcholinesterase (AChE) on cholinergic neurons. Moreover, MTT and LDH assays showed a dose dependent decrease of cell viability in NS56 cells. The ACh treatment of SN56 cells did not revert cell viability reduction induced by cadmium, but siRNA transfection against AChE partially reduced it. Our present results provide new understanding of the mechanisms contributing to the harmful effects of cadmium on the function and viability of neurons, and the possible relevance of cadmium in the pathogenesis of neurodegenerative diseases. PMID:25201352

  7. Opiate modulation of monoamines in the chick forebrain: possible role in emotional regulation?

    PubMed

    Baldauf, K; Braun, K; Gruss, M

    2005-02-01

    Numerous studies have shown that the opiate system is crucially involved in emotionally guided behavior. In the present study, we focussed on the medio-rostral neostriatum/hyperstriatum ventrale (MNH) of the chick forebrain. This avian prefrontal cortex analogue is critically involved in auditory filial imprinting, a well-characterized juvenile emotional learning event. The high density of mu-opiate receptors expressed in the MNH led to the hypothesis that mu-opiate receptor-mediated processes may modulate the glutamatergic, dopaminergic, and/or serotonergic neurotransmission within the MNH and thereby have a critical impact on filial imprinting. Using microdialysis and pharmaco-behavioral approaches in young chicks, we demonstrated that: the systemic application of the mu-opiate receptor antagonist naloxone (5, 50 mg/kg) significantly increased extracellular levels of 5-HIAA and HVA; the systemic application of the specific mu-opiate receptor agonist DAGO (5 mg/kg) increased the levels of HVA and taurine, an effect that was antagonized by simultaneously applied naloxone (5 mg/kg); the local application of DAGO (1 mM) had no effects on 5-HIAA, HVA, glutamate, and taurine, however, the effects of systemically injected naloxone (5 mg/kg) were abolished by simultaneously applied DAGO (1 mM); the systemic application of naloxone (5 mg/kg) increased distress behavior (measured as the duration of distress vocalization during separation from the peer group). These results are in line with our hypothesis that the mu-opiate receptor-mediated modulation of serotonergic and dopaminergic neurotransmission alters the emotional and motivational status of the animal and thereby may play a modulatory role during filial imprinting in the newborn animal. PMID:15452850

  8. Active recognition enhances the representation of behaviorally relevant information in single auditory forebrain neurons

    PubMed Central

    Knudsen, Daniel P.

    2013-01-01

    Sensory systems are dynamic. They must process a wide range of natural signals that facilitate adaptive behaviors in a manner that depends on an organism's constantly changing goals. A full understanding of the sensory physiology that underlies adaptive natural behaviors must therefore account for the activity of sensory systems in light of these behavioral goals. Here we present a novel technique that combines in vivo electrophysiological recording from awake, freely moving songbirds with operant conditioning techniques that allow control over birds' recognition of conspecific song, a widespread natural behavior in songbirds. We show that engaging in a vocal recognition task alters the response properties of neurons in the caudal mesopallium (CM), an avian analog of mammalian auditory cortex, in European starlings. Compared with awake, passive listening, active engagement of subjects in an auditory recognition task results in neurons responding to fewer song stimuli and a decrease in the trial-to-trial variability in their driven firing rates. Mean firing rates also change during active recognition, but not uniformly. Relative to nonengaged listening, active recognition causes increases in the driven firing rates in some neurons, decreases in other neurons, and stimulus-specific changes in other neurons. These changes lead to both an increase in stimulus selectivity and an increase in the information conveyed by the neurons about the animals' behavioral task. This study demonstrates the behavioral dependence of neural responses in the avian auditory forebrain and introduces the starling as a model for real-time monitoring of task-related neural processing of complex auditory objects. PMID:23303858

  9. Morphological characteristics of eosinophilic neuronal death after transient unilateral forebrain ischemia in Mongolian gerbils.

    PubMed

    Shen, Yanling; Wang, Zongli; Li, Fuying; Sun, Liyuan

    2016-06-01

    Various types of eosinophilic neurons (ENs) are found in the post-ischemic brain. The aim of the present study was to elucidate the temporal and spatial profile of ENs, the expression of TUNEL staining and ultrastructural characteristics in the core and peripheral regions of the cortex post-ischemia. Unilateral forebrain ischemia was induced in Mongolian gerbils by transient common carotid artery occlusions, and the brains from 3 h to 2 weeks post-ischemia were prepared for morphometric, electron microscopy (EM) and TUNEL staining of the ENs. Light microscopy showed that ENs with minimally abnormal nuclei and swollen cell bodies appeared at 3 h in the ischemic core and at 12 h in the periphery. Thereafter, ENs with pyknosis and irregular atrophic cytoplasm peaked at 12 h, pyknosis with scant cytoplasm peaked at 4 days, and TUNEL-positive staining was observed in the ischemic core. In the ischemic periphery, ENs had slightly atrophic cytoplasm and sequentially developed pyknosis, karyorrhexis and karyolysis over 1 week. These cells were also positive for TUNEL. In EM, severe organelle dilation and vacuolization preceded chromatin fragmentation in the ischemic core, while chromatin fragmentation and homogenization were the vital characteristics in the ischemic periphery. There might be two region-dependent pathways for EN changes in the post-ischemic brain: pyknosis with cytoplasmic shrinkage in the core and nuclear disintegration with slightly atrophic cytoplasm in the periphery. These pathways were comparable to necrosis and proceeded from non-classical apoptosis to necrosis, respectively. PMID:26607557

  10. Forebrain networks and the control of feeding by environmental learned cues

    PubMed Central

    Petrovich, Gorica D.

    2013-01-01

    The motivation to eat is driven by a complex sum of physiological and non-physiological influences computed by the brain. Physiological signals that inform the brain about energy and nutrient needs are the primary drivers, but environmental signals unrelated to energy balance also control appetite and eating. The two components could act in concert to support the homeostatic regulation of food intake. Often, however, environmental influences rival physiological control and stimulate eating irrespective of satiety, or inhibit eating irrespective of hunger. If persistent, such maladaptive challenges to the physiological system could lead to dysregulated eating and ultimately to eating disorders. Nevertheless, the brain mechanisms underlying environmental contribution in the control of food intake are poorly understood. This paper provides an overview in recent advances in deciphering the critical brain systems using rodent models for environmental control by learned cues. These models use associative learning to compete with the physiological control, and in one preparation food cues stimulate a meal despite satiety, while in another preparation fear cues stop a meal despite hunger. Thus far, four forebrain regions have been identified as part of the essential cue induced feeding circuitry. These are telencephalic areas critical for associative learning, memory encoding, and decision making, the amygdala, hippocampus and prefrontal cortex and the lateral hypothalamus, which functions to integrate feeding, reward, and motivation. This circuitry also engages two orexigenic peptides, ghrelin and orexin. A parallel amygdalar circuitry supports fear cue cessation of feeding. These findings illuminate the brain mechanisms underlying environmental control of food intake and might be also relevant to aspects of human appetite and maladaptive overeating and undereating. PMID:23562305

  11. Vascular endothelial growth factor (VEGF) isoform regulation of early forebrain development

    PubMed Central

    Darland, Diane C.; Cain, Jacob T.; Berosik, Matthew A.; Saint-Geniez, Magali; Odens, Patrick W.; Schaubhut, Geoffrey J.; Frisch, Sarah; Stemmer-Rachamimov, Anat; Darland, Tristan; D’Amore, Patricia A.

    2011-01-01

    This work was designed to determine the role of the vascular endothelial growth factor A (VEGF) isoforms during early neuroepithelial development in the mammalian central nervous system (CNS), specifically in the forebrain. An emerging model of interdependence between neural and vascular systems includes VEGF, with its dual roles as a potent angiogenesis factor and neural regulator. Although a number of studies have implicated VEGF in CNS development, little is known about the role that the different VEGF isoforms play in early neurogenesis. We used a mouse model of disrupted VEGF isoform expression that eliminates the predominant brain isoform, VEGF164, and expresses only the diffusible form, VEGF120. We tested the hypothesis that VEGF164 plays a key role in controlling neural precursor populations in developing cortex. We used microarray analysis to compare gene expression differences between wild type and VEGF120 mice at E9.5, the primitive stem cell stage of the neuroepithelium. We quantified changes in PHH3-positive nuclei, neural stem cell markers (Pax6 and nestin) and the Tbr2-positive intermediate progenitors at E11.5 when the neural precursor population is expanding rapidly. Absence of VEGF164 (and VEGF188) leads to reduced proliferation without an apparent effect on the number of Tbr2-positive cells. There is a corresponding reduction in the number of mitotic spindles that are oriented parallel to the ventricular surface relative to those with a vertical or oblique angle. These results support a role for the VEGF isoforms in supporting the neural precursor population of the early neuroepithelium. PMID:21803034

  12. Contribution of genoarchitecture to understanding forebrain evolution and development, with particular emphasis on the amygdala.

    PubMed

    Medina, Loreta; Bupesh, Munisamy; Abellán, Antonio

    2011-01-01

    The amygdala is a forebrain center involved in functions and behaviors that are critical for survival (such as control of the neuroendocrine system and homeostasis, and reproduction and fear/escape responses) and in cognitive functions such as attention and emotional learning. In mammals, the amygdala is highly complex, with multiple subdivisions, neuronal subtypes, and connections, making it very difficult to understand its functional organization and evolutionary origin. Since evolution is the consequence of changes that occurred in development, herein we review developmental data based on genoarchitecture and fate mapping in mammals (in the mouse model) and other vertebrates in order to identify its basic components and embryonic origin in different species and understand how they changed in evolution. In all tetrapods studied, the amygdala includes at least 4 components: (1) a ventral pallial part, characterized by expression of Lhx2 and Lhx9, that includes part of the basal amygdalar complex in mammals and a caudal part of the dorsal ventricular ridge in sauropsids and also produces a cell subpopulation of the medial amygdala; (2) a striatal part, characterized by expression of Pax6 and/or Islet1, which includes the central amygdala in different species; (3) a pallidal part, characterized by expression of Nkx2.1 and, in amniotes, Lhx6, which includes part of the medial amygdala, and (4) a hypothalamic part (derived from the supraoptoparaventricular domain or SPV), characterized by Otp and/or Lhx5 expression, which produces an important subpopulation of cells of the medial extended amygdala (medial amygdala and/or medial bed nucleus of the stria terminalis). Importantly, the size of the SPV domain increases upon reduction or lack of Nkx2.1 function in the hypothalamus. It appears that Nkx2.1 expression was downregulated in the alar hypothalamus during evolution to mammals, which may have produced an enlargement of SPV and the amygdalar cell subpopulation

  13. Signal detection in amplitude-modulated maskers. II. Processing in the songbird's auditory forebrain.

    PubMed

    Nieder, A; Klump, G M

    2001-03-01

    In the natural environment, acoustic signals have to be detected in ubiquitous background noise. Temporal fluctuations of background noise can be exploited by the auditory system to enhance signal detection, especially if spectral masking components are coherently amplitude modulated across several auditory channels (a phenomenon called 'comodulation masking release'). In this study of neuronal mechanisms of masking release in the primary auditory forebrain (field L) of awake European starlings (Sturnus vulgaris), we determined and compared neural detection thresholds for 20-ms probe tones presented in a background of sinusoidally amplitude modulated (10-Hz) noise maskers. Responses of a total of 34 multiunit clusters were recorded via radiotelemetry with chronically implanted microelectrodes from unrestrained birds. For maskers consisting of a single noise band centred around the recording site's characteristic frequency, a substantial reduction in detection threshold (21 dB on average) was found when probe tones were presented during envelope dips rather than during envelope peaks. Such effects could also explain results obtained for masking protocols where the on-frequency noise band was presented together with excitatory or inhibitory flanking bands that were either coherently modulated (in-phase) or incoherently modulated (phase-shifted). Generally, masking release for probe tones in maskers with flanking bands extending beyond the frequency range of a cell cluster's excitatory tuning curve was not substantially improved. Only some of the neurophysiological results are in agreement with behavioural data from the same species if only the average population response is considered. A subsample of individual neurons, however, could account for behavioural thresholds. PMID:11264677

  14. Changing Neuroestrogens Within the Auditory Forebrain Rapidly Transform Stimulus Selectivity in a Downstream Sensorimotor Nucleus

    PubMed Central

    Remage-Healey, Luke; Joshi, Narendra R.

    2012-01-01

    The activity of sensory circuits is shaped by neuromodulators, which can have downstream consequences for both sensorimotor integration and behavioral output. Recent evidence indicates that brain-derived estrogens (‘neuroestrogens’) can act as local circuit modulators in the songbird auditory forebrain. Specifically, neuroestrogens fluctuate in the auditory caudomedial nidopallium (NCM) during social interactions and in response to song stimuli. Within minutes of elevation, neuroestrogens also enhance auditory response properties of NCM neurons, and acute blockade of estrogen production in NCM disrupts behavioral song discrimination. Here, we test the hypothesis that fluctuating neuroestrogens within NCM influence stimulus selectivity in a downstream sensorimotor nucleus (HVC) that receives indirect auditory input from NCM. Dual extracellular recordings coupled with retrodialysis delivery show that song-selectivity in HVC is rapidly enhanced by increasing neuroestrogens in NCM in adult males. Conversely, inhibiting neuroestrogen production in NCM causes a rapid decline in song-selectivity in HVC, demonstrating the endogenous nature of this modulatory network. By contrast, HVC selectivity is unaffected by neuroestrogen delivery to either nearby caudomedial mesopallium (CMM) or into HVC itself, indicating that neuroestrogen actions are restricted to NCM. In juvenile males, identical E2 treatment in NCM also does not alter HVC selectivity, consistent with a developmental maturation of the auditory network. Lastly, the rapid actions of estrogens leading to enhanced HVC selectivity appear to be mediated by membrane-bound receptors in NCM. These findings indicate that steroid-dependent modulation of sensory processing is not locally restricted and can be transmitted transynaptically to influence downstream sensorimotor and premotor targets. PMID:22699904

  15. Estrogen Receptor Beta Expression in the Mouse Forebrain: Age and Sex Differences

    PubMed Central

    Zuloaga, Damian G.; Zuloaga, Kristen L.; Hinds, Laura R.; Carbone, David L.; Handa, Robert J.

    2016-01-01

    Estrogen receptors regulate multiple brain functions including stress, sexual, and memory associated behaviors as well as control of neuroendocrine and autonomic function. During development, estrogen signaling is involved in programming adult sex differences in physiology and behavior. Expression of estrogen receptor alpha changes across development in a region specific fashion. By contrast, estrogen receptor beta (ERβ) is expressed in many brain regions, yet few studies have explored sex and developmental differences in its expression largely due to the absence of selective reagents for anatomical localization of the protein. In this study, we utilized bacterial artificial chromosome transgenic mice expressing ERβ identified by enhanced green fluorescent protein (EGFP) to compare expression levels and distribution of ERβ in the male and female mouse forebrain on the day of birth (P0), postnatal day 4 (P4) and P21. Using qualitative analysis, we mapped the distribution of ERβ–EGFP and found developmental alterations in ERβ expression within the cortex, hippocampus, and hypothalamic regions including the arcuate, ventromedial, and paraventricular nuclei. We also report a sex difference in ERβ in the bed nucleus of the stria terminalis with males showing greater expression at P4 and P21. Another sex difference was found in the anteroventral periventricular nucleus of P21, but not P0 or P4 mice, where ERβ-EGFP-ir cells were densely clustered near the 3rd ventricle in females but not males. These developmental changes and sex differences in ERβ indicate a mechanism through which estrogens may differentially affect brain functions or program adult physiology at select times during development. PMID:23818057

  16. Distribution and Intrinsic Membrane Properties of Basal Forebrain GABAergic and Parvalbumin Neurons in the Mouse

    PubMed Central

    McKenna, James T.; Yang, Chun; Franciosi, Serena; Winston, Stuart; Abarr, Kathleen K.; Rigby, Matthew S.; Yanagawa, Yuchio; McCarley, Robert W.; Brown, Ritchie E.

