Sample records for rat developing forebrain

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

    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...

  2. Behavioral performance of rats following transient forebrain ischemia.

    Volpe, B T; Pulsinelli, W A; Tribuna, J; Davis, H P


    Rats subjected to transient forebrain ischemic injury by the method of four vessel occlusion (4-VO) develop irreversible injury to select populations of vulnerable neurons which include pyramidal cells in the CA-1 region of the hippocampus. This brain area is thought to be crucial for learning and memory. Rats subjected to 30 minutes of 4-VO, and then cerebral reperfusion were tested on a radial 8-arm maze task after they had recovered. The data shows that both 4-VO and control animals improve their performance over trials, but that 4-VO rats are impaired on "working" and "reference" tasks. The data suggest that 4-VO rats' impaired "working" performance is permanent, compared to their transient "reference" impairment. Alterations in sensorimotor activity could not account for these performance deficits since control and 4-VO rats demonstrated equivalent choice time per maze arm. Performance deficits in rats following forebrain ischemic injury may be similar to some of the cognitive deficits found in humans survivors of cerebral hypoxia-ischemia.

  3. Coexpression of high-voltage-activated ion channels Kv3.4 and Cav1.2 in pioneer axons during pathfinding in the developing rat forebrain.

    Huang, Chia-Yi; Chu, Dachen; Hwang, Wei-Chao; Tsaur, Meei-Ling


    Precise axon pathfinding is crucial for establishment of the initial neuronal network during development. Pioneer axons navigate without the help of preexisting axons and pave the way for follower axons that project later. Voltage-gated ion channels make up the intrinsic electrical activity of pioneer axons and regulate axon pathfinding. To elucidate which channel molecules are present in pioneer axons, immunohistochemical analysis was performed to examine 14 voltage-gated ion channels (Kv1.1-Kv1.3, Kv3.1-Kv3.4, Kv4.3, Cav1.2, Cav1.3, Cav2.2, Nav1.2, Nav1.6, and Nav1.9) in nine axonal tracts in the developing rat forebrain, including the optic nerve, corpus callosum, corticofugal fibers, thalamocortical axons, lateral olfactory tract, hippocamposeptal projection, anterior commissure, hippocampal commissure, and medial longitudinal fasciculus. We found A-type K⁺ channel Kv3.4 in both pioneer axons and early follower axons and L-type Ca²⁺ channel Cav1.2 in pioneer axons and early and late follower axons. Spatially, Kv3.4 and Cav1.2 were colocalized with markers of pioneer neurons and pioneer axons, such as deleted in colorectal cancer (DCC), in most fiber tracts examined. Temporally, Kv3.4 and Cav1.2 were expressed abundantly in most fiber tracts during axon pathfinding but were downregulated beginning in synaptogenesis. By contrast, delayed rectifier Kv channels (e.g., Kv1.1) and Nav channels (e.g., Nav1.2) were absent from these fiber tracts (except for the corpus callosum) during pathfinding of pioneer axons. These data suggest that Kv3.4 and Cav1.2, two high-voltage-activated ion channels, may act together to control Ca²⁺ -dependent electrical activity of pioneer axons and play important roles during axon pathfinding.

  4. Demonstration of muscarinic acetylcholine receptor-like immunoreactivity in the rat forebrain and upper brainstem

    Zee, E.A. van der; Matsuyama, T.; Strosberg, A.D.; Traber, J.; Luiten, P.G.M.


    The distribution of muscarinic acetylcholine receptor protein (mAChR) in the rat forebrain and upper brainstem was described by using a monoclonal antibody (M35) raised against mAChR purified from bovine forebrain homogenates. A method is investigated for light microscopic (LM) and electronmicroscop

  5. Regional energy balance in rat brain after transient forebrain ischemia.

    Pulsinelli, W A; Duffy, T E


    Phosphocreatine, ATP, and glucose were severely depleted, and the lactate levels were increased in the paramedian neocortex, dorsal-lateral striatum, and CA1 zone of hippocampus of rats exposed to 30 min of forebrain ischemia. Upon recirculation of the brain, phosphocreatine, ATP, and lactate concentrations recovered to control values in the paramedian neocortex and CA1 zone of hippocampus and to near-control values in the striatum. The phosphocreatine and ATP concentrations then fell and the lactate levels rose in the striatum after 6-24 h, and in the CA1 zone of hippocampus after 24-72 h. The initial recovery and subsequent delayed changes in the phosphocreatine, ATP, and lactate concentrations in the striatum and hippocampus coincided with the onset and progression of morphological injury in these brain regions. The results suggest that cells in these regions regain normal or near-normal mitochondrial function and are viable, in terms of energy production, for many hours before unknown mechanisms cause irreversible neuronal before unknown mechanisms cause irreversible neuronal injury.

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

    Le Moine, C.; Normand, E.; Guitteny, A.F.; Fouque, B.; Teoule, R.; Bloch, B. (Universite de Bordeaux II (France))


    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.

  7. Basal forebrain neurons suppress amygdala kindling via cortical but not hippocampal cholinergic projections in rats.

    Ferencz, I; Leanza, G; Nanobashvili, A; Kokaia, M; Lindvall, O


    Intraventricular administration of the immunotoxin 192 IgG-saporin in rats has been shown to cause a selective loss of cholinergic afferents to the hippocampus and cortical areas, and to facilitate seizure development in hippocampal kindling. Here we demonstrate that this lesion also accelerates seizure progression when kindling is induced by electrical stimulations in the amygdala. However, whereas intraventricular 192 IgG-saporin facilitated the development of the initial stages of hippocampal kindling, the same lesion promoted the late stages of amygdala kindling. To explore the role of various parts of the basal forebrain cholinergic system in amygdala kindling, selective lesions of the cholinergic projections to either hippocampus or cortex were produced by intraparenchymal injections of 192 IgG-saporin into medial septum/vertical limb of the diagonal band or nucleus basalis, respectively. Cholinergic denervation of the cortical regions caused acceleration of amygdala kindling closely resembling that observed after the more widespread lesion induced by intraventricular 192 IgG-saporin. In contrast, removal of the cholinergic input to the hippocampus had no effect on the development of amygdala kindling. These data indicate that basal forebrain cholinergic neurons suppress kindling elicited from amygdala, and that this dampening effect is mediated via cortical but not hippocampal projections.

  8. Limited participation of 5-HT1A and 5-HT2A/2C receptors in the clozapine-induced Fos-protein expression in rat forebrain regions

    Sebens, JB; Kuipers, SD; Koch, T; Ter Horst, GJ; Korf, J


    Through the development of tolerance following long-term clozapine treatment, we investigated whether 5-HT1A and 5-HT2A/2C receptors participate in the clozapine-induced Fos-protein expression in the rat forebrain. Tolerance exists when the acutely increased Fos responses to a challenge dose of the

  9. Dynamic behaviour of human neuroepithelial cells in the developing forebrain

    Subramanian, Lakshmi; Bershteyn, Marina; Paredes, Mercedes F.; Kriegstein, Arnold R.