    2013-01-01

    The basal forebrain (BF) strongly regulates cortical activation, sleep homeostasis, and attention. Many BF neurons involved in these processes are GABAergic, including a subpopulation of projection neurons containing the calcium-binding protein, parvalbumin (PV). However, technical difficulties in identification have prevented a precise mapping of the distribution of GABAergic and GABA/PV+ neurons in the mouse or a determination of their intrinsic membrane properties. Here we used mice expressing fluorescent proteins in GABAergic (GAD67-GFP knock-in mice) or PV+ neurons (PV-Tomato mice) to study these neurons. Immunohistochemical staining for GABA in GAD67-GFP mice confirmed that GFP selectively labeled BF GABAergic neurons. GFP+ neurons and fibers were distributed throughout the BF, with the highest density in the magnocellular preoptic area (MCPO). Immunohistochemistry for PV indicated that the majority of PV+ neurons in the BF were large (>20 μm) or medium-sized (15–20 μm) GFP+ neurons. Most medium and large-sized BF GFP+ neurons, including those retrogradely labeled from the neocortex, were fast-firing and spontaneously active in vitro. They exhibited prominent hyperpolarization-activated inward currents and subthreshold “spikelets,” suggestive of electrical coupling. PV+ neurons recorded in PV-Tomato mice had similar properties but had significantly narrower action potentials and a higher maximal firing frequency. Another population of smaller GFP+ neurons had properties similar to striatal projection neurons. The fast firing and electrical coupling of BF GABA/PV+ neurons, together with their projections to cortical interneurons and the thalamic reticular nucleus, suggest a strong and synchronous control of the neocortical fast rhythms typical of wakefulness and REM sleep. PMID:23254904

  17. Selective septohippocampal- but not forebrain amygdalar- cholinergic dysfunction in diencephalic amnesia

    PubMed Central

    Savage, Lisa M.; Roland, Jessica; Klintsova, Anna

    2007-01-01

    A rodent model of diencephalic amnesia, pyrithiamine-induced thiamine deficiency (PTD), was used to investigate diencephalic-limbic interactions. In-vivo acetylcholine (ACh) efflux, a marker of memory-related activation, was measured in the hippocampus and the amygdala of PTD-treated and pair-fed (PF) control rats while they were tested on a spontaneous alternation task. During behavioral testing, all animals displayed increases in ACh efflux in both the hippocampus and amygdala. However, during spontaneous alternation testing ACh efflux in the hippocampus and the alternation scores were higher in PF rats relative to PTD-treated rats. In contrast, ACh efflux in the amygdala was not suppressed in PTD treated rats, relative to PF rats, prior to or during behavioral testing. In addition, unbiased stereological estimates of the number of choline acetyltransferase (ChAT) immunopositive neurons in the medial septal/diagonal band (MS/DB) and nucleus basalis of Meynert (NBM) also reveal a selective cholinergic dysfunction: In PTD-treated rats a significant loss of ChAT-immunopositive cells was found only in the MS/DB, but not in the NBM. Significantly, these results demonstrate that thiamine deficiency causes selective cholinergic dysfunction in the septohippocampal pathway. PMID:17289001

  18. Immunization Against Specific Fragments of Neurotrophin p75 Receptor Protects Forebrain Cholinergic Neurons in the Olfactory Bulbectomized Mice

    PubMed Central

    Bobkova, Natalia; Vorobyov, Vasily; Medvinskaya, Natalia; Nesterova, Inna; Tatarnikova, Olga; Nekrasov, Pavel; Samokhin, Alexander; Deev, Alexander; Sengpiel, Frank; Koroev, Dmitry; Volpina, Olga

    2016-01-01

    Alzheimer’s disease (AD) is characterized by progressive cognitive impairment associated with marked cholinergic neuron loss and amyloid-β (Aβ) peptide accumulation in the brain. The cytotoxicity in AD is mediated, at least in part, by Aβ binding with the extracellular domain of the p75 neurotrophin receptor (p75NTR), localized predominantly in the membranes of acetylcholine-producing neurons in the basal forebrain. Hypothesizing that an open unstructured loop of p75NTR might be the effective site for Aβ binding, we have immunized both olfactory bulbectomized (OBX) and sham-operated (SO) mice (n = 82 and 49, respectively) with synthetic peptides, structurally similar to different parts of the loops, aiming to block them by specific antibodies. OBX-mice have been shown in previous studies, and confirmed in the present one, to be characterized by typical behavioral, morphological, and biochemical AD hallmarks, including cholinergic deficits in forebrain neurons. Immunization of OBX- or SO-mice with KLH conjugated fragments of p75NTR induced high titers of specific serum antibodies for each of nine chosen fragments. However, maximal protective effects on spatial memory, evaluated in a Morris water maze, and on activity of choline acetyltransferase in forebrain neurons, detected by immunoreactivity to specific antibodies, were revealed only for peptides with amino acid residue sequences of 155–164 and 167–176. We conclude that the approach based on immunological blockade of specific p75NTR sites, linked with the cytotoxicity, is a useful and effective tool for study of AD-associated mechanisms and for development of highly selective therapy of cholinergic malfunctioning in AD patients. PMID:27163825

  19. Effect of ischemic preconditioning on antioxidant status in the gerbil hippocampal CA1 region after transient forebrain ischemia

    PubMed Central

    Park, Seung Min; Park, Chan Woo; Lee, Tae-Kyeong; Cho, Jeong Hwi; Park, Joon Ha; Lee, Jae-Chul; Chen, Bai Hui; Shin, Bich-Na; Ahn, Ji Hyeon; Tae, Hyun-Jin; Shin, Myoung Cheol; Ohk, Taek Geun; Cho, Jun Hwi; Won, Moo-Ho; Choi, Soo Young; Kim, In Hye

    2016-01-01

    Ischemic preconditioning (IPC) is a condition of sublethal transient global ischemia and exhibits neuroprotective effects against subsequent lethal ischemic insult. We, in this study, examined the neuroprotective effects of IPC and its effects on immunoreactive changes of antioxidant enzymes including superoxide dismutase (SOD) 1 and SOD2, catalase (CAT) and glutathione peroxidase (GPX) in the gerbil hippocampal CA1 region after transient forebrain ischemia. Pyramidal neurons of the stratum pyramidale (SP) in the hippocampal CA1 region of animals died 5 days after lethal transient ischemia without IPC (8.6% (ratio of remanent neurons) of the sham-operated group); however, IPC prevented the pyramidal neurons from subsequent lethal ischemic injury (92.3% (ratio of remanent neurons) of the sham-operated group). SOD1, SOD2, CAT and GPX immunoreactivities in the sham-operated animals were easily detected in pyramidal neurons in the stratum pyramidale (SP) of the hippocampal CA1 region, while all of these immunoreactivities were rarely detected in the stratum pyramidale at 5 days after lethal transient ischemia without IPC. Meanwhile, their immunoreactivities in the sham-operated animals with IPC were similar to (SOD1, SOD2 and CAT) or higher (GPX) than those in the sham-operated animals without IPC. Furthermore, their immunoreactivities in the stratum pyramidale of the ischemia-operated animals with IPC were steadily maintained after lethal ischemia/reperfusion. Results of western blot analysis for SOD1, SOD2, CAT and GPX were similar to immunohistochemical data. In conclusion, IPC maintained or increased the expression of antioxidant enzymes in the stratum pyramidale of the hippocampal CA1 region after subsequent lethal transient forebrain ischemia and IPC exhibited neuroprotective effects in the hippocampal CA1 region against transient forebrain ischemia.

  20. Transformation from a pure time delay to a mixed time and phase delay representation in the auditory forebrain pathway.

    PubMed

    Vonderschen, Katrin; Wagner, Hermann

    2012-04-25

    Birds and mammals exploit interaural time differences (ITDs) for sound localization. Subsequent to ITD detection by brainstem neurons, ITD processing continues in parallel midbrain and forebrain pathways. In the barn owl, both ITD detection and processing in the midbrain are specialized to extract ITDs independent of frequency, which amounts to a pure time delay representation. Recent results have elucidated different mechanisms of ITD detection in mammals, which lead to a representation of small ITDs in high-frequency channels and large ITDs in low-frequency channels, resembling a phase delay representation. However, the detection mechanism does not prevent a change in ITD representation at higher processing stages. Here we analyze ITD tuning across frequency channels with pure tone and noise stimuli in neurons of the barn owl's auditory arcopallium, a nucleus at the endpoint of the forebrain pathway. To extend the analysis of ITD representation across frequency bands to a large neural population, we employed Fourier analysis for the spectral decomposition of ITD curves recorded with noise stimuli. This method was validated using physiological as well as model data. We found that low frequencies convey sensitivity to large ITDs, whereas high frequencies convey sensitivity to small ITDs. Moreover, different linear phase frequency regimes in the high-frequency and low-frequency ranges suggested an independent convergence of inputs from these frequency channels. Our results are consistent with ITD being remodeled toward a phase delay representation along the forebrain pathway. This indicates that sensory representations may undergo substantial reorganization, presumably in relation to specific behavioral output. PMID:22539852

  1. Early auditory experience induces frequency-specific, adaptive plasticity in the forebrain gaze fields of the barn owl.

    PubMed

    Miller, G L; Knudsen, E I

    2001-05-01

    Binaural acoustic cues such as interaural time and level differences (ITDs and ILDs) are used by many species to determine the locations of sound sources. The relationship between cue values and locations in space is frequency dependent and varies from individual to individual. In the current study, we tested the capacity of neurons in the forebrain localization pathway of the barn owl to adjust their tuning for binaural cues in a frequency-dependent manner in response to auditory experience. Auditory experience was altered by raising young owls with a passive acoustic filtering device that caused frequency-dependent changes in ITD and ILD. Extracellular recordings were made in normal and device-reared owls to characterize frequency-specific ITD and ILD tuning in the auditory archistriatum (AAr), an output structure of the forebrain localization pathway. In device-reared owls, individual sites in the AAr exhibited highly abnormal, frequency-dependent variations in ITD tuning, and across the population of sampled sites, there were frequency-dependent shifts in the representation of ITD. These changes were in a direction that compensated for the acoustic effects of the device on ITD and therefore tended to restore a normal representation of auditory space. Although ILD tuning was degraded relative to normal at many sites in the AAr of device-reared owls, the representation of frequency-specific ILDs across the population of sampled sites was shifted in the adaptive direction. These results demonstrate that early auditory experience shapes the representation of binaural cues in the forebrain localization pathway in an adaptive, frequency-dependent manner. PMID:11353033

  2. Characterization of a forebrain gaze field in the archistriatum of the barn owl: microstimulation and anatomical connections.

    PubMed

    Knudsen, E I; Cohen, Y E; Masino, T

    1995-07-01

    We present evidence that the archistriatum in the forebrain of the barn owl participates in gaze control, that it can mediate gaze changes independently of the optic tectum (OT), and that it projects in parallel to both the OT and to saccade-generating circuitry in the brainstem tegmentum. These properties are similar to those of the frontal eye fields (FEF) in the prefrontal cortex of primates. The forebrain was surveyed for sites where electrical microstimulation would induce head saccades. Head (and eye) saccades were elicited from the anterior 70% of the archistriatum, a region that we refer to as the archistriatal gaze fields (AGF). At single stimulation sites in the AGF, saccade amplitude tended to vary as a function of stimulation parameters (current strength, pulse frequency, and train duration) and starting head position. In contrast, saccade direction was largely independent of these parameters. Saccade direction did vary over a wide range of primarily contraversive directions with the site of stimulation in the AGF. Using anatomical pathway tracing techniques, we found that the archistriatum projects strongly and in parallel to the deep layers of the OT and to nuclei in the midline brainstem tegmentum. Previous work has shown that electrical microstimulation of either of these brainstem regions evokes saccadic movements of the head and/or eyes (du Lac and Knudsen, 1990; Masino and Knudsen, 1992b). Inactivation of the OT with lidocaine reduced the size but did not eliminate (or change the direction of) the saccades evoked by AGF stimulation. The direct anatomical pathway from the archistriatum to the midline tegmental nuclei can account for saccades that persist following OT inactivation. The similarities between the AGF in barn owls and the FEF in primates suggest that the same general plan of anatomical and functional organization supports the contribution of the forebrain to gaze control in a wide variety of species. PMID:7623141

  3. Derivation and Isolation of NKX2.1-Positive Basal Forebrain Progenitors from Human Embryonic Stem Cells

    PubMed Central

    Germain, Noélle D.; Banda, Erin C.; Becker, Sandy; Naegele, Janice R.

    2013-01-01

    Gamma aminobutyric acid (GABA)-expressing interneurons are the major inhibitory cells of the cerebral cortex and hippocampus. These interneurons originate in the medial ganglionic eminence (MGE) and lateral ganglionic eminence of the ventral forebrain during embryonic development and show reduced survival and function in a variety of neurological disorders, including temporal lobe epilepsy. We and others have proposed that embryonic stem cell (ESC)–derived ventral forebrain progenitors might provide a source of new GABAergic interneurons for cell-based therapies. While human ESCs (hESCs) are readily differentiated in vitro into dorsal telencephalic neural progenitors, standard protocols for generating ventral subtypes of telencephalic progenitors are less effective. We now report efficient derivation of GABAergic progenitors using an established hESC reporter line that expresses green fluorescent protein (GFP) under the control of an endogenous NKX2.1 promoter. GABAergic progenitors were derived from this hESC line by a modified monolayer neural differentiation protocol. Consistent with sonic hedgehog (SHH)-dependent specification of NKX2.1-positive progenitors in the embryonic MGE, we show a dose-dependent increase in the generation of NKX2.1:GFP-positive progenitors after SHH treatment in vitro. Characterization of NKX2.1:GFP-positive cells confirms their identity as MGE-like neural progenitors, based on gene expression profiles and their ability to differentiate into GABAergic interneurons. We are also able to generate highly enriched populations of NKX2.1:GFP-positive progenitors, including cells with telencephalic identity, by fluorescence-activated cell sorting. These hESC-derived ventral forebrain progenitors are suitable candidates for cell-based therapies that aim at replacing dysfunctional or damaged cortical or hippocampal GABAergic interneurons. PMID:23351095

  4. Can manipulation of differentiation conditions eliminate proliferative cells from a population of ES cell-derived forebrain cells?

    PubMed

    Precious, Sophie V; Kelly, Claire M; Allen, Nicholas D; Rosser, Anne E

    2016-01-01

    There is preliminary evidence that implantation of primary fetal striatal cells provides functional benefit in patients with Huntington's disease, a neurodegenerative condition resulting in loss of medium-sized spiny neurons (MSN) of the striatum. Scarcity of primary fetal tissue means it is important to identify a renewable source of cells from which to derive donor MSNs. Embryonic stem (ES) cells, which predominantly default to telencephalic-like precursors in chemically defined medium (CDM), offer a potentially inexhaustible supply of cells capable of generating the desired neurons. Using an ES cell line, with the forebrain marker FoxG1 tagged to the LacZ reporter, we assessed effects of known developmental factors on the yield of forebrain-like precursor cells in CDM suspension culture. Addition of FGF2, but not DKK1, increased the proportion of FoxG1-expressing cells at day 8 of neural induction. Oct4 was expressed at day 8, but was undetectable by day 16. Differentiation of day 16 precursors generated GABA-expressing neurons, with few DARPP32 positive MSNs. Transplantation of day 8 precursor cells into quinolinic acid-lesioned striata resulted in generation of teratomas. However, transplantation of day 16 precursors yielded grafts expressing neuronal markers including NeuN, calbindin and parvalbumin, but no DARPP32 6 weeks post-transplantation. Manipulation of fate of ES cells requires optimization of both concentration and timing of addition of factors to culture systems to generate the desired phenotypes. Furthermore, we highlight the value of increasing the precursor phase of ES cell suspension culture when directing differentiation toward forebrain fate, so as to dramatically reduce the risk of teratoma formation. PMID:27606335

  5. LASTING CHANGES IN NEURONAL ACTIVATION PATTERNS IN SELECT FOREBRAIN REGIONS OF AGGRESSIVE, ADOLESCENT ANABOLIC/ANDROGENIC STEROID-TREATED HAMSTERS

    PubMed Central

    Ricci, Lesley A.; Grimes, Jill M.; Melloni, Richard H.

    2007-01-01

    Repeated exposure to anabolic/androgenic steroids (AAS) during adolescence stimulates high levels of offensive aggression in Syrian hamsters. The current study investigated whether adolescent AAS exposure activated neurons in areas of hamster forebrain implicated in aggressive behavior by examining the expression of FOS, i.e., the protein product of the immediate early gene c-fos shown to be a reliably sensitive marker of neuronal activation. Adolescent AAS-treated hamsters and sesame oil-treated littermates were scored for offensive aggression and then sacrificed 1 day later and examined for the number of FOS immunoreactive (FOS-ir) cells in regions of the hamster forebrain important for aggression control. When compared with non-aggressive, oil-treated controls, aggressive AAS-treated hamsters showed persistent increases in the number of FOS-ir cells in select aggression regions, namely the anterior hypothalamus and lateral septum. However, no differences in FOS-ir cells were found in other areas implicated in aggression such as the ventrolateral hypothalamus, bed nucleus of the stria terminals, central and/or medial amygdala or in non-aggression areas such as the samatosensory cortex and the suprachiasmatic nucleus. These results suggest that adolescent AAS exposure may constitutively activate neurons in select forebrain areas critical for the regulation of aggression in hamsters. A model for how persistent activation of neurons in one of these brain regions (i.e., the anterior hypothalamus) may facilitate the development of the aggressive phenotype in adolescent-AAS exposed animals is presented. PMID:17113655

  6. Predominant neuronal differentiation of Olig1+ neural progenitors in forebrain cortex biased by β-catenin over-expression.

    PubMed

    Yang, Jialei; Liu, Xunyuan; Zhang, Xiufen; Zhao, Xianghui; Pan, Yuanhang; Qiu, Mengsheng; Wu, Shengxi; Zhao, Gang; Wang, Ya-Zhou

    2016-05-27

    Proper neuron-glia ratio is essential for normal brain development and function. Olig1 is a basic helix-loop-helix (bHLH) transcription factor generally used as a lineage tool for oligodendrocyte research in spinal cord. Recent studies have revealed a property of Olig1-positive cells as the common progenitors of GABAergic neurons and oligodendrocytes in the forebrain during embryogenesis, and a stage-dependent regulatory role of Wnt/β-catenin signaling in the differentiation of oligodendrocytes in spinal cord. Given the neurogenic role of Wnt/β-catenin signaling in neural progenitor cells, it is unclear how β-catenin affects the differentiation of Olig1-positive progenitors in brain. In the present study, we investigated the effects of β-catenin over-expression on the differentiation of Olig1-positive progenitors in the forebrain cortex, by using Olig1-Cre:β-cateninEX3 (loxp/+):ROSA-YFP (β-cateninEX3 CKO) mice as compared to Olig1-Cre:ROSA-YFP control. The results showed that in the cortex of Olig1-Cre:ROSA-YFP mice, approximately 28.6% of YFP labeled cells are GFAP-positive, 43.7% are NG2-positive, 23.4% are CC1-positive and 3.2% are NeuN-positive, showing that Olig1-positive cells are multi-potential and mainly gliogenic. However, in the cortex of β-cateninEX3 CKO mice, the percentage of astrocytes generated from Olig1-positive cells decreased dramatically to approximately 2%, NG2-positive cells to 0.4%, and CC1-positive cells to 0.5%. In contrast, the percentage of NeuN-positive cells increased to approximately 96% of YFP-labeled cells. Taken together, our data showed that the gliogenic property of Olig1-positive progenitors in forebrain can be efficiently switched to neurogenic by over-expressing β-catenin, revealing a neurogenic effect of β-catenin in the forebrain Olig1-positive progenitors. PMID:27084689

  7. Shifts in the Vascular endothelial growth factor (Vegf) isoforms result in transcriptome changes correlated with early neural stem cell proliferation and differentiation in mouse forebrain

    PubMed Central

    Cain, Jacob T.; Berosik, Matthew A.; Snyder, Stephanie D.; Crawford, Natalie F.; Nour, Shirin I.; Schaubhut, Geoffrey J.; Darland, Diane C.

    2014-01-01

    Regulation of neural stem cell (NSC) fate decisions is critical during the transition from a multicellular mammalian forebrain neuroepithelium to the multi-layered neocortex. Forebrain development requires coordinated vascular investment alongside NSC differentiation. Vascular endothelial growth factor A (Vegf) has proven to be a pleiotrophic gene whose multiple protein isoforms regulate a broad range of effects in neurovascular systems. To test the hypothesis that the Vegf isoforms (120, 164, and 188) are required for normal forebrain development, we analyzed the forebrain transcriptome of mice expressing specific Vegf isoforms, Vegf120, VegfF188, or a combination of Vegf120/188. Transcriptome analysis identified differentially expressed genes in embryonic day (E) 9.5 forebrain, a time point preceding dramatic neuroepithelial expansion and vascular investment in the telencephalon. Meta-analysis identified gene pathways linked to chromosome-level modifications, cell fate regulation, and neurogenesis that were altered in Vegf isoform mice. Based on these gene network shifts, we predicted that NSC populations would be affected in later stages of forebrain development. In the E11.5 telencephalon, we quantified mitotic cells [Phospho-Histone H3 (pHH3)-positive] and intermediate progenitor cells (Tbr2/Eomes-positive), observing quantitative and qualitative shifts in these populations. We observed qualitative shifts in cortical layering at P0, particularly with Ctip2-positive cells in layer V. The results identify a suite of genes and functional gene networks that can be used to further dissect the role of Vegf in regulating NSC differentiation and downstream consequences for NSC fate decisions. PMID:24124161

  8. Forebrain-specific Expression of Monoamine Oxidase A Reduces Neurotransmitter Levels, Restores the Brain Structure, and Rescues Aggressive Behavior in Monoamine Oxidase A-deficient Mice*

    PubMed Central

    Chen, Kevin; Cases, Olivier; Rebrin, Igor; Wu, Weihua; Gallaher, Timothy K.; Seif, Isabelle; Shih, Jean Chen

    2010-01-01

    Previous studies have established that abrogation of monoamine oxidase (MAO) A expression leads to a neurochemical, morphological, and behavioral specific phenotype with increased levels of serotonin (5-HT), norepinephrine, and dopamine, loss of barrel field structure in mouse somatosensory cortex, and an association with increased aggression in adults. Forebrain-specific MAO A transgenic mice were generated from MAO A knock-out (KO) mice by using the promoter of calcium-dependent kinase IIα (CaMKIIα). The presence of human MAO A transgene and its expression were verified by PCR of genomic DNA and reverse transcription-PCR of mRNA and Western blot, respectively. Significant MAO A catalytic activity, autoradiographic labeling of 5-HT, and immunocytochemistry of MAO A were found in the frontal cortex, striatum, and hippocampus but not in the cerebellum of the forebrain transgenic mice. Also, compared with MAO A KO mice, lower levels of 5-HT, norepinephrine, and DA and higher levels of MAO A metabolite 5-hydroxyin-doleacetic acid were found in the forebrain regions but not in the cerebellum of the transgenic mice. These results suggest that MAO A is specifically expressed in the forebrain regions of transgenic mice. This forebrain-specific differential expression resulted in abrogation of the aggressive phenotype. Furthermore, the disorganization of the somatosensory cortex barrel field structure associated with MAO A KO mice was restored and became morphologically similar to wild type. Thus, the lack of MAO A in the forebrain of MAO A KO mice may underlie their phenotypes. PMID:17090537

  9. Cytotoxicity of synthetic cannabinoids on primary neuronal cells of the forebrain: the involvement of cannabinoid CB{sub 1} receptors and apoptotic cell death

    SciTech Connect

    Tomiyama, Ken-ichi; Funada, Masahiko

    2014-01-01

    The abuse of herbal products containing synthetic cannabinoids has become an issue of public concern. The purpose of this paper was to evaluate the acute cytotoxicity of synthetic cannabinoids on mouse brain neuronal cells. Cytotoxicity induced by synthetic cannabinoid (CP-55,940, CP-47,497, CP-47,497-C8, HU-210, JWH-018, JWH-210, AM-2201, and MAM-2201) was examined using forebrain neuronal cultures. These synthetic cannabinoids induced cytotoxicity in the forebrain cultures in a concentration-dependent manner. The cytotoxicity was suppressed by preincubation with the selective CB{sub 1} receptor antagonist AM251, but not with the selective CB{sub 2} receptor antagonist AM630. Furthermore, annexin-V-positive cells were found among the treated forebrain cells. Synthetic cannabinoid treatment induced the activation of caspase-3, and preincubation with a caspase-3 inhibitor significantly suppressed the cytotoxicity. These synthetic cannabinoids induced apoptosis through a caspase-3-dependent mechanism in the forebrain cultures. Our results indicate that the cytotoxicity of synthetic cannabinoids towards primary neuronal cells is mediated by the CB{sub 1} receptor, but not by the CB{sub 2} receptor, and further suggest that caspase cascades may play an important role in the apoptosis induced by these synthetic cannabinoids. In conclusion, excessive synthetic cannabinoid abuse may present a serious acute health concern due to neuronal damage or deficits in the brain. - Highlights: • Synthetic cannabinoids (classical cannabinoids, non-classical cannabinoids, and aminoalkylindole derivatives) induce cytotoxicity in mouse forebrain cultures. • Synthetic cannabinoid-induced cytotoxicity towards forebrain cultures is mediated by the CB{sub 1} receptor, but not by the CB{sub 2} receptor, and involves caspase-dependent apoptosis. • A high concentration of synthetic cannabinoids may be toxic to neuronal cells that express CB{sub 1} receptors.

  10. [Novel calretinin-positive cells with polymorphous spines in the mouse forebrain during early postnatal ontogenesis].

    PubMed

    Revishchin, A V; Okhotin, V E; Pavlova, G V

    2009-01-01

    Using an immunocytochemical method for calretinin (CR) detection, we have earlier described (Morfologiya, 2009 v. 135. No. 3, p. 7-19) the population of previously unknown mono- and bipolar cells with polymorphous spines (PS) covering their cell bodies and processes, in adult mice forebrain structures adjacent to anterior horn of lateral ventricle. CR-positive spiny (CR+PS) cells were negative to GAD67 and were detected in the white matter and in layers V and VI of frontal area of dorsomedial cortex close to the cingulum, in in rostro-dorsal part of the caudate nucleus-putamen complex, anterior olfactory nucleus and in subependymal layer of the dorso-lateral angle of the lateral ventricle. In this work, the distribution of these cells in 7-day-old mice was studied. Comparative topographical analysis of definitive and early CR+PS cells demonstrated that in 7-day-old mice CR+PS cells were absent from the areas of their localization in adult animals - anterior olfactory nucleus, cortical plate and inner portion of neostriatum. Meanwhile, some CR+PS-like cells were detected in 7-day-old mice inside the rostral migratory route, close to neostriatum anterior boundary, along the dorsal border between neostriatum and corpus callosum, subependymal layer of lateral wall of the lateral ventricle, and in the cingulum area. These findings are indicative of the possible postnatal appearance of CR+PS cells. To test this hypothesis, the experiments were conducted in which bromodeoxyuridine (BrdU) was administered to the mice on their postnatal days 2-4 with the subsequent study of the brain sections of these animals sacrificed on their postnatal day 20. Double immunolabeling of these sections for CR and BrdU has detected the presence of CR+PS cells that contained postnatally administered BrdU. These results strongly suggest that, at least, some portion of CR+PS cells have their mitosis postnatally. It may be assumed, that CR+PS cells migrate to the sites of their distribution in

  11. New calretinin-positive cells with polymorphous spines in the mouse forebrain during early postnatal ontogeny.

    PubMed

    Revishchin, A V; Okhotin, V E; Pavlova, G V

    2010-10-01

    Immunohistochemical studies of calretinin (CR) in forebrain structures adjacent to the anterior horn of the lateral ventricle in adult mice allowed us to detect a population of previously unknown mono- and bipolar cells whose bodies and processes were coated with polymorphous spines (PS) (Morfologiya, 135, No. 3, 7-19 (2009)). CR-positive spiny (CR(+)PS) cells did not contain GAD67 and were located in the white matter and layers V-VI of the frontal area of the dorsomedial cortex close to the cingulum, the rostrodorsal part of the caudate-putamen, the anterior olfactory nucleus, and the subependyma of the dorsolateral angle of the lateral ventricle. We report here studies of the distribution of these cells in seven-day-old mice. Comparative topographic analysis of definitive and early CR(+)PS cells showed that in seven-day-old mice, CR(+)PS cells were absent from the sites at which they were seen in adults, i.e., the anterior olfactory cortex, the cortical plate, and the inner part of the neostriatum. In addition, small numbers of CR(+)PS-like cells were seen at this age within the dorsal migration pathway, at the anterior margin of the neostriatum, along the dorsal border of the neostriatum with the corpus callosum, in the subependymal layer of the lateral wall of the lateral ventricle, and in the cingulum area. These data demonstrate that CR(+)PS cells may have a postnatal origin. Experiments to verify this hypothesis were performed using postnatal administration of bromodeoxyuridine (BrdU) to mice aged 2-4 days, followed by assessment of brain sections fixed at age 20 days. Double immunolabeling of sections for CR and BrdU demonstrated the presence of CR(+)PS cells containing postnatally supplied BrdU. These data provide evidence that at least some CR(+)PS cells undergo mitosis at postnatal age. In all probability, during the period from 7 to 20 days of postnatal development, CR(+)PS cells migrate to the sites that they occupy in adult animals. PMID:20721693

  12. RE1 silencing transcription factor/neuron-restrictive silencing factor regulates expansion of adult mouse subventricular zone-derived neural stem/progenitor cells in vitro.

    PubMed

    Soldati, Chiara; Caramanica, Pasquale; Burney, Matthew J; Toselli, Camilla; Bithell, Angela; Augusti-Tocco, Gabriella; Stanton, Lawrence W; Biagioni, Stefano; Buckley, Noel J; Cacci, Emanuele

    2015-08-01

    Adult neural stem cell (aNSC) activity is tuned by external stimuli through the recruitment of transcription factors. This study examines the RE1 silencing transcription factor (REST) in neural stem/progenitor cells isolated from the subventricular zone of adult mouse brain and provides the first extensive characterization of REST-mediated control of the cellular and molecular properties. This study shows that REST knockdown affects the capacity of progenitor cells to generate neurospheres, reduces cell proliferation, and triggers cell differentiation despite the presence of growth factors. Genome- and transcriptome-wide analyses show that REST binding sites are significantly enriched in genes associated with synaptic transmission and nervous system development and function. Seeking candidate regulators of aNSC function, this study identifies a member of the bone morphogenetic protein (BMP) family, BMP6, the mRNA and protein of which increased after REST knockdown. The results of this study extend previous findings, demonstrating a reciprocal control of REST expression by BMPs. Administration of exogenous BMP6 inhibits aNSC proliferation and induces the expression of the astrocytic marker glial fibrillary acidic protein, highlighting its antimitogenic and prodifferentiative effects. This study suggests that BMP6 produced in a REST-regulated manner together with other signals can contribute to regulation of NSC maintenance and fate. PMID:25691247

  13. Inhibition of the histone demethylase Kdm5b promotes neurogenesis and derepresses Reln (reelin) in neural stem cells from the adult subventricular zone of mice

    PubMed Central

    Zhou, Qiong; Obana, Edwin A.; Radomski, Kryslaine L.; Sukumar, Gauthaman; Wynder, Christopher; Dalgard, Clifton L.; Doughty, Martin L.

    2016-01-01

    The role of epigenetic regulators in the control of adult neurogenesis is largely undefined. We show that the histone demethylase enzyme Kdm5b (Jarid1b) negatively regulates neurogenesis from adult subventricular zone (SVZ) neural stem cells (NSCs) in culture. shRNA-mediated depletion of Kdm5b in proliferating adult NSCs decreased proliferation rates and reduced neurosphere formation in culture. When transferred to differentiation culture conditions, Kdm5b-depleted adult NSCs migrated from neurospheres with increased velocity. Whole-genome expression screening revealed widespread transcriptional changes with Kdm5b depletion, notably the up-regulation of reelin (Reln), the inhibition of steroid biosynthetic pathway component genes and the activation of genes with intracellular transport functions in cultured adult NSCs. Kdm5b depletion increased extracellular reelin concentration in the culture medium and increased phosphorylation of the downstream reelin signaling target Disabled-1 (Dab1). Sequestration of extracellular reelin with CR-50 reelin-blocking antibodies suppressed the increase in migratory velocity of Kdm5b-depleted adult NSCs. Chromatin immunoprecipitation revealed that Kdm5b is present at the proximal promoter of Reln, and H3K4me3 methylation was increased at this locus with Kdm5b depletion in differentiating adult NSCs. Combined the data suggest Kdm5b negatively regulates neurogenesis and represses Reln in neural stem cells from the adult SVZ. PMID:26739753

  14. Abundant Occurrence of Basal Radial Glia in the Subventricular Zone of Embryonic Neocortex of a Lissencephalic Primate, the Common Marmoset Callithrix jacchus

    PubMed Central

    Kelava, Iva; Reillo, Isabel; Murayama, Ayako Y.; Kalinka, Alex T.; Stenzel, Denise; Tomancak, Pavel; Matsuzaki, Fumio; Lebrand, Cécile; Sasaki, Erika; Schwamborn, Jens C.; Okano, Hideyuki; Borrell, Víctor

    2012-01-01

    Subventricular zone (SVZ) progenitors are a hallmark of the developing neocortex. Recent studies described a novel type of SVZ progenitor that retains a basal process at mitosis, sustains expression of radial glial markers, and is capable of self-renewal. These progenitors, referred to here as basal radial glia (bRG), occur at high relative abundance in the SVZ of gyrencephalic primates (human) and nonprimates (ferret) but not lissencephalic rodents (mouse). Here, we analyzed the occurrence of bRG cells in the embryonic neocortex of the common marmoset Callithrix jacchus, a near-lissencephalic primate. bRG cells, expressing Pax6, Sox2 (but not Tbr2), glutamate aspartate transporter, and glial fibrillary acidic protein and retaining a basal process at mitosis, occur at similar relative abundance in the marmoset SVZ as in human and ferret. The proportion of progenitors in M-phase was lower in embryonic marmoset than developing ferret neocortex, raising the possibility of a longer cell cycle. Fitting the gyrification indices of 26 anthropoid species to an evolutionary model suggested that the marmoset evolved from a gyrencephalic ancestor. Our results suggest that a high relative abundance of bRG cells may be necessary, but is not sufficient, for gyrencephaly and that the marmoset's lissencephaly evolved secondarily by changing progenitor parameters other than progenitor type. PMID:22114084

  15. Intraventricular administration of endoneuraminidase-N facilitates ectopic migration of subventricular zone-derived neural progenitor cells into 6-OHDA lesioned striatum of mice.