    To understand how diverse progenitor cells contribute to human neocortex development, we examined forebrain progenitor behaviour using timelapse imaging. Here we find that cell cycle dynamics of human neuroepithelial (NE) cells differ from radial glial (RG) cells in both primary tissue and in stem cell-derived organoids. NE cells undergoing proliferative, symmetric divisions retract their basal processes, and both daughter cells regrow a new process following cytokinesis. The mitotic retraction of the basal process is recapitulated by NE cells in cerebral organoids generated from human-induced pluripotent stem cells. In contrast, RG cells undergoing vertical cleavage retain their basal fibres throughout mitosis, both in primary tissue and in older organoids. Our findings highlight developmentally regulated changes in mitotic behaviour that may relate to the role of RG cells to provide a stable scaffold for neuronal migration, and suggest that the transition in mitotic dynamics can be studied in organoid models. PMID:28139695

  10. Influence of interferon-gamma on the differentiation of cholinergic neurons in rat embryonic basal forebrain and septal nuclei

    Yanhong Luo; Lin An


    BACKGROUND: Interferon-gamma (IFN-γ) can make neurons in basal forebrain and septal nuclei differentiate into cholinergic neurons by treating the cells in cerebral cortex of newborn rats, without the inhibition from IFN-γ antibody. The important effect of IFN-γ on the development and differentiation of neurons has been found by some scholars.OBJ ECTIVE:To investigate whether IFN-γ has differentiational effect on cholinergic neurons in basal forebrain and septal nuclei, and make clear that the increased number of cholinergic neurons is resulted by cell differentiation or cell proliferation.DESIGN: Controlled observation trial.SETTING: Department of Cell Biology, Medical School, Beijing University.MATERIALS: Sixty-eight female Wistar rats at embryonic 16 days, weighing 250 to 350 g, were enrolled in this study, and they were provided by the Experimental Animal Center, Medical School, Beijing University.IFN-γ was the product of Gibco Company.METHODS: This study was carried out in the Department of Cell Biology, Medical School, Beijing University and Daheng Image Company of Chinese Academy of Sciences during September 1995 to December 2002.The female Wistar rats at embryonic 16 days were sacrificed, and their fetuses were taken out. Primary culture of the isolated basal forebrain and septal nuclei was performed. The cultured nerve cells were assigned into 3 groups: control group (nothing added), IFN-γ group(1×105 U/L interferon), IFN-γ+ IFN-γ antibody group (1 ×105 U/L IFN-γ± IFN-γ antibody). The specific marker enzyme (choline acetyl transferase) of cholinergic neuron was stained with immunohistochemical method. Choline acetyl transferase positive cells were counted, and 14C-acetyl CoA was used as substrate to detect the activity of choline acetyl transferase, so as to reflect the differentiational effect of IFN-γ on cholinergic neuron in basal forebrain and septal nuclei. Flow cytometry was used to analyze cell circle and detect the proliferation of

  11. Activity of basal forebrain neurons in the rat during motivated behaviors.

    Mink, J W; Sinnamon, H M; Adams, D B


    The activity of single neurons in the basal forebrain was recorded in the freely-moving rat with moveable fine-wire electrodes. Neural activity was observed while the water-deprived male rat was exposed to three different types of motivating stimuli that elicit locomotion in a running wheel: an estrous female rat; a drinking tube containing water; and grasping and lifting by the experimenter. The neural activity was also observed when the subject was presented with standardized sensory tests and during single pulse stimulation of other brain structures. A majority of the 76 neurons recorded in the forebrain changed their firing rate during orienting and/or locomotion in general (23 neurons) or during behavior related to only one of the specific motivational contexts: the conspecific female (4 neurons); water (7 neurons); or grasp by the experimenter (8 neurons). Whereas the neurons related to orienting and/or locomotion in general were scattered through various brain structures, those neurons related to specific motivational contexts were concentrated in specific areas: the sexually dimorphic nucleus of the medial preoptic area (conspecific female); lateral septum (water); and lateral preoptic area (water and grasp). The present results, although based on relatively few neurons, are consonant with results of research using other techniques. This indicates that analyses at the level of the single neuron promise to be useful for understanding the role of the basal forebrain in motivational systems.

  12. Complex and dynamic patterns of Wnt pathway gene expression in the developing chick forebrain

    Lumsden Andrew


    Full Text Available Abstract Background Wnt signalling regulates multiple aspects of brain development in vertebrate embryos. A large number of Wnts are expressed in the embryonic forebrain; however, it is poorly understood which specific Wnt performs which function and how they interact. Wnts are able to activate different intracellular pathways, but which of these pathways become activated in different brain subdivisions also remains enigmatic. Results We have compiled the first comprehensive spatiotemporal atlas of Wnt pathway gene expression at critical stages of forebrain regionalisation in the chick embryo and found that most of these genes are expressed in strikingly dynamic and complex patterns. Several expression domains do not respect proposed compartment boundaries in the developing forebrain, suggesting that areal identities are more dynamic than previously thought. Using an in ovo electroporation approach, we show that Wnt4 expression in the thalamus is negatively regulated by Sonic hedgehog (Shh signalling from the zona limitans intrathalamica (ZLI, a known organising centre of forebrain development. Conclusion The forebrain is exposed to a multitude of Wnts and Wnt inhibitors that are expressed in a highly dynamic and complex fashion, precluding simple correlative conclusions about their respective functions or signalling mechanisms. In various biological systems, Wnts are antagonised by Shh signalling. By demonstrating that Wnt4 expression in the thalamus is repressed by Shh from the ZLI we reveal an additional level of interaction between these two pathways and provide an example for the cross-regulation between patterning centres during forebrain regionalisation.




    Both acute and long-term effects of haloperidol and clozapine on Fos-like immunoreactive nuclei in several rat forebrain areas were quantified. Rats were treated with saline (1 ml/, control), haloperidol (1 mg/ and clozapine (20 mg/ i.p. for 21 days. Two hours before perfusion fi

  14. Expanded expression of Sonic Hedgehog in Astyanax cavefish: multiple consequences on forebrain development and evolution.

    Menuet, Arnaud; Alunni, Alessandro; Joly, Jean-Stéphane; Jeffery, William R; Rétaux, Sylvie


    Ventral midline Sonic Hedgehog (Shh) signalling is crucial for growth and patterning of the embryonic forebrain. Here, we report how enhanced Shh midline signalling affects the evolution of telencephalic and diencephalic neuronal patterning in the blind cavefish Astyanax mexicanus, a teleost fish closely related to zebrafish. A comparison between cave- and surface-dwelling forms of Astyanax shows that cavefish display larger Shh expression in all anterior midline domains throughout development. This does not affect global forebrain regional patterning, but has several important consequences on specific regions and neuronal populations. First, we show expanded Nkx2.1a expression and higher levels of cell proliferation in the cavefish basal diencephalon and hypothalamus. Second, we uncover an Nkx2.1b-Lhx6-GABA-positive migratory pathway from the subpallium to the olfactory bulb, which is increased in size in cavefish. Finally, we observe heterochrony and enlarged Lhx7 expression in the cavefish basal forebrain. These specific increases in olfactory and hypothalamic forebrain components are Shh-dependent and therefore place the telencephalic midline organisers in a crucial position to modulate forebrain evolution through developmental events, and to generate diversity in forebrain neuronal patterning.

  15. Acute uptake inhibition increases extracellular serotonin in the rat forebrain.

    Rutter, J J; Auerbach, S B


    The effect of acute uptake inhibition on serotonin (5-HT) in the rat central nervous system was monitored by using in vivo dialysis. Peripheral administration of the selective 5-HT uptake blocker, fluoxetine, caused a dose-dependent increase in extracellular 5-HT in both the diencephalon and the striatum. Administration of fluoxetine or sertraline, another selective 5-HT uptake inhibitor, caused a prolonged (24 hr) increase in 5-HT and decrease in 5-hydroxyindoleacetic acid. In addition, fluoxetine and sertraline attenuated the 5-HT releasing effect of fenfluramine administered 24 hr later. Local infusion of fluoxetine into the diencephalon caused an increase in 5-HT that was twice as large as the effect of peripheral injection. Peripheral fluoxetine, by enhancing extracellular 5-HT in the raphe, probably resulted in activation of somatodendritic autoreceptors and inhibition of 5-HT neuronal discharge. Thus, the increase in 5-HT in the diencephalon after peripheral fluoxetine presumably reflected a balance between decreased release and inhibition of reuptake. In support of this, after first infusing fluoxetine into the diencephalon to maximally block reuptake, peripheral injection of the uptake inhibitor caused a decrease in 5-HT.

  16. Altered mitochondrial respiration in selectively vulnerable brain subregions following transient forebrain ischemia in the rat.

    Sims, N R; Pulsinelli, W A


    Mitochondrial respiratory function, assessed from the rate of oxygen uptake by homogenates of rat brain subregions, was examined after 30 min of forebrain ischemia and at recirculation periods of up to 48 h. Ischemia-sensitive regions which develop extensive neuronal loss during the recirculation period (dorsal-lateral striatum, CA1 hippocampus) were compared with ischemia-resistant areas (paramedian neocortex, CA3 plus CA4 hippocampus). All areas showed reductions (to 53-69% of control) during ischemia for oxygen uptake rates determined in the presence of ADP or an uncoupling agent, which then recovered within 1 h of cerebral recirculation. In the ischemia-resistant regions, oxygen uptake rates remained similar to control values for at least 48 h of recirculation. After 3 h of recirculation, a significant decrease in respiratory activity (measured in the presence of ADP or uncoupling agent) was observed in the dorsal-lateral striatum which progressed to reductions of greater than 65% of the initial activity by 24 h. In the CA1 hippocampus, oxygen uptake rates were unchanged for 24 h, but were significantly reduced (by 30% in the presence of uncoupling agent) at 48 h. These alterations parallel the development of histological evidence of ischemic cell change determined previously and apparently precede the appearance of differential changes between sensitive and resistant regions in the content of high-energy phosphate compounds. These results suggest that alterations of mitochondrial activity are a relatively early change in the development of ischemic cell death and provide a sensitive biochemical marker for this process.

  17. Reference and working memory of rats following hippocampal damage induced by transient forebrain ischemia.

    Davis, H P; Tribuna, J; Pulsinelli, W A; Volpe, B T


    Acquisition of reference and working memory was evaluated in an animal model of cerebral ischemia. Rats were subjected to 30 minutes of transient forebrain ischemia, allowed to recover, and then tested for 95 trials on an 8-arm maze with 5 arms baited. During the 95 trials post ischemic (PI) rats made significantly more working and reference errors than controls (p less than 0.05). However, an analysis of the last 20 trials (75-95) showed that while PI rats and control rats had comparable reference memory (p greater than 0.8). PI rats tended to have a persistent working memory deficit compared to controls (p less than 0.06). Subsequent morphologic analysis showed that PI rats had almost complete loss of pyramidal neurons in the anterior CA1 region of the hippocampus, moderate to severe loss in mid-dorsal posterior hippocampus, and less damage to the dorsolateral striatum. These results suggest that the PI animal is a reasonable model for the permanent behavioral impairment and pathologic damage found in some human survivors of cardiac arrest.

  18. Long-term effects of cholinergic basal forebrain lesions on neuropeptide Y and somatostatin immunoreactivity in rat neocortex

    Gaykema, R.P.A.; Compaan, J.C.; Nyakas, C.; Horvath, E.; Luiten, P.G.M.


    The effect of cholinergic basal forebrain lesions on immunoreactivity to somatostatin (SOM-i) and neuropeptide-Y (NPY-i) was investigated in the rat parietal cortex, 16-18 months after multiple bilateral ibotenic acid injections in the nucleus basalis complex. As a result of the lesion, the choliner

  19. Fgf19 regulated by Hh signaling is required for zebrafish forebrain development.

    Miyake, Ayumi; Nakayama, Yoshiaki; Konishi, Morichika; Itoh, Nobuyuki


    Fibroblast growth factor (Fgf) signaling plays important roles in brain development. Fgf3 and Fgf8 are crucial for the formation of the forebrain and hindbrain. Fgf8 is also required for the midbrain to form. Here, we identified zebrafish Fgf19 and examined its roles in brain development by knocking down Fgf19 function. We found that Fgf19 expressed in the forebrain, midbrain and hindbrain was involved in cell proliferation and cell survival during embryonic brain development. Fgf19 was also essential for development of the ventral telencephalon and diencephalon. Regional specification is linked to cell type specification. Fgf19 was also essential for the specification of gamma-aminobutyric acid (GABA)ergic interneurons and oligodendrocytes generated in the ventral telencephalon and diencephalon. The cross talk between Fgf and Hh signaling is critical for brain development. In the forebrain, Fgf19 expression was down-regulated on inhibition of Hh but not of Fgf3/Fgf8, and overexpression of Fgf19 rescued partially the phenotype on inhibition of Hh. The present findings indicate that Fgf19 signaling is crucial for forebrain development by interacting with Hh and provide new insights into the roles of Fgf signaling in brain development.

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

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


    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.

  1. Novel AAV-based rat model of forebrain synucleinopathy shows extensive pathologies and progressive loss of cholinergic interneurons.

    Patrick Aldrin-Kirk

    Full Text Available 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

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

    Alexander, M.J.; Miller, M.A.; Dorsa, D.M.; Bullock, B.P.; Helloni, R.H. Jr.; Dobner, P.R.; Leeman, S.E. (Univ. of Massachusetts Medical Center, Worcester (USA))


    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.

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

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


    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.

  4. Forebrain Ischemia Triggers GABAergic System Degeneration in Substantia Nigra at Chronic Stages in Rats

    B. Lin


    Full Text Available The long-term consequences of forebrain ischemia include delayed Parkinson's syndrome. This study revealed delayed neurodegeneration in the substantia nigra 8 weeks after 12.5 minutes of global ischemia in rat brain. Following neuronal loss of 30–40% in central and dorsolateral striatum at day 3, neuronal damage in the substantia nigra (SN was assessed at 4–8 weeks using immunohistochemistry for glutamate decarboxylase 67 (GAD67, vesicular GABA transporter (VGAT, and calretinin (CR. At day 56, the optical density of GAD67-, but not VGAT-, immunoreactivity in substantia nigra pars reticulata (SNR—significantly decreased. CR-neurons concentrated in substantia nigra pars compacta (SNC were reduced by 27% from day 3 (n=5 to day 56 (n=7, ANOVA, p<.01. Movement coordination was impaired at day 56, as evaluated using beam-walking test (time-to-traverse 5.6±1.2 sec versus 11.8±5.4 sec; sham versus ischemia, p<.05, n=5, and 7, resp.. Our results demonstrate delayed impairment of the GABAergic system components in SN and associated with movement deficits after global ischemia.

  5. Contribution of the cholinergic basal forebrain to proactive interference from stored odor memories during associative learning in rats.