    PubMed

    Li, Chen; Zhang, Yong-Xin; Yang, Chun; Hao, Fei; Chen, Sha-Sha; Hao, Qiang; Lu, Tao; Qu, Ting-Yu; Zhao, Li-Ru; Duan, Wei-Ming

    2016-03-01

    Polysialic acid (PSA), a carbohydrate polymer associated with the neural cell adhesion molecule (NCAM), plays an important role in the migration, differentiation and maturation of neuroblasts. Endoneuraminidase-N (Endo-N) can specifically cleave PSA from NCAM. The objective of the present study was to examine: the effect of Endo-N on characteristics of subventricular zone (SVZ)-derived neural progenitor cells (NPCs) in vitro; whether intraventricular administration of Endo-N could increase ectopic migration of SVZ-derived NPCs into 6-hydroxydopamine (6-OHDA)-lesioned striatum, and whether migrated NPCs could differentiate into neuronal and glial cells. In in vitro study, Endo-N was found to inhibit the migration of NPCs, and to enhance the differentiation of NPCs. In in vivo study, mice sequentially received injections of 6-OHDA into the right striatum, Endo-N into the right lateral ventricle, and bromodeoxyuridine (BrdU) intraperitoneally. The data showed that intraventricular injections of Endo-N disorganized the normal structure of the rostral migratory stream (RMS), and drastically increased the number of BrdU-immunoreactive (IR) cells in 6-OHDA-lesioned striatum. In addition, a number of BrdU-IR cells were double labeled for doublecortin (DCX), NeuN or glial fibrillary acidic protein (GFAP). The results suggest that interruption of neuroblast chain pathway with Endo-N facilitates ectopic migration of SVZ-derived NPCs into the lesioned striatum, and migrated NPCs can differentiate into neurons and astrocytes. PMID:26724216

  16. Cell Sorting of Neural Stem and Progenitor Cells from the Adult Mouse Subventricular Zone and Live-imaging of their Cell Cycle Dynamics.

    PubMed

    Daynac, Mathieu; Morizur, Lise; Kortulewski, Thierry; Gauthier, Laurent R; Ruat, Martial; Mouthon, Marc-André; Boussin, François D

    2015-01-01

    Neural stem cells (NSCs) in the subventricular zone of the lateral ventricles (SVZ) sustain olfactory neurogenesis throughout life in the mammalian brain. They successively generate transit amplifying cells (TACs) and neuroblasts that differentiate into neurons once they integrate the olfactory bulbs. Emerging fluorescent activated cell sorting (FACS) techniques have allowed the isolation of NSCs as well as their progeny and have started to shed light on gene regulatory networks in adult neurogenic niches. We report here a cell sorting technique that allows to follow and distinguish the cell cycle dynamics of the above-mentioned cell populations from the adult SVZ with a LeX/EGFR/CD24 triple staining. Isolated cells are then plated as adherent cells to explore in details their cell cycle progression by time-lapse video microscopy. To this end, we use transgenic Fluorescence Ubiquitination Cell Cycle Indicator (FUCCI) mice in which cells are red-fluorescent during G1 phase due to a G1 specific red-Cdt1 reporter. This method has recently revealed that proliferating NSCs progressively lengthen their G1 phase during aging, leading to neurogenesis impairment. This method is easily transposable to other systems and could be of great interest for the study of the cell cycle dynamics of brain cells in the context of brain pathologies. PMID:26436641

  17. GABAA Increases Calcium in Subventricular Zone Astrocyte-Like Cells Through L- and T-Type Voltage-Gated Calcium Channels

    PubMed Central

    Young, Stephanie Z.; Platel, Jean-Claude; Nielsen, Jakob V.; Jensen, Niels A.; Bordey, Angélique

    2010-01-01

    In the adult neurogenic subventricular zone (SVZ), the behavior of astrocyte-like cells and some of their functions depend on changes in intracellular Ca2+ levels and tonic GABAA receptor activation. However, it is unknown whether, and if so how, GABAA receptor activity regulates intracellular Ca2+ dynamics in SVZ astrocytes. To monitor Ca2+ activity selectively in astrocyte-like cells, we used two lines of transgenic mice expressing either GFP fused to a Gq-coupled receptor or DsRed under the human glial fibrillary acidic protein (hGFAP) promoter. GABAA receptor activation induced Ca2+ increases in 40–50% of SVZ astrocytes. GABAA-induced Ca2+ increases were prevented with nifedipine and mibefradil, blockers of L- and T-type voltage-gated calcium channels (VGCC). The L-type Ca2+ channel activator BayK 8644 increased the percentage of GABAA-responding astrocyte-like cells to 75%, suggesting that the majority of SVZ astrocytes express functional VGCCs. SVZ astrocytes also displayed spontaneous Ca2+ activity, the frequency of which was regulated by tonic GABAA receptor activation. These data support a role for ambient GABA in tonically regulating intracellular Ca2+ dynamics through GABAA receptors and VGCC in a subpopulation of astrocyte-like cells in the postnatal SVZ. PMID:20422045

  18. CD133 is not present on neurogenic astrocytes in the adult subventricular zone, but on embryonic neural stem cells, ependymal cells, and glioblastoma cells.

    PubMed

    Pfenninger, Cosima V; Roschupkina, Teona; Hertwig, Falk; Kottwitz, Denise; Englund, Elisabet; Bengzon, Johan; Jacobsen, Sten Eirik; Nuber, Ulrike A

    2007-06-15

    Human brain tumor stem cells have been enriched using antibodies against the surface protein CD133. An antibody recognizing CD133 also served to isolate normal neural stem cells from fetal human brain, suggesting a possible lineage relationship between normal neural and brain tumor stem cells. Whether CD133-positive brain tumor stem cells can be derived from CD133-positive neural stem or progenitor cells still requires direct experimental evidence, and an important step toward such investigations is the identification and characterization of normal CD133-presenting cells in neurogenic regions of the embryonic and adult brain. Here, we present evidence that CD133 is a marker for embryonic neural stem cells, an intermediate radial glial/ependymal cell type in the early postnatal stage, and for ependymal cells in the adult brain, but not for neurogenic astrocytes in the adult subventricular zone. Our findings suggest two principal possibilities for the origin of brain tumor stem cells: a derivation from CD133-expressing cells, which are normally not present in the adult brain (embryonic neural stem cells and an early postnatal intermediate radial glial/ependymal cell type), or from CD133-positive ependymal cells in the adult brain, which are, however, generally regarded as postmitotic. Alternatively, brain tumor stem cells could be derived from proliferative but CD133-negative neurogenic astrocytes in the adult brain. In the latter case, brain tumor development would involve the production of CD133. PMID:17575139

  19. Inhibition of the histone demethylase Kdm5b promotes neurogenesis and derepresses Reln (reelin) in neural stem cells from the adult subventricular zone of mice.

    PubMed

    Zhou, Qiong; Obana, Edwin A; Radomski, Kryslaine L; Sukumar, Gauthaman; Wynder, Christopher; Dalgard, Clifton L; Doughty, Martin L

    2016-02-15

    The role of epigenetic regulators in the control of adult neurogenesis is largely undefined. We show that the histone demethylase enzyme Kdm5b (Jarid1b) negatively regulates neurogenesis from adult subventricular zone (SVZ) neural stem cells (NSCs) in culture. shRNA-mediated depletion of Kdm5b in proliferating adult NSCs decreased proliferation rates and reduced neurosphere formation in culture. When transferred to differentiation culture conditions, Kdm5b-depleted adult NSCs migrated from neurospheres with increased velocity. Whole-genome expression screening revealed widespread transcriptional changes with Kdm5b depletion, notably the up-regulation of reelin (Reln), the inhibition of steroid biosynthetic pathway component genes and the activation of genes with intracellular transport functions in cultured adult NSCs. Kdm5b depletion increased extracellular reelin concentration in the culture medium and increased phosphorylation of the downstream reelin signaling target Disabled-1 (Dab1). Sequestration of extracellular reelin with CR-50 reelin-blocking antibodies suppressed the increase in migratory velocity of Kdm5b-depleted adult NSCs. Chromatin immunoprecipitation revealed that Kdm5b is present at the proximal promoter of Reln, and H3K4me3 methylation was increased at this locus with Kdm5b depletion in differentiating adult NSCs. Combined the data suggest Kdm5b negatively regulates neurogenesis and represses Reln in neural stem cells from the adult SVZ. PMID:26739753

  20. Cholinergic Basal Forebrain Structure Influences the Reconfiguration of White Matter Connections to Support Residual Memory in Mild Cognitive Impairment

    PubMed Central

    Ray, Nicola J.; Metzler-Baddeley, Claudia; Khondoker, Mizanur R.; Grothe, Michel J.; Teipel, Stefan; Wright, Paul; Heinsen, Helmut; Jones, Derek K.; Aggleton, John P.

    2015-01-01

    The fornix and hippocampus are critical to recollection in the healthy human brain. Fornix degeneration is a feature of aging and Alzheimer's disease. In the presence of fornix damage in mild cognitive impairment (MCI), a recognized prodrome of Alzheimer's disease, recall shows greater dependence on other tracts, notably the parahippocampal cingulum (PHC). The current aims were to determine whether this shift is adaptive and to probe its relationship to cholinergic signaling, which is also compromised in Alzheimer's disease. Twenty-five human participants with MCI and 20 matched healthy volunteers underwent diffusion MRI, behavioral assessment, and volumetric measurement of the basal forebrain. In a regression model for recall, there was a significant group × fornix interaction, indicating that the association between recall and fornix structure was weaker in patients. The opposite trend was present for the left PHC. To further investigate this pattern, two regression models were generated to account for recall performance: one based on fornix microstructure and the other on both fornix and left PHC. The realignment to PHC was positively correlated with free recall but not non-memory measures, implying a reconfiguration that is beneficial to residual memory. There was a positive relationship between realignment to PHC and basal forebrain gray matter volume despite this region demonstrating atrophy at a group level, i.e., the cognitive realignment to left PHC was most apparent when cholinergic areas were relatively spared. Therefore, cholinergic systems appear to enable adaptation to injury even as they degenerate, which has implications for functional restoration. PMID:25589767

  1. Defects in GPI biosynthesis perturb Cripto signaling during forebrain development in two new mouse models of holoprosencephaly

    PubMed Central

    McKean, David M.; Niswander, Lee

    2012-01-01

    Summary Holoprosencephaly is the most common forebrain defect in humans. We describe two novel mouse mutants that display a holoprosencephaly-like phenotype. Both mutations disrupt genes in the glycerophosphatidyl inositol (GPI) biosynthesis pathway: gonzo disrupts Pign and beaker disrupts Pgap1. GPI anchors normally target and anchor a diverse group of proteins to lipid raft domains. Mechanistically we show that GPI anchored proteins are mislocalized in GPI biosynthesis mutants. Disruption of the GPI-anchored protein Cripto (mouse) and TDGF1 (human ortholog) have been shown to result in holoprosencephaly, leading to our hypothesis that Cripto is the key GPI anchored protein whose altered function results in an HPE-like phenotype. Cripto is an obligate Nodal co-factor involved in TGFβ signaling, and we show that TGFβ signaling is reduced both in vitro and in vivo. This work demonstrates the importance of the GPI anchor in normal forebrain development and suggests that GPI biosynthesis genes should be screened for association with human holoprosencephaly. PMID:23213481

  2. Recent experience modulates forebrain gene-expression in response to mate-choice cues in European starlings.

    PubMed

    Sockman, Keith W; Gentner, Timothy Q; Ball, Gregory F

    2002-12-01

    Mate-choice decisions can be experience dependent, but we know little about how the brain processes stimuli that release such decisions. Female European starlings (Sturnus vulgaris) prefer males with long-bout songs over males with short-bout songs, and show higher expression of the immediate early gene (IEG) ZENK in the auditory forebrain when exposed to long-bout songs than when exposed to short-bout songs. We exposed female starlings to a short-day photoperiod for one of three durations and then, on an increased photophase, exposed them to one week of long-bout or short-bout song experience. We then examined their IEG response to novel long-bout versus novel short-bout songs by quantifying ZENK protein in two song-processing areas: the caudo-medial hyperstriatum ventrale and the caudo-medial neostriatum. ZENK expression in both areas increased with tenure on short-day photoperiods, suggesting that short days sensitize females to song. The ZENK response bias toward long-bout songs was greater in females with long-bout experience than in females with short-bout experience, indicating that the forebrain response bias toward a preferred trait depends on recent experience with that category of trait. This surprising level of neuroplasticity is immediately relevant to the natural history and fitness of the organism, and may underlie a mechanism for optimizing mate-choice criteria amidst locally variable distributions of secondary sexual characteristics. PMID:12495492

  3. Distribution of sup 125 I-neurotensin binding sites in human forebrain: Comparison with the localization of acetylcholinesterase

    SciTech Connect

    Szigethy, E.; Quirion, R.; Beaudet, A. )

    1990-07-22

    The distribution of 125I-neurotensin binding sites was compared with that of acetylcholinesterase reactivity in the human basal forebrain by using combined light microscopic radioautography/histochemistry. High 125I-neurotensin binding densities were observed in the bed nucleus of the stria terminalis, islands of Calleja, claustrum, olfactory tubercle, and central nucleus of the amygdala; lower levels were seen in the caudate, putamen, medial septum, diagonal band nucleus, and nucleus basalis of Meynert. Adjacent sections processed for cholinesterase histochemistry demonstrated a regional overlap between the distribution of labeled neurotensin binding sites and that of intense acetylcholinesterase staining in all of the above regions, except in the bed nucleus of the stria terminalis, claustrum, and central amygdaloid nucleus, where dense 125I-neurotensin labeling was detected over areas containing only weak to moderate cholinesterase staining. At higher magnification, 125I-neurotensin-labeled binding sites in the islands of Calleja, supraoptic nucleus of the hypothalamus, medial septum, diagonal band nucleus, and nucleus basalis of Meynert were selectively associated with neuronal perikarya found to be cholinesterase-positive in adjacent sections. Moderate 125I-neurotensin binding was also apparent over the cholinesterase-reactive neuropil of these latter three regions. These data suggest that neurotensin (NT) may directly influence the activity of magnocellular cholinergic neurons in the human basal forebrain, and may be involved in the physiopathology of dementing disorders such as Alzheimer's disease, in which these neurons have been shown to be affected.

  4. Recent experience modulates forebrain gene-expression in response to mate-choice cues in European starlings.

    PubMed Central

    Sockman, Keith W; Gentner, Timothy Q; Ball, Gregory F

    2002-01-01

    Mate-choice decisions can be experience dependent, but we know little about how the brain processes stimuli that release such decisions. Female European starlings (Sturnus vulgaris) prefer males with long-bout songs over males with short-bout songs, and show higher expression of the immediate early gene (IEG) ZENK in the auditory forebrain when exposed to long-bout songs than when exposed to short-bout songs. We exposed female starlings to a short-day photoperiod for one of three durations and then, on an increased photophase, exposed them to one week of long-bout or short-bout song experience. We then examined their IEG response to novel long-bout versus novel short-bout songs by quantifying ZENK protein in two song-processing areas: the caudo-medial hyperstriatum ventrale and the caudo-medial neostriatum. ZENK expression in both areas increased with tenure on short-day photoperiods, suggesting that short days sensitize females to song. The ZENK response bias toward long-bout songs was greater in females with long-bout experience than in females with short-bout experience, indicating that the forebrain response bias toward a preferred trait depends on recent experience with that category of trait. This surprising level of neuroplasticity is immediately relevant to the natural history and fitness of the organism, and may underlie a mechanism for optimizing mate-choice criteria amidst locally variable distributions of secondary sexual characteristics. PMID:12495492

  5. Relationship between the anterior forebrain mesocircuit and the default mode network in the structural bases of disorders of consciousness

    PubMed Central

    Lant, Nicholas D.; Gonzalez-Lara, Laura E.; Owen, Adrian M.; Fernández-Espejo, Davinia

    2015-01-01

    The specific neural bases of disorders of consciousness (DOC) are still not well understood. Some studies have suggested that functional and structural impairments in the default mode network may play a role in explaining these disorders. In contrast, others have proposed that dysfunctions in the anterior forebrain mesocircuit involving striatum, globus pallidus, and thalamus may be the main underlying mechanism. Here, we provide the first report of structural integrity of fiber tracts connecting the nodes of the mesocircuit and the default mode network in 8 patients with DOC. We found evidence of significant damage to subcortico-cortical and cortico-cortical fibers, which were more severe in vegetative state patients and correlated with clinical severity as determined by Coma Recovery Scale—Revised (CRS-R) scores. In contrast, fiber tracts interconnecting subcortical nodes were not significantly impaired. Lastly, we found significant damage in all fiber tracts connecting the precuneus with cortical and subcortical areas. Our results suggest a strong relationship between the default mode network – and most importantly the precuneus – and the anterior forebrain mesocircuit in the neural basis of the DOC. PMID:26693399

  6. Efficient generation of region-specific forebrain neurons from human pluripotent stem cells under highly defined condition

    PubMed Central

    Yuan, Fang; Fang, Kai-Heng; Cao, Shi-Ying; Qu, Zhuang-Yin; Li, Qi; Krencik, Robert; Xu, Min; Bhattacharyya, Anita; Su, Yu-Wen; Zhu, Dong-Ya; Liu, Yan

    2015-01-01

    Human pluripotent stem cells (hPSCs) have potential to differentiate to unlimited number of neural cells, which provide powerful tools for neural regeneration. To date, most reported protocols were established with an animal feeder system. However, cells derived on this system are inappropriate for the translation to clinical applications because of the introduction of xenogenetic factors. In this study, we provided an optimized paradigm to generate region-specific forebrain neurons from hPSCs under a defined system. We assessed five conditions and found that a vitronectin-coated substrate was the most efficient method to differentiate hPSCs to neurons and astrocytes. More importantly, by applying different doses of purmorphamine, a small-molecule agonist of sonic hedgehog signaling, hPSCs were differentiated to different region-specific forebrain neuron subtypes, including glutamatergic neurons, striatal medium spiny neurons, and GABA interneurons. Our study offers a highly defined system without exogenetic factors to produce human neurons and astrocytes for translational medical studies, including cell therapy and stem cell-based drug discovery. PMID:26670131

  7. Genealogical correspondence of a forebrain centre implies an executive brain in the protostome-deuterostome bilaterian ancestor.

    PubMed

    Wolff, Gabriella H; Strausfeld, Nicholas J

    2016-01-01

    Orthologous genes involved in the formation of proteins associated with memory acquisition are similarly expressed in forebrain centres that exhibit similar cognitive properties. These proteins include cAMP-dependent protein kinase A catalytic subunit (PKA-Cα) and phosphorylated Ca(2+)/calmodulin-dependent protein kinase II (pCaMKII), both required for long-term memory formation which is enriched in rodent hippocampus and insect mushroom bodies, both implicated in allocentric memory and both possessing corresponding neuronal architectures. Antibodies against these proteins resolve forebrain centres, or their equivalents, having the same ground pattern of neuronal organization in species across five phyla. The ground pattern is defined by olfactory or chemosensory afferents supplying systems of parallel fibres of intrinsic neurons intersected by orthogonal domains of afferent and efferent arborizations with local interneurons providing feedback loops. The totality of shared characters implies a deep origin in the protostome-deuterostome bilaterian ancestor of elements of a learning and memory circuit. Proxies for such an ancestral taxon are simple extant bilaterians, particularly acoels that express PKA-Cα and pCaMKII in discrete anterior domains that can be properly referred to as brains. PMID:26598732

  8. Genome-wide analysis of epigenomic alterations in fetal mouse forebrain after exposure to low doses of bisphenol A.

    PubMed

    Yaoi, Takeshi; Itoh, Kyoko; Nakamura, Keiko; Ogi, Hiroshi; Fujiwara, Yasuhiro; Fushiki, Shinji

    2008-11-21

    Bisphenol A (BPA) is one of endocrine disrupting chemicals, being distributed widely in the environment. We have been studying the low dose effects of BPA on murine forebrain development. Here, we have investigated the genome-wide effect of maternal exposure to BPA on the epigenome in mouse forebrain at E12.5 and at E14.5. We scanned CpG methylation status in 2500 NotI loci, representing 48 (de)methylated unique loci. Methylation status in most of them was primarily developmental stage-dependent. Each of almost all cloned NotI loci was located in a CpG island (CGI) adjacent to 5' end of the transcriptional unit. The mRNA expression of two functionally related genes changed with development as well as the exposure to BPA. In both genes, changes at the transcriptional level correlated well with the changes in NotI methylation status. Taken together, epigenetic alterations in promoter-associated CGIs after exposure to BPA may underlie some effects on brain development. PMID:18804091

  9. Expression of Fos during sham sucrose intake in rats with central gustatory lesions

    PubMed Central

    Mungarndee, Suriyaphun S.; Lundy, Robert F.; Norgren, Ralph

    2008-01-01

    For humans and rodents, ingesting sucrose is rewarding. This experiment tested the prediction that the neural activity produced by sapid sucrose reaches reward systems via projections from the pons through the limbic system. Gastric cannulas drained ingested fluid before absorption. For 10 days, the rats alternated an hour of this sham ingestion between sucrose and water. On the final test day, half of them sham drank water and the other half 0.6 M sucrose. Thirty minutes later, the rats were killed and their brains immunohistochemically stained for Fos. The groups consisted of controls and rats with excitotoxic lesions in the gustatory thalamus (TTA), the medial (gustatory) parabrachial nucleus (PBN), or the lateral (visceral afferent) parabrachial nucleus. In controls, compared with water, sham ingesting sucrose produced significantly more Fos-positive neurons in the nucleus of the solitary tract, PBN, TTA, and gustatory cortex (GC). In the ventral forebrain, sucrose sham licking increased Fos in the bed nucleus of the stria terminalis, central nucleus of amygdala, and the shell of nucleus accumbens. Thalamic lesions blocked the sucrose effect in GC but not in the ventral forebrain. After lateral PBN lesions, the Fos distributions produced by distilled H2O or sucrose intake did not differ from controls. Bilateral medial PBN damage, however, eliminated the sucrose-induced Fos increase not only in the TTA and GC but also in the ventral forebrain. Thus ventral forebrain areas associated with affective responses appear to be activated directly by PBN gustatory neurons rather than via the thalamocortical taste system. PMID:18635449

  10. Expression of Fos during sham sucrose intake in rats with central gustatory lesions.

    PubMed

    Mungarndee, Suriyaphun S; Lundy, Robert F; Norgren, Ralph

    2008-09-01

    For humans and rodents, ingesting sucrose is rewarding. This experiment tested the prediction that the neural activity produced by sapid sucrose reaches reward systems via projections from the pons through the limbic system. Gastric cannulas drained ingested fluid before absorption. For 10 days, the rats alternated an hour of this sham ingestion between sucrose and water. On the final test day, half of them sham drank water and the other half 0.6 M sucrose. Thirty minutes later, the rats were killed and their brains immunohistochemically stained for Fos. The groups consisted of controls and rats with excitotoxic lesions in the gustatory thalamus (TTA), the medial (gustatory) parabrachial nucleus (PBN), or the lateral (visceral afferent) parabrachial nucleus. In controls, compared with water, sham ingesting sucrose produced significantly more Fos-positive neurons in the nucleus of the solitary tract, PBN, TTA, and gustatory cortex (GC). In the ventral forebrain, sucrose sham licking increased Fos in the bed nucleus of the stria terminalis, central nucleus of amygdala, and the shell of nucleus accumbens. Thalamic lesions blocked the sucrose effect in GC but not in the ventral forebrain. After lateral PBN lesions, the Fos distributions produced by distilled H(2)O or sucrose intake did not differ from controls. Bilateral medial PBN damage, however, eliminated the sucrose-induced Fos increase not only in the TTA and GC but also in the ventral forebrain. Thus ventral forebrain areas associated with affective responses appear to be activated directly by PBN gustatory neurons rather than via the thalamocortical taste system. PMID:18635449

  11. The role of cholinergic basal forebrain neurons in adenosine-mediated homeostatic control of sleep: lessons from 192 IgG-saporin lesions.

    PubMed

    Kalinchuk, A V; McCarley, R W; Stenberg, D; Porkka-Heiskanen, T; Basheer, R

    2008-11-11

    A topic of high current interest and controversy is the basis of the homeostatic sleep response, the increase in non-rapid-eye-movement (NREM) sleep and NREM-delta activity following sleep deprivation (SD). Adenosine, which accumulates in the cholinergic basal forebrain (BF) during SD, has been proposed as one of the important homeostatic sleep factors. It is suggested that sleep-inducing effects of adenosine are mediated by inhibiting the wake-active neurons of the BF, including cholinergic neurons. Here we examined the association between SD-induced adenosine release, the homeostatic sleep response and the survival of cholinergic neurons in the BF after injections of the immunotoxin 192 immunoglobulin G (IgG)-saporin (saporin) in rats. We correlated SD-induced adenosine level in the BF and the homeostatic sleep response with the cholinergic cell loss 2 weeks after local saporin injections into the BF, as well as 2 and 3 weeks after i.c.v. saporin injections. Two weeks after local saporin injection there was an 88% cholinergic cell loss, coupled with nearly complete abolition of the SD-induced adenosine increase in the BF, the homeostatic sleep response, and the sleep-inducing effects of BF adenosine infusion. Two weeks after i.c.v. saporin injection there was a 59% cholinergic cell loss, correlated with significant increase in SD-induced adenosine level in the BF and an intact sleep response. Three weeks after i.c.v. saporin injection there was an 87% cholinergic cell loss, nearly complete abolition of the SD-induced adenosine increase in the BF and the homeostatic response, implying that the time course of i.c.v. saporin lesions is a key variable in interpreting experimental results. Taken together, these results strongly suggest that cholinergic neurons in the BF are important for the SD-induced increase in adenosine as well as for its sleep-inducing effects and play a major, although not exclusive, role in sleep homeostasis. PMID:18805464

  12. High affinity ( sup 3 H)glibenclamide binding sites in rat neuronal and cardiac tissue: Localization and developmental characteristics

    SciTech Connect

    Miller, J.A.; Velayo, N.L.; Dage, R.C.; Rampe, D. )

    1991-01-01

    We examined the binding of the antidiabetic sulfonylurea (3H) glibenclamide to rat brain and heart membranes. High affinity binding was observed in adult rat forebrain (Kd = 137.3 pM, maximal binding site density = 91.8 fmol/mg of protein) and ventricle (Kd = 77.1 pM, maximal binding site density = 65.1 fmol/mg of protein). Binding site density increased approximately 250% in forebrain membranes during postnatal development but was constant in ventricular membranes. Quantitative autoradiography was used to examine the regional distribution of (3H) glibenclamide binding sites in sections from rat brain, spinal cord and heart. The greatest density of binding in adult brain was found in the substantia nigra and globus pallidus, whereas the other areas displayed heterogenous binding. In agreement with the membrane binding studies, 1-day-old rat brain had significantly fewer (3H)glibenclamide binding sites than adult brain. Additionally, the pattern of distribution of these sites was qualitatively different from that of the adult. In adult rat spinal cord, moderate binding densities were observed in spinal cord gray and displayed a rostral to caudal gradient. In adult rat heart, moderate binding densities were observed and the sites were distributed homogeneously. In conclusion, significant development of (3H)glibenclamide binding sites was seen in the brain but not the heart during postnatal maturation. Furthermore, a heterogeneous distribution of binding sites was observed in both the brain and spinal cord of adult rats.

  13. Adolescent Intermittent Ethanol Exposure Is Associated with Increased Risky Choice and Decreased Dopaminergic and Cholinergic Neuron Markers in Adult Rats

    PubMed Central

    Boutros, Nathalie; Semenova, Svetlana; Liu, Wen; Crews, Fulton T.

    2015-01-01

    Background: Binge drinking is prevalent during adolescence and may have effects on the adult brain and behavior. The present study investigated whether adolescent intermittent ethanol exposure alters adult risky choice and prefrontal dopaminergic and forebrain cholinergic neuronal marker levels in male Wistar rats. Methods: Adolescent (postnatal day 28–53) rats were administered 5g/kg of 25% (vol/vol) ethanol 3 times/d in a 2-days–on/2-days–off exposure pattern. In adulthood, risky choice was assessed in the probability discounting task with descending and ascending series of large reward probabilities and after acute ethanol challenge. Immunohistochemical analyses assessed tyrosine hydroxylase, a marker of dopamine and norepinephrine in the prelimbic and infralimbic cortices, and choline acetyltransferase, a marker of cholinergic neurons, in the basal forebrain. Results: All of the rats preferred the large reward when it was delivered with high probability. When the large reward became unlikely, control rats preferred the smaller, safe reward, whereas adolescent intermittent ethanol-exposed rats continued to prefer the risky alternative. Acute ethanol had no effect on risky choice in either group of rats. Tyrosine hydroxylase (prelimbic cortex only) and choline acetyltransferase immunoreactivity levels were decreased in adolescent intermittent ethanol-exposed rats compared with controls. Risky choice was negatively correlated with choline acetyltransferase, implicating decreased forebrain cholinergic activity in risky choice. Conclusions: The decreases in tyrosine hydroxylase and choline acetyltransferase immunoreactivity suggest that adolescent intermittent ethanol exposure has enduring neural effects that may lead to altered adult behaviors, such as increased risky decision making. In humans, increased risky decision making could lead to maladaptive, potentially harmful consequences. PMID:25612895

  14. Screening for candidate genes involved in the production of mouse subventricular zone proliferative cells and an estimation of their changes in evolutionary pressure during primate evolution

    PubMed Central

    Tabata, Hidenori; Hachiya, Tsuyoshi; Nagata, Koh-ichi; Sakakibara, Yasubumi; Nakajima, Kazunori

    2013-01-01

    During neocortical development, excitatory neurons are produced from apical progenitors in the ventricular zone (VZ) or from dividing cells in the subventricular zone (SVZ). We previously reported that the direct progenies of VZ cells in mice slowly exit the VZ and accumulate just above the VZ (lower SVZ) as multipolar migrating neurons, whereas subsequently dividing cells in the SVZ exit the VZ earlier than the former and become widely distributed in the SVZ. These two populations are named the slowly exiting population (SEP) and the rapidly exiting population (REP), respectively. In mice, REP cells include basal progenitors as the major population and are characterized by a long ascending process; their morphology resembles that of basal radial glial cells (bRGs), which have been observed in the inner and outer SVZ in primates. The dramatic increase in the number of bRGs in primates, especially in humans, is thought to underlie the acquisition of a huge cortex during evolution. We previously reported that the REP/SEP production rate in the lateral cortical VZ is higher than that in the dorsomedial VZ in mice. To search for molecules responsible for the higher REP production in the lateral cortical VZ, we conducted microarray analyses and identified genes that were differentially expressed between the lateral and medial VZs in mice. These genes were considered to be among the candidates responsible for the regulation of the REP/SEP production rate. To investigate the selection pressures during primate evolution on these candidate genes, we estimated the synonymous vs. non-synonymous base substitution rates. As a result, the negative selection pressures on the Megf11, Dmrt3, and Cntn3 genes were found to be significantly weaker in primates than in non-primates, while those on Jag1, Ntrk2, and Pmp22 were stronger. Candidate molecules responsible for primate cortical expansion through an increase in bRGs may be included among these genes. PMID:23914158

  15. Increased doublecortin (DCX) expression and incidence of DCX-immunoreactive multipolar cells in the subventricular zone-olfactory bulb system of suicides

    PubMed Central

    Maheu, Marissa E.; Devorak, Julia; Freibauer, Alexander; Davoli, Maria Antonietta; Turecki, Gustavo; Mechawar, Naguib