    De Rosa, E; Hasselmo, M E; Baxter, M G


    E. De Rosa and M. E. Hasselmo (2000) demonstrated that 0.25 mg/kg scopolamine (SCOP) selectively increased proactive interference (PI) from stored odor memories during learning. In the present study, rats with bilateral cholinergic lesions limited to the horizontal limb of the diagonal band of Broca, made with 192 IgG-saporin, were not impaired in acquiring the same olfactory discrimination task relative to control rats. Rats with bilateral 192 IgG-saporin lesions to all basal forebrain cholinergic nuclei (BF) also showed no impairment in acquisition of this task. However, the BF-saporin rats were hypersensitive to oxotremorine-induced hypothermia and demonstrated an increased sensitivity to PI following a low dose of SCOP (0.125 mg/kg) relative to control rats. The results suggest that weaker cholinergic modulation after cholinergic BF lesions makes the system more sensitive to PI during blockade of the remaining cholinergic elements.

  6. Forebrain patterns of c-Fos and FosB induction during cancer-associated anorexia-cachexia in rat.

    Konsman, Jan Pieter; Blomqvist, Anders


    Forebrain structures are necessary for the initiation of food intake and its coupling to energy expenditure. The cancer-related anorexia-cachexia syndrome is typified by a prolonged increase in metabolic rate resulting in body weight loss which, paradoxically, is accompanied by reduced food intake. The aim of the present work was to study the forebrain expression of Fos proteins as activation markers and thus to identify potential neurobiological mechanisms favouring catabolic processes or modulating food intake in rats suffering from cancer-related anorexia-cachexia. Neurons in forebrain structures showing most pronounced induction of Fos proteins were further identified neurochemically. To provoke anorexia-cachexia, cultured Morris hepatoma 7777 cells were injected subcutaneously in Buffalo rats. This resulted in a slowly growing tumour inducing approximately 7% body weight loss and a 20% reduction in food intake when the tumour represented 1-2% of body mass. Anorexia-cachexia in these animals was found to be accompanied by Fos induction in several hypothalamic nuclei including the paraventricular and ventromedial hypothalamus, in the parastrial nucleus, the amygdala, the bed nucleus of the stria terminalis, ventral striatal structures and the piriform and somatosensory cortices. Neurochemical identification revealed that the vast majority of FosB-positive neurons in the nucleus accumbens, ventral caudate-putamen and other ventral striatal structures contained prodynorphin or proenkephalin mRNA. These findings indicate that forebrain structures that are part of neuronal networks modulating catabolic pathways and food ingestion are activated during tumour-associated anorexia-cachexia and may contribute to the lack of compensatory eating in response to weight loss characterizing this syndrome.

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

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


    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.

  8. Effects of olanzapine on regional C-Fos expression in rat forebrain.

    Robertson, G S; Fibiger, H C


    Compared to typical antipsychotic drugs, clozapine produces a unique pattern of Fos-like immunoreactive neurons in the rat forebrain. It has been proposed, therefore, that this approach may be useful in identifying other agents with clozapine's therapeutic profile. In the present study, we examined the ability of olanzapine to increase the number of Fos-like immunoreactive neurons in the striatum, nucleus accumbens, lateral septal nucleus, and prefrontal cortex. Olanzapine (5, 10 mg/kg) produced dose-dependent increases in the number of Fos-positive neurons in the nucleus accumbens and lateral septal nucleus, important components of the limbic system that may mediate some of the therapeutic actions of neuroleptics. Olanzapine also produced dose-dependent increases in the number of Fos-positive neurons in the dorsolateral striatum, an effect that correlates with the ability of neuroleptics to produce extrapyramidal side-effects. The effects of olanzapine on regional c-fos expression are not therefore identical to clozapine, which is without effect in the dorsolateral striatum. However, olanzapine-induced increases in the dorsolateral striatum were considerably smaller than those generated in the nucleus accumbens suggesting that at low, potentially therapeutic doses olanzapine may not generate significant extrapyramidal side effects. Olanzapine also increased the number of Fos-positive neurons in medical prefrontal cortex, an action unique to clozapine and a few other atypical antipsychotics. These findings are consistent with the hypothesis that olanzapine is an atypical antipsychotic in the sense that it does not produce significant extrapyramidal side-effects at low therapeutic doses. However, extrapyramidal side-effects at higher doses can be predicted by these results. Finally, olanzapine's actions in the medial prefrontal cortex may be predictive of a clozapine-like profile with respect to actions on negative symptoms in schizophrenia. Additional clinical

  9. Antagonism of Muscarinic Acetylcholine Receptors Alters Synaptic ERK Phosphorylation in the Rat Forebrain.

    Mao, Li-Min; Wang, Henry H; Wang, John Q


    Acetylcholine (ACh) is a key transmitter in the mesocorticolimbic circuit. By interacting with muscarinic ACh receptors (mAChR) enriched in the circuit, ACh actively regulates various neuronal and synaptic activities. The extracellular signal-regulated kinase (ERK) is one of members of the mitogen-activated protein kinase family and is subject to the regulation by dopamine receptors, although the regulation of ERKs by limbic mAChRs is poorly understood. In this study, we investigated the role of mAChRs in the regulation of ERK phosphorylation (activation) in the mesocorticolimbic system of adult rat brains in vivo. We targeted a sub-pool of ERKs at synaptic sites. We found that a systemic injection of the mAChR antagonist scopolamine increased phosphorylation of synaptic ERKs in the striatum (caudate putamen and nucleus accumbens) and medial prefrontal cortex (mPFC). Increases in ERK phosphorylation in both forebrain regions were rapid and transient. Notably, pretreatment with a dopamine D1 receptor (D1R) antagonist SCH23390 blocked the scopolamine-stimulated ERK phosphorylation in these brain regions, while a dopamine D2 receptor antagonist eticlopride did not. Scopolamine and SCH23390 did not change the amount of total ERK proteins. These results demonstrate that mAChRs inhibit synaptic ERK phosphorylation in striatal and mPFC neurons under normal conditions. Blockade of this inhibitory mAChR tone leads to the upregulation of ERK phosphorylation likely through a mechanism involving the level of D1R activity.

  10. Extraction of total RNA in the developing chicken forebrain

    Sayed Rasoul Zaker


    Full Text Available Background: Gene expression of Gama-Aminobutyric acid (GABA A receptor subunits may change during development. Procedures in molecular biology are required to understand the gene expression profile GABA A R in chicken. The outcome of the results depends on good-quality high-molecular-weight RNA. Several procedures can be used to isolate RNA from the brain of chicken; however, most of them are time-consuming and require disruption of cells or freeze and thaw in the presence of RNase inhibitors. The aim of this experiment was isolation of RNA from chicken embryonic brain tissues using appropriate RNA extraction kit. Materials and Methods: Fertilized eggs from Ross breed (Gallus gallus were incubated at 38°C and 60% relative humidity in a forced-draft incubator and were turned every 3 h. After 3, 7, 14 and 20 days of incubation, eggs were cooled on ice to induce deep anesthesia. Then whole brains were dissected out. As brains could not be excised in a reproducible way from earlier embryos (embryonic days 4 and 6, whole heads were collected. Chicken embryos between day 7 to 20 and 1 day after birth were decapitated, and their brains removed. Samples were immediately inserted into lysis buffer and stored at −70°C. Total RNA was isolated and a contaminating genomic deoxyribonucleic acid (DNA was digested. RNA quality was checked using gel electrophoresis. Results: We obtained 52 mg/ml to 745 mg/ml with A260/280 1.7-2.2. Only high-quality RNA, with no signs of degradation, was used for further experiments. Conclusion: In conclusion, protocol was found to be suitable for the isolation of total RNA from embryonic chicken cells.

  11. Vulnerability of mossy fiber targets in the rat hippocampus to forebrain ischemia.

    Hsu, M; Buzsáki, G


    Much of the work on forebrain ischemia in the hippocampus has focused on the phenomenon of delayed neuronal death in CA1. It is established that dentate granule cells and CA3 pyramidal cells are resistant to ischemia. However, much less is known about interneuronal involvement in CA3 or ischemic injury in the dentate hilus other than the fact that somatostatin neurons in the latter lose their immunoreactivity. We combined two sensitive methods--heat-shock protein (HSP72) immunocytochemistry and a newly developed Gallyas silver stain for demonstrating impaired cytoskeletal elements--to investigate the extent of ischemic damage to CA3 and the dentate hilus using the four-vessel-occlusion model for inducing forebrain ischemia. HSP72-like immunoreactivity was induced in neuronal populations previously shown to be vulnerable to ischemia. In addition, a distinct subset of interneurons in CA3 was also extremely sensitive to ischemia, even more so than the CA1 pyramidal cells. These neurons are located in the stratum lucidum of CA3 and possess a very high density of dendritic spines. In silver preparations, they were among the first to be impregnated as "dark" neurons, before CA1 pyramidal cells; microglial reaction was also initiated first in the stratum lucidum of CA3. Whereas CA1 damage was most prominent in the septal half of the hippocampus, hilar and CA3 interneuronal damage had a more extensive dorsoventral distribution. Our results also show a far greater extent of damage in hilar neurons than previously reported. At least four hilar cell types were consistently compromised: mossy cells, spiny fusiform cells, sparsely spiny fusiform cells, and long-spined multipolar cells. A common denominator of the injured neurons in CA3 and the hilus was the presence of spines on their dendrites, which in large part accounted for the far greater number of mossy fiber terminals they receive than their non-spiny neighbors. We suggest that the differential vulnerability of neuronal

  12. Forebrain development in fetal MRI: evaluation of anatomical landmarks before gestational week 27.

    Schmook, Maria T; Brugger, Peter C; Weber, Michael; Kasprian, Gregor; Nemec, Stefan; Krampl-Bettelheim, Elisabeth; Prayer, Daniela


    Forebrain malformations include some of the most severe developmental anomalies and require early diagnosis. The proof of normal or abnormal prosencephalic development may have an influence on further management in the event of a suspected fetal malformation. The purpose of this retrospective study was to evaluate the detectability of anatomical landmarks of forebrain development using in vivo fetal magnetic resonance imaging (MRI) before gestational week (gw) 27. MRI studies of 83 singleton fetuses (gw 16-26, average +/- sd: gw 22 +/- 2) performed at 1.5 Tesla were assessed. T2-weighted (w) fast spin echo, T1w gradient-echo and diffusion-weighted sequences were screened for the detectability of anatomical landmarks as listed below. The interhemispheric fissure, ocular bulbs, corpus callosum, infundibulum, chiasm, septum pellucidum (SP), profile, and palate were detectable in 95%, 95%, 89%, 87%, 82%, 81%, 78%, 78% of cases. Olfactory tracts were more easily delineated than bulbs and sulci (37% versus 18% and 8%), with significantly higher detection rates in the coronal plane. The pituitary gland could be detected on T1w images in 60% with an increasing diameter with gestational age (p = 0.041). The delineation of olfactory tracts (coronal plane), chiasm, SP and pituitary gland were significantly increased after week 21 (p < 0.05). Pathologies were found in 28% of cases. This study provides detection rates for anatomical landmarks of forebrain development with fetal MRI before gw 27. Several anatomical structures are readily detectable with routine fetal MRI sequences; thus, if these landmarks are not delineable, it should raise the suspicion of a pathology. Recommendations regarding favorable sequences/planes are provided.

  13. Forebrain development in fetal MRI: evaluation of anatomical landmarks before gestational week 27

    Schmook, Maria T.; Weber, Michael; Kasprian, Gregor; Nemec, Stefan; Prayer, Daniela [Medical University of Vienna, Department of Radiology/Division of Neuro- and Musculoskeletal Radiology, Vienna (Austria); Brugger, Peter C. [Medical University of Vienna, Integrative Morphology Group, Center for Anatomy and Cell Biology, Vienna (Austria); Krampl-Bettelheim, Elisabeth [Department of Obstetrics and Gynecology / Division of Obstetrics and Feto-maternal Medicine, Vienna (Austria)


    Forebrain malformations include some of the most severe developmental anomalies and require early diagnosis. The proof of normal or abnormal prosencephalic development may have an influence on further management in the event of a suspected fetal malformation. The purpose of this retrospective study was to evaluate the detectability of anatomical landmarks of forebrain development using in vivo fetal magnetic resonance imaging (MRI) before gestational week (gw) 27. MRI studies of 83 singleton fetuses (gw 16-26, average {+-}sd: gw 22 {+-} 2) performed at 1.5 Tesla were assessed. T2-weighted (w) fast spin echo, T1w gradient-echo and diffusion-weighted sequences were screened for the detectability of anatomical landmarks as listed below. The interhemispheric fissure, ocular bulbs, corpus callosum, infundibulum, chiasm, septum pellucidum (SP), profile, and palate were detectable in 95%, 95%, 89%, 87%, 82%, 81%, 78%, 78% of cases. Olfactory tracts were more easily delineated than bulbs and sulci (37% versus 18% and 8%), with significantly higher detection rates in the coronal plane. The pituitary gland could be detected on T1w images in 60% with an increasing diameter with gestational age (p=0.041). The delineation of olfactory tracts (coronal plane), chiasm, SP and pituitary gland were significantly increased after week 21 (p<0.05). Pathologies were found in 28% of cases. This study provides detection rates for anatomical landmarks of forebrain development with fetal MRI before gw 27. Several anatomical structures are readily detectable with routine fetal MRI sequences; thus, if these landmarks are not delineable, it should raise the suspicion of a pathology. Recommendations regarding favorable sequences/planes are provided. (orig.)

  14. Newly identified patterns of Pax2 expression in the developing mouse forebrain

    Mason John O


    Full Text Available Abstract Background The availability of specific markers expressed in different regions of the developing nervous system provides a useful tool for the study of mouse mutants. One such marker, the transcription factor Pax2, is expressed at the midbrain-hindbrain boundary and in the cerebellum, spinal cord, retina, optic stalk, and optic chiasm. We recently described a group of diencephalic cells that express Pax2 as early as embryonic day (E 10.5, and become part of the eminentia thalami by E11.5. The discovery of this previously undescribed cell population prompted us to examine Pax2 protein expression in the developing mouse forebrain in more detail. Results We determined the expression pattern of Pax2 in the forebrain of wild type mouse embryos between E10.5 and postnatal day (P 15. Pax2 expression was detected in the septum of the basal forebrain, hypothalamus, eminentia thalami and in the subfornical organ. To evaluate Pax2 as a marker for septal cells, we examined Pax2 expression in Pax6Sey/Sey mutants, which have an enlarged septum. We found that Pax2 clearly marks a population of septal cells equivalent to that seen in wild types, indicating its utility as a marker of septal identity. These cells did not express the GABAergic marker calbindin nor the cholinergic marker choline acetyltransferase and were not detectable after P15. Conclusion Pax2 is expressed in populations of cells within the developing septum, hypothalamus, and eminentia thalami. It seems especially useful as a marker of the telencephalic septum, because of its early, strong and characteristic expression in this structure. Further, its expression is maintained in the enlarged septum of Pax6Sey/Sey mutants.