    2015-01-01

    Postmortem studies have confirmed the occurrence of adult hippocampal neurogenesis in humans and implicated this process in antidepressant response, yet neurogenesis in other regions remains to be examined in the context of depression. Here we assess the extent of subventricular zone-olfactory bulb (SVZ-OB) neurogenesis in adult humans having died by suicide. Protein expression of proliferative and neurogenic markers Sox2, proliferating cell nuclear antigen, and doublecortin (DCX) were examined in postmortem SVZ and OB samples from depressed suicides and matched sudden-death controls. In the SVZ, DCX-immunoreactive (IR) cells displayed phenotypes typical of progenitors, whereas in the olfactory tract (OT), they were multipolar with variable size and morphologies suggestive of differentiating cells. DCX expression was significantly increased in the OB of suicides, whereas SVZ DCX expression was higher among unmedicated, but not antidepressant-treated, suicides. Although very few DCX-IR cells were present in the control OT, they were considerably more common in suicides and correlated with OB DCX levels. Suicides also displayed higher DCX-IR process volumes. These results support the notion that OB neurogenesis is minimal in adult humans. They further raise the possibility that the differentiation and migration of SVZ-derived neuroblasts may be altered in unmedicated suicides, leading to an accumulation of ectopically differentiating cells in the OT. Normal SVZ DCX expression among suicides receiving antidepressants suggests a potentially novel mode of action of antidepressant medication. Given the modest group sizes and rarity of DCX-IR cells assessed here, a larger-scale characterization will be required before firm conclusions can be made regarding the identity of these cells. PMID:26082689

  16. New Striatal Neurons in a Mouse Model of Progressive Striatal Degeneration Are Generated in both the Subventricular Zone and the Striatal Parenchyma

    PubMed Central

    Luzzati, Federico; De Marchis, Silvia; Parlato, Rosanna; Gribaudo, Simona; Schütz, Günther; Fasolo, Aldo; Peretto, Paolo

    2011-01-01

    Acute striatal lesions increase proliferation in the subventricular zone (SVZ) and induce migration of SVZ neuroblasts to the striatum. However, the potential of these cells to replace acutely degenerated neurons is controversial. The possible contribution of parenchymal progenitors to striatal lesion-induced neurogenesis has been poorly explored. Here, we present a detailed investigation of neurogenesis in the striatum of a mouse model showing slow progressive neurodegeneration of striatal neurons, the Creb1Camkcre4Crem−/− mutant mice (CBCM). By using BrdU time course analyses, intraventricular injections of a cell tracker and 3D reconstructions we showed that neurodegeneration in CBCM mice stimulates the migration of SVZ neuroblasts to the striatum without altering SVZ proliferation. SVZ-neuroblasts migrate as chains through the callosal striatal border and then enter within the striatal parenchyma as individual cells. In addition, a population of clustered neuroblasts showing high turnover rates were observed in the mutant striatum that had not migrated from the SVZ. Clustered neuroblasts might originate within the striatum itself because they are specifically associated with parenchymal proliferating cells showing features of intermediate neuronal progenitors such as clustering, expression of EGF receptor and multiple glial (SOX2, SOX9, BLBP) and neuronal (Dlx, Sp8, and to some extent DCX) markers. Newborn striatal neurons had a short lifespan and did not replace projection neurons nor expressed sets of transcription factors involved in their specification. The differentiation failure of endogenous neuroblasts likely occurred cell autonomously because transplanted wild type embryonic precursors correctly differentiated into striatal projection neurons. Thus, we propose that under progressive degeneration, neither SVZ derived nor intra-striatal generated neurons have the potential to differentiate into striatal projection neurons. PMID:21980380

  17. Egr-1 is a critical regulator of EGF-receptor-mediated expansion of subventricular zone neural stem cells and progenitors during recovery from hypoxia–hypoglycemia

    PubMed Central

    Alagappan, Dhivyaa; Balan, Murugabaskar; Jiang, Yuhui; Cohen, Rachel B.; Kotenko, Sergei V.; Levison, Steven W.

    2013-01-01

    We recently established that the EGF-R (epidermal growth factor receptor) (EGF-R) is an essential regulator of the reactive expansion of SVZ (subventricular zone) NPs (neural precursors) that occurs during recovery from hypoxic-ischemic brain injury. The purpose of the current studies was to identify the conditions and the transcription factor (s) responsible for inducing the EGF-R. Here, we show that the increase in EGF-R expression and the more rapid division of the NPs can be recapitulated in in vitro by exposing SVZ NPs to hypoxia and hypoglycemia simultaneously, but not separately. The EGF-R promoter has binding sites for multiple transcription factors that includes the zinc finger transcription factor, Egr-1. We show that Egr-1 expression increases in NPs, but not astrocytes, following hypoxia and hypoglycemia where it accumulates in the nucleus. To determine whether Egr-1 is necessary for EGF-R expression, we used SiRNAs (small interfering RNA) specific for Egr-1 to decrease Egr-1 expression. Knocking-down Egr-1 decreased basal levels of EGF-R and it abolished the stress-induced increase in EGF-R expression. By contrast, HIF-1 accumulation did not contribute to EGF-R expression and FGF-2 only modestly induced EGF-R. These studies establish a new role for Egr-1 in regulating the expression of the mitogenic EGF-R. They also provide new information into mechanisms that promote NP expansion and provide insights into strategies for amplifying the numbers of stem cells for CNS (central nervous system) regeneration. PMID:23763269

  18. Post-stroke transplantation of adult subventricular zone derived neural progenitor cells--A comprehensive analysis of cell delivery routes and their underlying mechanisms.

    PubMed

    Doeppner, Thorsten R; Kaltwasser, Britta; Teli, Mahesh K; Sanchez-Mendoza, Eduardo H; Kilic, Ertugrul; Bähr, Mathias; Hermann, Dirk M

    2015-11-01

    With neuroprotective approaches having failed until recently, current focus on experimental stroke research has switched towards manipulation of post-ischemic neuroregeneration. Transplantation of subventricular zone (SVZ) derived neural progenitor cells (NPCs) is a promising strategy for promotion of neurological recovery. Yet, fundamental questions including the optimal cell delivery route still have to be addressed. Consequently, male C57BL6 mice were exposed to transient focal cerebral ischemia and allowed to survive for as long as 84 days post-stroke. At 6h post-stroke, NPCs were grafted using six different cell delivery routes, i.e., intravenous, intraarterial, ipsilateral intrastriatal, contralateral intrastriatal, ipsilateral intraventricular and ipsilateral intracortical injection. Control mice received PBS only using the aforementioned delivery routes. Intralesional numbers of GFP(+) NPCs were high only after ipsilateral intrastriatal transplantation, whereas other injection paradigms only yielded comparatively small numbers of grafted cells. However, acute neuroprotection and improved functional outcome were observed after both systemic (i.e., intraarterial and intravenous) and ipsilateral intrastriatal transplantation only. Whereas systemic cell delivery induced acute and long-term neuroprotection, reduction of brain injury after ipsilateral intrastriatal cell grafting was only temporary, in line with the loss of transplanted NPCs in the brain. Both systemic and ipsilateral intrastriatal NPC delivery reduced microglial activation and leukocyte invasion, thus reducing free radical formation within the ischemic brain. On the contrary, only systemic NPC administration stabilized the blood-brain-barrier and reduced leukocytosis in the blood. Although intraarterial NPC transplantation was as effective as intravenous cell grafting, mortality of stroke mice was high using the intraarterial delivery route. Consequently, intravenous delivery of native NPCs in

  19. Targeting p38 mitogen-activated protein kinase signaling restores subventricular zone neural stem cells and corrects neuromotor deficits in Atm knockout mouse.

    PubMed

    Kim, Jeesun; Wong, Paul K Y

    2012-07-01

    Ataxia-telangiectasia (A-T) is a progressive degenerative disorder that results in major neurological disability. In A-T patients, necropsy has revealed atrophy of cerebellar cortical layers along with Purkinje and granular cell loss. We have previously identified an oxidative stress-mediated increase in phospho-p38 mitogen-activated protein kinase (MAPK) and the resultant downregulation of Bmi-1 and upregulation of p21 as key components of the mechanism causing defective proliferation of neural stem cells (NSCs) isolated from the subventricular zone (SVZ) of Atm(-/-) mice. However, the in vivo aspect of alteration in SVZ tissue and the functional significance of p38MAPK activation in NSCs for neuropathogenesis of ATM deficiency remain unknown. Here we show that the NSC population was abnormally decreased in the SVZ of 3-month-old Atm(-/-) mice; this decrease was accompanied by p38MAPK activation. However, after a 2-month treatment with the p38MAPK inhibitor SB203580, starting at 1 month old, Atm(-/-) mice showed restoration of normal levels of Bmi-1 and p21 with the rescue of NSC population in the SVZ. In addition, treated Atm(-/-) mice exhibited more Purkinje cells in the cerebellum. Most importantly, motor coordination of Atm(-/-) mice was significantly improved in the treatment group. Our results show for the first time in vivo evidence of depleted NSCs in the SVZ of Atm(-/-) mice and also demonstrate that pharmacologic inhibition of p38MAPK signaling has the potential to treat neurological defects of A-T. This study provides a promising approach targeting the oxidative stress-dependent p38 signaling pathway not only for A-T but also for other neurodegenerative disorders. PMID:23197859

  20. Distinct effects of pramipexole on the proliferation of adult mouse sub-ventricular zone-derived cells and the appearance of a neuronal phenotype.

    PubMed

    Merlo, Sara; Canonico, Pier Luigi; Sortino, Maria Angela

    2011-05-01

    Pramipexole (PPX) is a dopamine agonist with an 8-fold higher affinity for D3 than D2 receptor, whose efficacy in the treatment of Parkinson's disease is based on dopamine agonistic activity. PPX has also been recently shown to be endowed with neuroprotective activity and neurogenic potential. The aim of this study was a more detailed characterization of PPX-induced neurogenesis. Both D2 and D3 receptors are expressed in floating and differentiated neurospheres obtained from the sub-ventricular zone (SVZ) of adult mice. Treatment of secondary neurospheres with 10 μM PPX causes a marked induction of cell proliferation, assessed by enhanced cell number and S phase population at cell cycle analysis. Stimulation of proliferation by PPX is still detectable in plated neurospheres before the onset of migration and differentiation, as by enhanced BrdU incorporation. This effect is sensitive to the selective D3 dopamine receptor antagonist U99194A, as well as to sulpiride. A 24 h treatment with PPX does not modify the morphology of neurosphere-derived cells, but causes an increase of glial fibrillary acidic protein (GFAP)-positive cells, an effect sensitive to both D2 and D3 antagonism. Differentiation toward the neuronal lineage is increased by PPX as shown by enhancement of the cell population positive to the early neuronal marker doublecortin (DCX) at 24 h and the mature neuronal marker microtubule associated protein (MAP2) at 72 h. This effect is not modified by treatment with U99194A and is mimicked by BDNF. Accordingly, PPX increases BDNF release with a mechanism involving D2 but not D3 receptors. PMID:21272591

  1. Acute and long-term exposure to chlorpyrifos induces cell death of basal forebrain cholinergic neurons through AChE variants alteration.

    PubMed

    del Pino, Javier; Moyano, Paula; Anadon, María José; García, José Manuel; Díaz, María Jesús; García, Jimena; Frejo, María Teresa

    2015-10-01

    Chlorpyrifos (CPF) is one of the most widely used organophosphates insecticides that has been reported to induce cognitive disorders both after acute and repeated administration similar to those induced in Alzheimer's disease (AD). However, the mechanisms through which it induces these effects are unknown. On the other hand, the cholinergic system, mainly basal forebrain cholinergic neurons, is involved in learning and memory regulation, and an alteration of cholinergic transmission or/and cholinergic cell loss could induce these effects. In this regard, it has been reported that CPF can affect cholinergic transmission, and alter AChE variants, which have been shown to be related with basal forebrain cholinergic neuronal loss. According to these data, we hypothesized that CPF could induce basal forebrain cholinergic neuronal loss through cholinergic transmission and AChE variants alteration. To prove this hypothesis, we evaluated in septal SN56 basal forebrain cholinergic neurons, the CPF toxic effects after 24h and 14 days exposure on neuronal viability and the cholinergic mechanisms related to it. This study shows that CPF impaired cholinergic transmission, induced AChE inhibition and, only after long-term exposure, increased CHT expression, which suggests that acetylcholine levels alteration could be mediated by these actions. Moreover, CPF induces, after acute and long-term exposure, cell death in cholinergic neurons in the basal forebrain and this effect is independent of AChE inhibition and acetylcholine alteration, but was mediated partially by AChE variants alteration. Our present results provide a new understanding of the mechanisms contributing to the harmful effects of CPF on neuronal function and viability, and the possible relevance of CPF in the pathogenesis of neurodegenerative diseases. PMID:26210949

  2. Neurons in the Primate Medial Basal Forebrain Signal Combined Information about Reward Uncertainty, Value, and Punishment Anticipation

    PubMed Central

    Leopold, David A.; Hikosaka, Okihide

    2015-01-01

    It has been suggested that the basal forebrain (BF) exerts strong influences on the formation of memory and behavior. However, what information is used for the memory-behavior formation is unclear. We found that a population of neurons in the medial BF (medial septum and diagonal band of Broca) of macaque monkeys encodes a unique combination of information: reward uncertainty, expected reward value, anticipation of punishment, and unexpected reward and punishment. The results were obtained while the monkeys were expecting (often with uncertainty) a rewarding or punishing outcome during a Pavlovian procedure, or unexpectedly received an outcome outside the procedure. In vivo anterograde tracing using manganese-enhanced MRI suggested that the major recipient of these signals is the intermediate hippocampal formation. Based on these findings, we hypothesize that the medial BF identifies various contexts and outcomes that are critical for memory processing in the hippocampal formation. PMID:25972172

  3. Rescue of NGF-deficient mice II: basal forebrain cholinergic projections require NGF for target innervation but not guidance.

    PubMed

    Phillips, Heidi S; Nishimura, Merry; Armanini, Mark P; Chen, Karen; Albers, Kathryn M; Davis, Brian M

    2004-04-29

    Basal forebrain cholinergic (BFC) neurons are an important substrate of cognitive function and are hypothesized to require the presence of nerve growth factor (NGF) for survival and target innervation. NGF-deficient mice develop BFC neurons that extend projections into telencephalic targets, but the mice perish before innervation is fully established. Rescue of NGF-deficient mice by transgenic expression of NGF under the keratin promoter yields viable mice with disrupted CNS expression of NGF. In the current study, rescued NGF-deficient mice contain normal numbers of septal cholinergic neurons yet reveal severe compromise of cholinergic innervation of both cortex and hippocampus. Surprisingly, intracerebroventricular infusion of NGF into juvenile mice can induce an essentially normal pattern of cholinergic innervation of the hippocampus. These results indicate that NGF is required for induction of proper innervation by BFC neurons, but that the cellular pattern of expression of this factor is not critical for specifying the distribution of axon terminals. PMID:15093680

  4. Neurons in the Primate Medial Basal Forebrain Signal Combined Information about Reward Uncertainty, Value, and Punishment Anticipation.

    PubMed

    Monosov, Ilya E; Leopold, David A; Hikosaka, Okihide

    2015-05-13

    It has been suggested that the basal forebrain (BF) exerts strong influences on the formation of memory and behavior. However, what information is used for the memory-behavior formation is unclear. We found that a population of neurons in the medial BF (medial septum and diagonal band of Broca) of macaque monkeys encodes a unique combination of information: reward uncertainty, expected reward value, anticipation of punishment, and unexpected reward and punishment. The results were obtained while the monkeys were expecting (often with uncertainty) a rewarding or punishing outcome during a Pavlovian procedure, or unexpectedly received an outcome outside the procedure. In vivo anterograde tracing using manganese-enhanced MRI suggested that the major recipient of these signals is the intermediate hippocampal formation. Based on these findings, we hypothesize that the medial BF identifies various contexts and outcomes that are critical for memory processing in the hippocampal formation. PMID:25972172

  5. The Planar Cell Polarity Transmembrane Protein Vangl2 Promotes Dendrite, Spine and Glutamatergic Synapse Formation in the Mammalian Forebrain.

    PubMed

    Okerlund, Nathan D; Stanley, Robert E; Cheyette, Benjamin N R

    2016-07-01

    The transmembrane protein Vangl2, a key regulator of the Wnt/planar cell polarity (PCP) pathway, is involved in dendrite arbor elaboration, dendritic spine formation and glutamatergic synapse formation in mammalian central nervous system neurons. Cultured forebrain neurons from Vangl2 knockout mice have simpler dendrite arbors, fewer total spines, less mature spines and fewer glutamatergic synapse inputs on their dendrites than control neurons. Neurons from mice heterozygous for a semidominant Vangl2 mutation have similar but not identical phenotypes, and these phenotypes are also observed in Golgi-stained brain tissue from adult mutant mice. Given increasing evidence linking psychiatric pathophysiology to these subneuronal sites and structures, our findings underscore the relevance of core PCP proteins including Vangl2 to the underlying biology of major mental illnesses and their treatment. PMID:27606324

  6. Human neural stem cells promote proliferation of endogenous neural stem cells and enhance angiogenesis in ischemic rat brain

    PubMed Central

    Ryu, Sun; Lee, Seung-Hoon; Kim, Seung U.; Yoon, Byung-Woo

    2016-01-01

    Transplantation of human neural stem cells into the dentate gyrus or ventricle of rodents has been reportedly to enhance neurogenesis. In this study, we examined endogenous stem cell proliferation and angiogenesis in the ischemic rat brain after the transplantation of human neural stem cells. Focal cerebral ischemia in the rat brain was induced by middle cerebral artery occlusion. Human neural stem cells were transplanted into the subventricular zone. The behavioral performance of human neural stem cells-treated ischemic rats was significantly improved and cerebral infarct volumes were reduced compared to those in untreated animals. Numerous transplanted human neural stem cells were alive and preferentially localized to the ipsilateral ischemic hemisphere. Furthermore, 5-bromo-2′-deoxyuridine-labeled endogenous neural stem cells were observed in the subventricular zone and hippocampus, where they differentiated into cells immunoreactive for the neural markers doublecortin, neuronal nuclear antigen NeuN, and astrocyte marker glial fibrillary acidic protein in human neural stem cells-treated rats, but not in the untreated ischemic animals. The number of 5-bromo-2′-deoxyuridine-positive ⁄ anti-von Willebrand factor-positive proliferating endothelial cells was higher in the ischemic boundary zone of human neural stem cells-treated rats than in controls. Finally, transplantation of human neural stem cells in the brains of rats with focal cerebral ischemia promoted the proliferation of endogenous neural stem cells and their differentiation into mature neural-like cells, and enhanced angiogenesis. This study provides valuable insights into the effect of human neural stem cell transplantation on focal cerebral ischemia, which can be applied to the development of an effective therapy for stroke. PMID:27073384

  7. Constitutive and inflammatory induction of alpha and beta chemokines in human first trimester forebrain astrocytes and neurons.

    PubMed

    Bakhiet, Moiz; Mousa, Alyaa; Seiger, Ake; Andersson, Jan

    2002-05-01

    Chemokine effects on leukocyte infiltration into the central nervous system (CNS) are key events in the inflammatory processes of neuroimmunologic and neuroinfectious diseases. Because, chemokines may play important roles in proliferation and differentiation of brain cells and in the initiation and progression of CNS inflammatory disorders, we analyzed constitutive and inflammatory-induced expression of alpha and beta chemokines in human first trimester forebrain cells. Constitutive induction of IL-8, MIP-1alpha, MIP-1beta, MCP-1 and regulated on activation, normal T-cell expressed, and secreted (Rantes) was detected in cryostat sections of embryonic forebrains in an age-dependent manner. Dissociated cell cultures were studied for spontaneous chemokine induction and after stimulation with the trypanosome lymphocyte triggering factor (TLTF), a novel trypanokine secreted by African trypanosomes that triggers a complex of immune responses. LPS and variant surface glycoprotein (VSG) were used as controls. In cultures, unstimulated cells expressed minimal chemokine levels except for Rantes. In response to TLTF and LPS, but not VSG, all chemokines were highly induced at the mRNA and protein levels in a dose- and age-dependent manner. Combined assays (in situ hybridization and immunohistochemistry) revealed that astrocytes and neurons are major sources for chemokines. These results illustrate the ability of resident brain cells to constitutively express chemokine genes, which may suggest an important role for chemokines during brain development. Furthermore, TLTF-induced chemokine expression in astrocytes and neurons indicate the capacity of TLTF to provoke neuroinflammation in the brain, which may have important therapeutic implications for the neurological manifestations of African trypanosomiasis. PMID:12009570

  8. Distribution of secretagogin-containing neurons in the basal forebrain of mice, with special reference to the cholinergic corticopetal system

    PubMed Central

    Gyengesi, Erika; Andrews, Zane B.; Paxinos, George; Zaborszky, Laszlo

    2013-01-01

    Cholinergic and GABAergic corticopetal neurons in the basal forebrain play important roles in cortical activation, sensory processing, and attention. Cholinergic neurons are intermingled with peptidergic, and various calcium binding protein-containing cells, however, the functional role of these neurons is not well understood. In this study we examined the expression pattern of secretagogin (Scgn), a newly described calcium-binding protein, in neurons of the basal forebrain. We also assessed some of the corticopetal projections of Scgn neurons and their co-localization with choline acetyltransferase (ChAT), neuropeptide-Y, and other calcium-binding proteins (i.e., calbindin, calretinin, and parvalbumin). Scgn is expressed in cell bodies of the medial and lateral septum, vertical and horizontal diagonal band nuclei, and of the extension of the amygdala but it is almost absent in the ventral pallidum. Scgn is co-localized with ChAT in neurons of the bed nucleus of the stria terminalis, extension of the amygdala, and interstitial nucleus of the posterior limb of the anterior commissure. Scgn was co-localized with calretinin in the accumbens nucleus, medial division of the bed nucleus of stria terminalis, the extension of the amygdala, and interstitial nucleus of the posterior limb of the anterior commissure. We have not found co-expression of Scgn with parvalbumin, calbindin, or neuropeptide-Y. Retrograde tracing studies using Fluoro Gold in combination with Scgn-specific immunohistochemistry revealed that Scgn neurons situated in the nucleus of the horizontal limb of the diagonal band project to retrosplenial and cingulate cortical areas. PMID:23376788

  9. Cytoskeletal Regulation Dominates Temperature-Sensitive Proteomic Changes of Hibernation in Forebrain of 13-Lined Ground Squirrels

    PubMed Central

    Hindle, Allyson G.; Martin, Sandra L.

    2013-01-01

    13-lined ground squirrels, Ictidomys tridecemlineatus, are obligate hibernators that transition annually between summer homeothermy and winter heterothermy – wherein they exploit episodic torpor bouts. Despite cerebral ischemia during torpor and rapid reperfusion during arousal, hibernator brains resist damage and the animals emerge neurologically intact each spring. We hypothesized that protein changes in the brain underlie winter neuroprotection. To identify candidate proteins, we applied a sensitive 2D gel electrophoresis method to quantify protein differences among forebrain extracts prepared from ground squirrels in two summer, four winter and fall transition states. Proteins that differed among groups were identified using LC-MS/MS. Only 84 protein spots varied significantly among the defined states of hibernation. Protein changes in the forebrain proteome fell largely into two reciprocal patterns with a strong body temperature dependence. The importance of body temperature was tested in animals from the fall; these fall animals use torpor sporadically with body temperatures mirroring ambient temperatures between 4 and 21°C as they navigate the transition between summer homeothermy and winter heterothermy. Unlike cold-torpid fall ground squirrels, warm-torpid individuals strongly resembled the homeotherms, indicating that the changes observed in torpid hibernators are defined by body temperature, not torpor per se. Metabolic enzymes were largely unchanged despite varied metabolic activity across annual and torpor-arousal cycles. Instead, the majority of the observed changes were cytoskeletal proteins and their regulators. While cytoskeletal structural proteins tended to differ seasonally, i.e., between summer homeothermy and winter heterothermy, their regulatory proteins were more strongly affected by body temperature. Changes in the abundance of various isoforms of the microtubule assembly and disassembly regulatory proteins dihydropyrimidinase

  10. Song environment affects singing effort and vasotocin immunoreactivity in the forebrain of male Lincoln’s sparrows

    PubMed Central

    Sewall, Kendra B.; Dankoski, Elyse C.; Sockman, Keith W.

    2010-01-01

    Male songbirds often establish territories and attract mates by singing, and some song features can reflect the singer’s condition or quality. The quality of the song environment can change, so male songbirds should benefit from assessing the competitiveness of the song environment and appropriately adjusting their own singing behavior and the neural substrates by which song is controlled. In a wide range of taxa social modulation of behavior is partly mediated by the arginine vasopressin or vasotocin (AVP/AVT) systems. To examine the modulation of singing behavior in response to the quality of the song environment we compared the song output of laboratory-housed male Lincoln’s sparrows (Melospiza lincolnii) exposed to one week of chronic playback of songs categorized as either high or low quality, based on song length, complexity and trill performance. To explore the neural basis of any facultative shifts in behavior, we also quantified the subjects’ AVT immunoreactivity (AVT-IR) in three forebrain regions that regulate socio-sexual behavior: the medial bed nucleus of the stria terminalis (BSTm), the lateral septum (LS) and the preoptic area. We found that high quality songs increased singing effort and reduced AVT-IR in the BSTm and LS, relative to low quality songs. The effect of the quality of the song environment on both singing effort and forebrain AVT-IR raises the hypothesis that AVT within these brain regions plays a role in the modulation of behavior in response to competition that individual males may assess from the prevailing song environment. PMID:20399213

  11. Xenon Combined with Therapeutic Hypothermia Is Not Neuroprotective after Severe Hypoxia-Ischemia in Neonatal Rats

    PubMed Central

    Sabir, Hemmen; Osredkar, Damjan; Maes, Elke; Wood, Thomas; Thoresen, Marianne

    2016-01-01

    Background Therapeutic hypothermia (TH) is standard treatment following perinatal asphyxia in newborn infants. Experimentally, TH is neuroprotective after moderate hypoxia-ischemia (HI) in seven-day-old (P7) rats. However, TH is not neuroprotective after severe HI. After a moderate HI insult in newborn brain injury models, the anesthetic gas xenon (Xe) doubles TH neuroprotection. The aim of this study was to examine whether combining Xe and TH is neuroprotective as applied in a P7 rat model of severe HI. Design/Methods 120 P7 rat pups underwent a severe HI insult; unilateral carotid artery ligation followed by hypoxia (8% O2 for 150min at experimental normothermia (NT-37: Trectal 37°C). Surviving pups were randomised to immediate NT-37 for 5h (n = 36), immediate TH-32: Trectal 32°C for 5h (n = 25) or immediate TH-32 plus 50% inhaled Xe for 5h (n = 24). Pups were sacrificed after one week of survival. Relative area loss of the ligated hemisphere was measured, and neurons in the subventricular zone of this injured hemisphere were counted, to quantify brain damage. Results Following the HI insult, median (interquartile range, IQR) hemispheric brain area loss was similar in all groups: 63.5% (55.5–75.0) for NT-37 group, 65.0% (57.0–65.0) for TH-32 group, and 66.5% (59.0–72.0) for TH-32+Xe50% group (not significant). Correspondingly, there was no difference in neuronal cell count (NeuN marker) in the subventricular zone across the three treatment groups. Conclusions Immediate therapeutic hypothermia with or without additional 50% inhaled Xe, does not provide neuroprotection one week after severe HI brain injury in the P7 neonatal rat. This model aims to mimic the clinical situation in severely asphyxiated neonates and treatment these newborns remains an ongoing challenge. PMID:27253085

  12. New insights into the relationship of neurogenesis and affect: tickling induces hippocampal cell proliferation in rats emitting appetitive 50-kHz ultrasonic vocalizations.

    PubMed

    Wöhr, M; Kehl, M; Borta, A; Schänzer, A; Schwarting, R K W; Höglinger, G U

    2009-11-10

    Adult hippocampal cell proliferation (HCP) has been associated with psychopathology, especially depression. However, it is controversial whether a constitutively low rate of HCP is a trait predisposing an individual to psychopathology or whether HCP varies with the subject's affective state. We made use of a so-far neglected measure of affect, namely ultrasonic vocalizations, to gain new insights into the relationship of HCP and affect. Rats emit distinct types of ultrasonic vocalizations, which serve as situation-dependent affective signals. In appetitive situations, rats produce 50-kHz-calls, whereas 22-kHz-calls occur in aversive situations. We applied a standardized protocol of repeated tickling and assessed tickling-induced ultrasonic vocalizations as an index of the animals affect. Stereological quantifications of 5-bromo-2'-deoxyuridine (BrdU) and proliferating-cells-nuclear-antigen (PCNA) immunolabeled cells were used to estimate the rate of cell proliferation in the subventricular zone and the subgranular zone of the dentate gyrus in the hippocampus. The rate of cell proliferation was compared between the groups of tickled vs. non-tickled rats and between subgroups of tickled rats defined by the effect of tickling on ultrasonic vocalizations. Tickling induced ultrasonic vocalizations in a subject-dependent manner. HCP correlated positively with appetitive 50-kHz-calls, but negatively with aversive 22-kHz-calls in individual animals, while cell proliferation in the subventricular zone was not associated with the emission of ultrasonic vocalizations. Repeated tickling did not change HCP in all rats, but increased HCP in the subgroup of rats, which experienced this procedure as appetitive, i.e. in rats emitting high numbers of 50-kHz-calls or low numbers of 22-kHz-calls. Together, these data indicate that the effect of tickling on HCP depends on an interaction between a predisposing trait and stimulation-dependent variations of the subject's affective state

  13. Ontogenic profile of seizures evoked by the beta-carboline DMCM (methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate) in rats

    PubMed Central

    Kulick, Catherine; Gutherz, Samuel; Kondratyev, Alexei; Forcelli, Patrick A.

    2014-01-01

    The beta-carboline, methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM), is a potent chemoconvulsant. While it has been utilized in adult rodents, it has not been previously examined for effects across postnatal development. DMCM is a negative allosteric modulator of benzodiazepine-sensitive GABAA receptors, receptor subtypes that are particularly enriched in limbic brain regions. This raises the possibility that DMCM may be particularly effective at evoking forebrain seizures, which is a challenge in neonatal animals due to the relative immaturity of the forebrain seizure network. The ability to selectively evoke forebrain seizures is desirable when screening for drugs to use in temporal lobe epilepsy, which is characterized by seizures within the forebrain (limbic) network. To determine the profile of DMCM action across development, we examined the dose-dependent ability of DMCM to induce seizures in rats at P7, P10, P13, P14, P21 and in adulthood. We found that the highest sensitivity to DMCM occurred in P10, P13, and P14 rats. The lowest sensitivity occurred in P21 rats. Neonatal (P7) and adult (P60+) rats displayed moderate sensitivity. With moderate (0.2–0.4mg/kg) doses of DMCM, we were able to reliably evoke limbic motor seizures without tonic-clonic components in animals as young as P7. These data support the utility of DMCM in assessing seizure threshold during development and raise the possibility for future exploration of DMCM as an agent to screen anticonvulsant drugs during the postnatal period. PMID:24967532

  14. Dose-escalated intensity-modulated radiotherapy and irradiation of subventricular zones in relation to tumor control outcomes of patients with glioblastoma multiforme

    PubMed Central

    Kusumawidjaja, Grace; Gan, Patricia Zhun Hong; Ong, Whee Sze; Teyateeti, Achiraya; Dankulchai, Pittaya; Tan, Daniel Yat Harn; Chua, Eu Tiong; Chua, Kevin Lee Min; Tham, Chee Kian; Wong, Fuh Yong; Chua, Melvin Lee Kiang

    2016-01-01

    Background Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with high relapse rate. In this study, we aimed to determine if dose-escalated (DE) radiotherapy improved tumor control and survival in GBM patients. Methods We conducted a retrospective analysis of 49 and 23 newly-diagnosed histology-proven GBM patients, treated with DE radiotherapy delivered in 70 Gy (2.33 Gy per fraction) and conventional doses (60 Gy), respectively, between 2007 and 2013. Clinical target volumes for 70 and 60 Gy were defined by 0.5 and 2.0 cm expansion of magnetic resonance imaging T1-gadolinium-enhanced tumor/surgical cavity, respectively. Bilateral subventricular zones (SVZ) were contoured on a co-registered pre-treatment magnetic resonance imaging and planning computed tomography dataset as a 5 mm wide structure along the lateral margins of the lateral ventricles. Survival outcomes of both cohorts were compared using log-rank test. Radiation dose to SVZ in the DE cohort was evaluated. Results Median follow-up was 13.6 and 15.1 months for the DE- and conventionally-treated cohorts, respectively. Median overall survival (OS) of patients who received DE radiotherapy was 15.2 months (95% confidence interval [CI] =11.0–18.6), while median OS of the latter cohort was 18.4 months (95% CI =12.5–31.4, P=0.253). Univariate analyses of clinical and dosimetric parameters among the DE cohort demonstrated a trend of longer progression-free survival, but not OS, with incremental radiation doses to the ipsilateral SVZ (hazard ratio [HR] =0.95, 95% CI =0.90–1.00, P=0.052) and proportion of ipsilateral SVZ receiving 50 Gy (HR =0.98, 95% CI =0.97–1.00, P=0.017). Conclusion DE radiotherapy did not improve survival in patients with GBM. Incorporation of ipsilateral SVZ as a radiotherapy target volume for patients with GBM requires prospective validation. PMID:27042103

  15. Dopaminergic Neuronal Differentiation from the Forebrain-Derived Human Neural Stem Cells Induced in Cultures by Using a Combination of BMP-7 and Pramipexole with Growth Factors

    PubMed Central

    Yang, HongNa; Wang, Jing; Wang, Feng; Liu, XiaoDun; Chen, Heng; Duan, WeiMing; Qu, TingYu

    2016-01-01

    Transplantation of dopaminergic (DA) neurons is considered to be the most promising therapeutic strategy for replacing degenerated dopamine cells in the midbrain of Parkinson's disease (PD), thereby restoring normal neural circuit function and slow clinical progression of the disease. Human neural stem cells (hNSCs) derived from fetal forebrain are thought to be the important cell sources for producing DA neurons because of their multipotency for differentiation and long-term expansion property in cultures. However, low DA differentiation of the forebrain-derived hNSCs limited their therapeutic potential in PD. In the current study, we explored a combined application of Pramipexole (PRX), bone morphogenetic proteins 7 (BMP-7), and growth factors, including acidic fibroblast factor (aFGF), forskolin, and phorbol-12-myristae-13-acetate (TPA), to induce differentiation of forebrain-derived hNSCs toward DA neurons in cultures. We found that DA neuron-associated genes, including Nurr1, Neurogenin2 (Ngn2), and tyrosine hydroxylase (TH) were significantly increased after 24 h of differentiation by RT-PCR analysis (p < 0.01). Fluorescent examination showed that about 25% of cells became TH-positive neurons at 24 h, about 5% of cells became VMAT2 (vascular monoamine transporter 2)-positive neurons, and less than 5% of cells became DAT (dopamine transporter)-positive neurons at 72 h following differentiation in cultures. Importantly, these TH-, VMAT2-, and DAT-expressing neurons were able to release dopamine into cultures under both of the basal and evoked conditions. Dopamine levels released by DA neurons produced using our protocol were significantly higher compared to the control groups (P < 0.01), as examined by ELISA. Our results demonstrated that the combination of PRX, BMP-7, and growth factors was able to greatly promote differentiation of the forebrain-derived hNSCs into DA-releasing neurons. PMID:27147976

  16. Binaural tuning of auditory units in the forebrain archistriatal gaze fields of the barn owl: local organization but no space map.