  15. Evidence for neuroprotective effects of endogenous brain-derived neurotrophic factor after global forebrain ischemia in rats.

    Larsson, E; Nanobashvili, A; Kokaia, Z; Lindvall, O


    The levels of brain-derived neurotrophic factor (BDNF) vary between different forebrain areas and show region-specific changes after cerebral ischemia. The present study explores the possibility that the levels of endogenous BDNF determine the susceptibility to ischemic neuronal death. To block BDNF activity the authors used the TrkB-Fc fusion protein, which was infused intraventricularly in rats during 1 week before and 1 week after 5 or 30 minutes of global forebrain ischemia. Ischemic damage was quantified in the striatum and hippocampal formation after 1 week of reperfusion using immunocytochemistry and stereological procedures. After the 30-minute insult, there was a significantly lower number of surviving CA4 pyramidal neurons, neuropeptide Y-immunoreactive dentate hilar neurons, and choline acetyltransferase- and TrkA-positive, cholinergic striatal interneurons in the TrkB-Fc-infused rats as compared to controls. In contrast, the TrkB-Fc treatment did not influence survival of CA1 or CA3 pyramidal neurons or striatal projection neurons. Also, after the mild ischemic insult (5 minutes), neuronal death in the CA1 region was similar in the TrkB-Fc-treated and control groups. These results indicate that endogenous BDNF can protect certain neuronal populations against ischemic damage. It is conceivable, though, that efficient neuroprotection after brain insults is dependent not only on this factor but on the concerted action of a large number of neurotrophic molecules.

  16. The hallucinogen d-lysergic acid diethylamide (d-LSD) induces the immediate-early gene c-Fos in rat forebrain.

    Frankel, Paul S; Cunningham, Kathryn A


    The hallucinogen d-lysergic acid diethylamide (d-LSD) evokes dramatic somatic and psychological effects. In order to analyze the neural activation induced by this unique psychoactive drug, we tested the hypothesis that expression of the immediate-early gene product c-Fos is induced in specific regions of the rat forebrain by a relatively low, behaviorally active, dose of d-LSD (0.16 mg/kg, i.p.); c-Fos protein expression was assessed at 30 min, and 1, 2 and 4 h following d-LSD injection. A time- and region-dependent expression of c-Fos was observed with a significant increase (PLSD administration. These data demonstrate a unique pattern of c-Fos expression in the rat forebrain following a relatively low dose of d-LSD and suggest that activation of these forebrain regions contributes to the unique behavioral effects of d-LSD. Copyright 2002 Elsevier Science B.V.

  17. Pathway for interferon-gamma to promote the differentiation of cholinergic neurons in rat embryonic basal forebrain/septal nuclei


    BACKGROUND: The supernatant of interferon-gamma (IFN γ ) co-cultured with neonatal rat cortical glia can promote the cells in embryonic basal forebrain/septal nuclei to differentiate into cholinergic neurons, but the mechanism is still unclear.OBJECTIVE: To analyze the pathways for IFN γ to promote the differentiation of primarily cultured cholinergic neurons in rat embryonic basal forebrain/septal nuclei through culture in different conditioned medium.DESIGN: A controlled experiment taking cells as the observational target.SETTINGS: Department of Biochemistry and Molecular Biology, Youjiang Medical College for Nationalities; Department of Cell Biology, Beijing University Health Science Center.MATERIALS: Sixty-four pregnant Wistar rats for 16 days (250 - 350 g) and 84 Wistar rats (either male or female, 5 - 7 g) of 0 - 1 day after birth were provided by the experimental animal department of Beijing University Health Science Center. Rat IFN γ were provided by Gibco Company; Glial fibrillary acidic protein by Huamei Company.METHODS: The experiments were carried out in the Department of Cell Biology, Beijing University Health Science Center and Daheng Image Company of Chinese Academy of Science from July 1995 to December 2002. ① Interventions: The nerve cells in the basal forebrain/septal nuclei of the pregnant Wistar rats for 16 days were primarily cultured, and then divided into four groups: Blank control group (not any supernatant and medium was added); Control group (added by mixed glial cell or astrocyte conditioned medium); IFN γ group (added by mixed glial cell or astrocyte conditioned medium+IFN γ ). Antibody group (added by mixed glial cell or astrocyte conditioned medium+IFN γ +Ab-IFN γ ). Mixed glial cell or astrocyte conditioned medium was prepared using cerebral cortex of Wistar rats of 0 - 1 day after birth. ② Evaluation: The immunohistochemical method was used to perform the choline acetyltransferase (ChAT) staining of cholinergic neurons

  18. Orexin-A facilitates emergence of the rat from isoflurane anesthesia via mediation of the basal forebrain.

    Zhang, Li-Na; Yang, Cen; Ouyang, Peng-Rong; Zhang, Zhi-Chao; Ran, Ming-Zi; Tong, Li; Dong, Hai-Long; Liu, Yong


    Previous studies have demonstrated that orexinergic neurons involve in promoting emergence from anesthesia of propofol, an intravenous anesthetics, while whether both of orexin-A and orexin-B have promotive action on emergence via mediation of basal forebrain (BF) in isoflurane anesthesia has not been elucidated. In this study, we observed c-Fos expressions in orexinergic neurons following isoflurane inhalation (for 0, 30, 60, and 120min) and at the time when the righting reflex returned after the cessation of anesthesia. The plasma concentrations of orexin-A and -B in anesthesia-arousal process were measured by radioimmunoassay. Orexin-A and -B (30 or 100pmol) or the orexin receptor-1 and -2 antagonist SB-334867A and TCS-OX2-29 (5 or 20μg) were microinjected into the basal forebrain respectively. The effects of them on the induction (loss of the righting reflex) and the emergence time (return of the righting reflex) under isoflurane anesthesia were observed. The results showed that the numbers of c-Fos-immunoreactive orexinergic neurons in the hypothalamus decreased over time with continued isoflurane inhalation, but restored at emergence. Similar alterations were observed in changes of plasma orexin-A concentrations but not in orexin-B during emergence. Administration of orexins had no effect on the induction time, but orexin-A facilitated the emergence of rats from isoflurane anesthesia while orexin-B didn't. Conversely, microinjection of the orexin receptor-1 antagonist SB-334867A delayed emergence from isoflurane anesthesia. The results indicate that orexin-A plays a promotive role in the emergence of isoflurane anesthesia and this effect is mediated by the basal forebrain.

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

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


    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.

  20. Blockade of the AMPA receptor prevents CA1 hippocampal injury following severe but transient forebrain ischemia in adult rats.

    Buchan, A M; Li, H; Cho, S; Pulsinelli, W A


    The cytoprotective effect of NBQX, a selective AMPA receptor antagonist, was tested following 10 min of severe forebrain ischemia using the 4-vessel occlusion model. Immediately, and at 15 and 30 min following reperfusion, adult Wistar rats received intraperitoneal injections of either saline (n = 5), 1 mg lithium chloride (n = 17) or 30 mg/kg of the lithium salt of NBQX (n = 18). In saline-treated animals 82 +/- 12% of CA1 hippocampal neurons were lost. Of those treated with lithium 70 +/- 23% were injured, while those given NBQX sustained only 40 +/- 34% CA1 necrosis (P less than 0.01). Twelve of 18 NBQX-treated animals had less than 30% CA1 injury as compared with 1 of 17 lithium-treated animals. The AMPA receptor may play a more important role than the NMDA receptor in selective ischemic necrosis of hippocampal neurons.

  1. Estradiol replacement enhances sleep deprivation-induced c-Fos immunoreactivity in forebrain arousal regions of ovariectomized rats.

    Deurveilher, S; Cumyn, E M; Peers, T; Rusak, B; Semba, K


    To understand how female sex hormones influence homeostatic mechanisms of sleep, we studied the effects of estradiol (E(2)) replacement on c-Fos immunoreactivity in sleep/wake-regulatory brain areas after sleep deprivation (SD) in ovariectomized rats. Adult rats were ovariectomized and implanted subcutaneously with capsules containing 17beta-E(2) (10.5 microg; to mimic diestrous E(2) levels) or oil. After 2 wk, animals with E(2) capsules received a single subcutaneous injection of 17beta-E(2) (10 microg/kg; to achieve proestrous E(2) levels) or oil; control animals with oil capsules received an oil injection. Twenty-four hours later, animals were either left undisturbed or sleep deprived by "gentle handling" for 6 h during the early light phase, and killed. E(2) treatment increased serum E(2) levels and uterus weights dose dependently, while attenuating body weight gain. Regardless of hormonal conditions, SD increased c-Fos immunoreactivity in all four arousal-promoting areas and four limbic and neuroendocrine nuclei studied, whereas it decreased c-Fos labeling in the sleep-promoting ventrolateral preoptic nucleus (VLPO). Low and high E(2) treatments enhanced the SD-induced c-Fos immunoreactivity in the laterodorsal subnucleus of the bed nucleus of stria terminalis and the tuberomammillary nucleus, and in orexin-containing hypothalamic neurons, with no effect on the basal forebrain and locus coeruleus. The high E(2) treatment decreased c-Fos labeling in the VLPO under nondeprived conditions. These results indicate that E(2) replacement modulates SD-induced or spontaneous c-Fos expression in sleep/wake-regulatory and limbic forebrain nuclei. These modulatory effects of E(2) replacement on neuronal activity may be, in part, responsible for E(2)'s influence on sleep/wake behavior.

  2. Tesofensine induces appetite suppression and weight loss with reversal of low forebrain dopamine levels in the diet-induced obese rat

    Hansen, Henrik H; Jensen, Majbrit M; Overgaard, Agnete


    Tesofensine is a triple monoamine reuptake inhibitor which inhibits noradrenaline, 5-HT and dopamine reuptake. Tesofensine is currently in clinical development for the treatment of obesity, however, the pharmacological basis for its strong and sustained effects in obesity management is not clarif......, tesofensine produces weight loss together with reversal of lowered forebrain dopamine levels in DIO rats, suggesting that tesofensine's anti-obesity effects, at least in part, are associated with positive modulation of central dopaminergic activity....... is not clarified. Tesofensine effectively induces appetite suppression in the diet-induced obese (DIO) rat partially being ascribed to an indirect stimulation of central dopamine receptor function subsequent to blocked dopamine transporter activity. This is interesting, as obese patients have reduced central...... dopaminergic activity thought to provide a drive for compensatory overeating, but whether treatment with an uptake inhibitor counteracts these changes or not has not been investigated. Tesofensine treatment (2.0mg/kg/day for 14days) caused a pronounced anorexigenic and weight-reducing response in DIO rats...

  3. Ontogenetic distribution of the transcription factor Nkx2.2 in the developing forebrain of Xenopus laevis

    Laura eDominguez


    Full Text Available The expression of the Nkx2.2 gene is involved in the organization of the alar-basal boundary in the forebrain of vertebrates. Its expression in different diencephalic and telencephalic regions, helped to define distinct progenitor domains in mouse and chick. Here we investigated the pattern of Nkx2.2 protein distribution throughout the development of the forebrain of the anuran amphibian, Xenopus laevis. We used immunohistochemical and in situ hybridization techniques for its detection in combination with other essential territorial markers in the forebrain. No expression was observed in the telencephalon. In the alar hypothalamus, Nkx2.2 positive cells were scattered in the suprachiasmatic territory, but also in the supraoptoparaventricular area, as defined by the expression of the transcription factor Otp and the lack of xDll4. In the basal hypothalamus Nkx2.2 expressing cells were localized in the tuberal region, with the exception of the arcuate nucleus, rich in Otp expressing cells. In the diencephalon it was expressed in all three prosomeres (P1-P3 and not in the zona limitans intrathalamica. The presence of Nkx2.2 expressing cells in P3 was restricted to the alar portion, as well as in prosomere P2, whereas in P1 the Nkx2.2 expressing cells were located in the basal plate and identified the alar/basal boundary. These results showed that Nkx2.2 and Sonic hedgehog are expressed in parallel adjacent stripes along the anterior-posterior axis. The results of this study showed a conserved distribution pattern of Nkx2.2 among vertebrates, crucial to recognize subdivisions that are otherwise indistinct, and supported the relevance of this transcription factor in the organization of the forebrain, particularly in the delineation of the alar/basal boundary of the forebrain.

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

    Yamaguchi, Ken'ichi; Yamada, Takaho


    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.

  5. Cerebrovascular endothelin-1 hyper-reactivity is associated with transient receptor potential canonical channels 1 and 6 activation and delayed cerebral hypoperfusion after forebrain ischaemia in rats

    Johansson, S E; Andersen, X E D R; Hansen, R H;


    AIM: In this study, we aimed to investigate whether changes in cerebrovascular voltage-dependent calcium channels and non-selective cation channels contribute to the enhanced endothelin-1-mediated vasoconstriction in the delayed hypoperfusion phase after experimental transient forebrain ischaemia....... METHODS: Experimental forebrain ischaemia was induced in Wistar male rats by a two-vessel occlusion model, and the cerebral blood flow was measured by magnetic resonance imaging two days after reperfusion. In vitro vasoreactivity studies, immunofluorescence and quantitative PCR were performed on cerebral...... arteries from ischaemic or sham-operated rats to evaluate changes in vascular voltage-dependent calcium channels, transient receptor potential canonical channels as well as endothelin-1 receptor function and expression. RESULTS: The expression of transient receptor potential canonical channels 1 and 6...

  6. Effects of L-NAME, a non-specific nitric oxide synthase inhibitor, on AlCl3-induced toxicity in the rat forebrain cortex.