    PubMed

    Cohen, Y E; Knudsen, E I

    1995-07-01

    We identified a region in the archistriatum of the barn owl forebrain that contains neurons sensitive to auditory stimuli. Nearly all of these neurons are tuned for binaural localization cues. The archistriatum is known to be the primary source of motor-related output from the avian forebrain and, in barn owls, contributes to the control of gaze, much like the frontal eye fields in monkeys. The auditory region is located in the medial portion of the archistriatum, at the level of the anterior commissure, and is within the region of the archistriatum from which head saccades can be elicited by electrical microstimulation (see preceding companion article, Knudsen et al., 1995). Free-field measurements revealed that auditory sites have large, spatial receptive fields. However, within these large receptive fields, responses are tuned sharply for sound source location. Dichotic measurements showed that auditory sites are tuned broadly for frequency and that the majority are tuned to particular values of interaural time differences and interaural level differences, the principal cues used by barn owls for sound localization. The tuning of sites to these binaural cues is essentially independent of sound level. The auditory properties of units in the medial archistriatum are similar to those of units in the optic tectum, a structure that also contributes to gaze control. Unlike the optic tectum, however, the auditory region of the archistriatum does not contain a single, continuous auditory map of space. Instead, it is organized into dorsoventral clusters of sites with similar binaural (spatial) tuning. The different representations of auditory space in closely related structures in the forebrain (archistriatum) and midbrain (optic tectum) probably reflect the fact that the forebrain contributes to a wide variety of sensorimotor tasks more complicated than gaze control. PMID:7623142

  17. Dopaminergic Neuronal Differentiation from the Forebrain-Derived Human Neural Stem Cells Induced in Cultures by Using a Combination of BMP-7 and Pramipexole with Growth Factors.

    PubMed

    Yang, HongNa; Wang, Jing; Wang, Feng; Liu, XiaoDun; Chen, Heng; Duan, WeiMing; Qu, TingYu

    2016-01-01

    Transplantation of dopaminergic (DA) neurons is considered to be the most promising therapeutic strategy for replacing degenerated dopamine cells in the midbrain of Parkinson's disease (PD), thereby restoring normal neural circuit function and slow clinical progression of the disease. Human neural stem cells (hNSCs) derived from fetal forebrain are thought to be the important cell sources for producing DA neurons because of their multipotency for differentiation and long-term expansion property in cultures. However, low DA differentiation of the forebrain-derived hNSCs limited their therapeutic potential in PD. In the current study, we explored a combined application of Pramipexole (PRX), bone morphogenetic proteins 7 (BMP-7), and growth factors, including acidic fibroblast factor (aFGF), forskolin, and phorbol-12-myristae-13-acetate (TPA), to induce differentiation of forebrain-derived hNSCs toward DA neurons in cultures. We found that DA neuron-associated genes, including Nurr1, Neurogenin2 (Ngn2), and tyrosine hydroxylase (TH) were significantly increased after 24 h of differentiation by RT-PCR analysis (p < 0.01). Fluorescent examination showed that about 25% of cells became TH-positive neurons at 24 h, about 5% of cells became VMAT2 (vascular monoamine transporter 2)-positive neurons, and less than 5% of cells became DAT (dopamine transporter)-positive neurons at 72 h following differentiation in cultures. Importantly, these TH-, VMAT2-, and DAT-expressing neurons were able to release dopamine into cultures under both of the basal and evoked conditions. Dopamine levels released by DA neurons produced using our protocol were significantly higher compared to the control groups (P < 0.01), as examined by ELISA. Our results demonstrated that the combination of PRX, BMP-7, and growth factors was able to greatly promote differentiation of the forebrain-derived hNSCs into DA-releasing neurons. PMID:27147976

  18. Identification of in vivo DNA-binding mechanisms of Pax6 and reconstruction of Pax6-dependent gene regulatory networks during forebrain and lens development

    PubMed Central

    Sun, Jian; Rockowitz, Shira; Xie, Qing; Ashery-Padan, Ruth; Zheng, Deyou; Cvekl, Ales

    2015-01-01

    The transcription factor Pax6 is comprised of the paired domain (PD) and homeodomain (HD). In the developing forebrain, Pax6 is expressed in ventricular zone precursor cells and in specific subpopulations of neurons; absence of Pax6 results in disrupted cell proliferation and cell fate specification. Pax6 also regulates the entire lens developmental program. To reconstruct Pax6-dependent gene regulatory networks (GRNs), ChIP-seq studies were performed using forebrain and lens chromatin from mice. A total of 3514 (forebrain) and 3723 (lens) Pax6-containing peaks were identified, with ∼70% of them found in both tissues and thereafter called ‘common’ peaks. Analysis of Pax6-bound peaks identified motifs that closely resemble Pax6-PD, Pax6-PD/HD and Pax6-HD established binding sequences. Mapping of H3K4me1, H3K4me3, H3K27ac, H3K27me3 and RNA polymerase II revealed distinct types of tissue-specific enhancers bound by Pax6. Pax6 directly regulates cortical neurogenesis through activation (e.g. Dmrta1 and Ngn2) and repression (e.g. Ascl1, Fezf2, and Gsx2) of transcription factors. In lens, Pax6 directly regulates cell cycle exit via components of FGF (Fgfr2, Prox1 and Ccnd1) and Wnt (Dkk3, Wnt7a, Lrp6, Bcl9l, and Ccnd1) signaling pathways. Collectively, these studies provide genome-wide analysis of Pax6-dependent GRNs in lens and forebrain and establish novel roles of Pax6 in organogenesis. PMID:26138486

  19. Low Level Chlorpyrifos Exposure Increases Anandamide Accumulation in Juvenile Rat Brain in the Absence of Brain Cholinesterase Inhibition

    PubMed Central

    Carr, Russell L.; Graves, Casey A.; Mangum, Lee C.; Nail, Carole A.; Ross, Matthew K.

    2014-01-01

    The prevailing dogma is that chlorpyrifos (CPF) mediates its toxicity through inhibition of cholinesterase (ChE). However, in recent years, the toxicological effects of developmental CPF exposure have been attributed to an unknown non-cholinergic mechanism of action. We hypothesize that the endocannabinoid system may be an important target because of its vital role in nervous system development. We have previously reported that repeated exposure to CPF results in greater inhibition of fatty acid amide hydrolase (FAAH), the enzyme that metabolizes the endocannabinoid anandamide (AEA), than inhibition of either forebrain ChE or monoacylglycerol lipase (MAGL), the enzyme that metabolizes the endocannabinoid 2-arachidonylglycerol (2-AG). This exposure resulted in the accumulation of 2-AG and AEA in the forebrain of juvenile rats; however, even at the lowest dosage level used (1.0 mg/kg), forebrain ChE inhibition was still present. Thus, it is not clear if FAAH activity would be inhibited at dosage levels that do not inhibit ChE. To determine this, 10 day old rat pups were exposed daily for 7 days to either corn oil or 0.5 mg/kg CPF by oral gavage. At 4 and 12 h post-exposure on the last day of administration, the activities of serum ChE and carboxylesterase (CES) and forebrain ChE, MAGL, and FAAH were determined as well as the forebrain AEA and 2-AG levels. Significant inhibition of serum ChE and CES was present at both 4 and 12 h. There was no significant inhibition of the activities of forebrain ChE or MAGL and no significant change in the amount of 2-AG at either time point. On the other hand, while no statistically significant effects were observed at 4 h, FAAH activity was significantly inhibited at 12 h resulting in a significant accumulation of AEA. Although it is not clear if this level of accumulation impacts brain maturation, this study demonstrates that developmental CPF exposure at a level that does not inhibit brain ChE can alter components of

  20. Parallel pathways mediating both sound localization and gaze control in the forebrain and midbrain of the barn owl.

    PubMed

    Knudsen, E I; Knudsen, P F; Masino, T

    1993-07-01

    The hypothesis that sound localization and gaze control are mediated in parallel in the midbrain and forebrain was tested in the barn owl. The midbrain pathway for gaze control was interrupted by reversible inactivation (muscimol injection) or lesion of the optic tectum. Auditory input to the forebrain was disrupted by reversible inactivation or lesion of the primary thalamic auditory nucleus, nucleus ovoidalis (homolog of the medial geniculate nucleus). Barn owls were trained to orient their gaze toward auditory or visual stimuli presented from random locations in a darkened sound chamber. Auditory and visual test stimuli were brief so that the stimulus was over before the orienting response was completed. The accuracy and kinetics of the orienting responses were measured with a search coil attached to the head. Unilateral inactivation of the optic tectum had immediate and long-lasting effects on auditory orienting behavior. The owls failed to respond on a high percentage of trials when the auditory test stimulus was located on the side contralateral to the inactivated tectum. When they did respond, the response was usually (but not always) short of the target, and the latency of the response was abnormally long. When the auditory stimulus was located on the side ipsilateral to the inactivated tectum, responses were reliable and accurate, and the latency of responses was shorter than normal. In a tectally lesioned animal, response probability and latency to contralateral sounds returned to normal within 2 weeks, but the increase in response error (due to undershooting) persisted for at least 12 weeks. Despite abnormalities in the response, all of the owls were capable of localizing and orienting to contralateral auditory stimuli on some trials with the optic tectum inactivated or lesioned. This was not true for contralateral visual stimuli. Immediately following tectal inactivation, the owls exhibited complete neglect for visual stimuli located more than 20

  1. Differential maturation of vesicular glutamate and GABA transporter expression in the mouse auditory forebrain during the first weeks of hearing.

    PubMed

    Hackett, Troy A; Clause, Amanda R; Takahata, Toru; Hackett, Nicholas J; Polley, Daniel B

    2016-06-01

    Vesicular transporter proteins are an essential component of the presynaptic machinery that regulates neurotransmitter storage and release. They also provide a key point of control for homeostatic signaling pathways that maintain balanced excitation and inhibition following changes in activity levels, including the onset of sensory experience. To advance understanding of their roles in the developing auditory forebrain, we tracked the expression of the vesicular transporters of glutamate (VGluT1, VGluT2) and GABA (VGAT) in primary auditory cortex (A1) and medial geniculate body (MGB) of developing mice (P7, P11, P14, P21, adult) before and after ear canal opening (~P11-P13). RNA sequencing, in situ hybridization, and immunohistochemistry were combined to track changes in transporter expression and document regional patterns of transcript and protein localization. Overall, vesicular transporter expression changed the most between P7 and P21. The expression patterns and maturational trajectories of each marker varied by brain region, cortical layer, and MGB subdivision. VGluT1 expression was highest in A1, moderate in MGB, and increased with age in both regions. VGluT2 mRNA levels were low in A1 at all ages, but high in MGB, where adult levels were reached by P14. VGluT2 immunoreactivity was prominent in both regions. VGluT1 (+) and VGluT2 (+) transcripts were co-expressed in MGB and A1 somata, but co-localization of immunoreactive puncta was not detected. In A1, VGAT mRNA levels were relatively stable from P7 to adult, while immunoreactivity increased steadily. VGAT (+) transcripts were rare in MGB neurons, whereas VGAT immunoreactivity was robust at all ages. Morphological changes in immunoreactive puncta were found in two regions after ear canal opening. In the ventral MGB, a decrease in VGluT2 puncta density was accompanied by an increase in puncta size. In A1, perisomatic VGAT and VGluT1 terminals became prominent around the neuronal somata. Overall, the

  2. Treatment of beta amyloid 1–42 (Aβ1–42)-induced basal forebrain cholinergic damage by a non-classical estrogen signaling activator in vivo

    PubMed Central

    Kwakowsky, Andrea; Potapov, Kyoko; Kim, SooHyun; Peppercorn, Katie; Tate, Warren P.; Ábrahám, István M.

    2016-01-01

    In Alzheimer’s disease (AD), there is a loss in cholinergic innervation targets of basal forebrain which has been implicated in substantial cognitive decline. Amyloid beta peptide (Aβ1–42) accumulates in AD that is highly toxic for basal forebrain cholinergic (BFC) neurons. Although the gonadal steroid estradiol is neuroprotective, the administration is associated with risk of off-target effects. Previous findings suggested that non-classical estradiol action on intracellular signaling pathways has ameliorative potential without estrogenic side effects. After Aβ1–42 injection into mouse basal forebrain, a single dose of 4-estren-3α, 17β-diol (estren), the non-classical estradiol pathway activator, restored loss of cholinergic cortical projections and also attenuated the Aβ1–42-induced learning deficits. Estren rapidly and directly phosphorylates c-AMP-response–element-binding-protein and extracellular-signal-regulated-kinase-1/2 in BFC neurons and restores the cholinergic fibers via estrogen receptor-α. These findings indicated that selective activation of non-classical intracellular estrogen signaling has a potential to treat the damage of cholinergic neurons in AD. PMID:26879842

  3. Deletion of forebrain glycine transporter 1 enhances conditioned freezing to a reliable, but not an ambiguous, cue for threat in a conditioned freezing paradigm

    PubMed Central

    Dubroqua, Sylvain; Singer, Philipp; Yee, Benjamin K.

    2014-01-01

    Enhanced expression of Pavlovian aversive conditioning but not appetitive conditioning may indicate a bias in the processing of threatening or fearful events. Mice with disruption of glycine transporter 1 in forebrain neurons exhibit such a bias, but they are at the same time highly sensitive to manipulations that hinder the development of the conditioned response (CR) – suggesting that the mutation may modify higher cognitive processes that extract predictive information between environmental cues. Here, we further investigated the development of fear conditioning in forebrain neuronal GlyT1 knockout mice when the predictiveness of a tone stimulus for foot shock was rendered ambiguous by interspersing [tone → no shock] trials in-between [tone → shock] trials during acquisition. The CR to the ambiguous tone CS (conditioned stimulus) was compared with that generated by an unambiguous CS that was always followed by the shock US (unconditioned stimulus) during acquisition. We showed that rendering the CS ambiguous as described significantly attenuated the CR in the mutants, but it was not sufficient to modify the CR in the control mice. It is concluded that disruption of GlyT1 in forebrain neurons does not increase the risk of forming spurious and potentially maladaptive fear associations. PMID:25043729

  4. The kinetic behaviour of the cranial neural epithelium during neurulation in the rat.

    PubMed

    Tuckett, F; Morriss-Kay, G M

    1985-02-01

    The kinetic behaviour of the cranial neuroepithelial cells of rat embryos during neurulation is described. Serial transverse sections of 4-, 8-, 12- and 16-somite-stage embryos show that differential mitosis does not play a part in the mechanisms responsible for effecting cranial neural tube closure. A constant cell number is found in the midbrain/hindbrain neural epithelium during all four stages; the mitotic spindle axes are oriented parallel to the long axis of the embryo, so that increase in cell number occurs in this direction only. Growth is only expressed by an expansion in the volume of the forebrain, whi