    Stevanović, Ivana D; Jovanović, Marina D; Jelenković, Ankica; Colić, Miodrag; Stojanović, Ivana; Ninković, Milica


    The present experiments were done to determine the effectiveness of a non-specific nitric oxide synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME), on oxidative stress parameters induced by aluminium chloride (AlCl(3)) intrahippocampal injections in Wistar rats. Animals were sacrificed 3 h and 30 d after treatments, heads were immediately frozen in liquid nitrogen and forebrain cortices were removed. Crude mitochondrial fraction preparations of forebrain cortices were used for the biochemical analyses: nitrite levels, superoxide production, malondialdehyde concentrations, superoxide dismutase (SOD) activities and reduced glutathione contents. AlCl(3) injection resulted in increased nitrite concentrations, superoxide anion production, malondialdehyde concentrations and reduced glutathione contents in the forebrain cortex, suggesting that AlCl(3) exposure promoted oxidative stress in this brain structure. The biochemical changes observed in neuronal tissues showed that aluminium acted as a pro-oxidant. However, the nonspecific nitric oxide synthase (NOS) inhibitor, L-NAME, exerted anti-oxidant actions in AlCl(3)-treated animals. These results revealed that NO-mediated neurotoxicity due to intrahippocampal AlCl3 injection spread temporally and spatially to the forebrain cortex, and suggested a potentially neuroprotective effect for L-NAME.

  7. Transcriptional Networks Controlled by NKX2-1 in the Development of Forebrain GABAergic Neurons.

    Sandberg, Magnus; Flandin, Pierre; Silberberg, Shanni; Su-Feher, Linda; Price, James D; Hu, Jia Sheng; Kim, Carol; Visel, Axel; Nord, Alex S; Rubenstein, John L R


    The embryonic basal ganglia generates multiple projection neurons and interneuron subtypes from distinct progenitor domains. Combinatorial interactions of transcription factors and chromatin are thought to regulate gene expression. In the medial ganglionic eminence, the NKX2-1 transcription factor controls regional identity and, with LHX6, is necessary to specify pallidal projection neurons and forebrain interneurons. Here, we dissected the molecular functions of NKX2-1 by defining its chromosomal binding, regulation of gene expression, and epigenetic state. NKX2-1 binding at distal regulatory elements led to a repressed epigenetic state and transcriptional repression in the ventricular zone. Conversely, NKX2-1 is required to establish a permissive chromatin state and transcriptional activation in the sub-ventricular and mantle zones. Moreover, combinatorial binding of NKX2-1 and LHX6 promotes transcriptionally permissive chromatin and activates genes expressed in cortical migrating interneurons. Our integrated approach provides a foundation for elucidating transcriptional networks guiding the development of the MGE and its descendants.

  8. Brainstem stimulation increases functional connectivity of basal forebrain-paralimbic network in isoflurane-anesthetized rats.

    Pillay, Siveshigan; Liu, Xiping; Baracskay, Péter; Hudetz, Anthony G


    Brain states and cognitive-behavioral functions are precisely controlled by subcortical neuromodulatory networks. Manipulating key components of the ascending arousal system (AAS), via deep-brain stimulation, may help facilitate global arousal in anesthetized animals. Here we test the hypothesis that electrical stimulation of the oral part of the pontine reticular nucleus (PnO) under light isoflurane anesthesia, associated with loss of consciousness, leads to cortical desynchronization and specific changes in blood-oxygenation-level-dependent (BOLD) functional connectivity (FC) of the brain. BOLD signals were acquired simultaneously with frontal epidural electroencephalogram before and after PnO stimulation. Whole-brain FC was mapped using correlation analysis with seeds in major centers of the AAS. PnO stimulation produced cortical desynchronization, a decrease in δ- and θ-band power, and an increase in approximate entropy. Significant increases in FC after PnO stimulation occurred between the left nucleus Basalis of Meynert (NBM) as seed and numerous regions of the paralimbic network. Smaller increases in FC were present between the central medial thalamic nucleus and retrosplenium seeds and the left caudate putamen and NBM. The results suggest that, during light anesthesia, PnO stimulation preferentially modulates basal forebrain-paralimbic networks. We speculate that this may be a reflection of disconnected awareness.

  9. The N-methyl-D-aspartate antagonist, MK-801, fails to protect against neuronal damage caused by transient, severe forebrain ischemia in adult rats.

    Buchan, A; Li, H; Pulsinelli, W A


    The neuroprotective effects of dizocilipine maleate (MK-801), a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor/channel, were tested in the 4-vessel occlusion rat model of forebrain ischemia. Adult Wistar rats, treated intraperitoneally with MK-801 or saline using several different treatment paradigms were subjected to 5 (n = 208) or 15 (n = 62) min of severe, transient forebrain ischemia. In saline-treated animals, 15 min of ischemia (n = 13) produced extensive and consistent loss of pyramidal neurons in the CA1 zone of hippocampus. The degree and distribution of cell loss were not reduced by single dose preischemic administration of MK-801 at 1 (n = 7), 2.5 (n = 4), or 5 mg/kg (n = 8). In other animals subjected to 15 min of forebrain ischemia, multiple doses of MK-801 (5, 2.5, and 2.5 mg/kg) given immediately and at approximately 8 and 20 hr after cerebral reperfusion (n = 5) did not alter CA1 injury compared to saline-treated controls (n = 5). Five minutes of forebrain ischemia in saline-treated animals, (n = 82) resulted in significantly fewer (p less than 0.001) dead CA1 pyramidal cells and a greater variance compared to animals subjected to 15 min of ischemia. Power analysis of the preliminary saline-treated animals subjected to 5 min of ischemia (n = 22) indicated that 60 animals per group were necessary to detect a 15% difference between MK-801 and vehicle-treated groups. Multidose treatment with MK-801 (1 mg/kg) given 1 hr prior to 5 min of ischemia (n = 60) and again at approximately 8 and 16 hr after recirculation failed to attenuate hippocampal injury.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Long-term inhibition of Rho-kinase restores the LTP impaired in chronic forebrain ischemia rats by regulating GABAA and GABAB receptors.

    Huang, L; Zhao, L B; Yu, Z Y; He, X J; Ma, L P; Li, N; Guo, L J; Feng, W Y


    We previously demonstrated that inactivation of Rho-kinase by hydroxyfasudil could impact N-methyl-d-aspartate (NMDA) excitatory interneurons in the hippocampus and attenuate the spatial learning and memory dysfunction of rats caused by chronic forebrain hypoperfusion ischemia. Complementary interactions between the excitatory neurotransmitter glutamate and the inhibitory neurotransmitter GABA form the molecular basis of synaptic plasticity and cognitive performance. However, whether the GABAergic inhibitory interneurons are involved in the mechanisms underlying these processes remains unclear. Here, we further examined the role of GABAergic interneurons in the neuroprotective effect of the Rho-kinase inhibitor. Chronic forebrain ischemia was induced in Wistar rats by bilateral common carotid artery occlusion (BCAO). The general synaptic transmission and long-term potentiation (LTP) of hippocampal CA3 neurons were evaluated at 30 days after sham surgery or BCAO. Real-time PCR and Western blot analyses were conducted to determine the effect of the Rho-kinase inhibitor hydroxyfasudil on GABAergic inhibitory interneuron expression and function after ischemia. Hydroxyfasudil showed no significant effect on general synaptic transmission, but it could abolish the inhibition of LTP induced by chronic forebrain ischemia. Moreover, the mRNA and protein levels of GABAA and GABAB in three brain regions after ischemia were markedly decreased, and hydroxyfasudil could up-regulate all mRNA and protein expression levels in these areas except for GABAA mRNA in the cerebral cortex and striatum. Using phosphorylation antibodies against specific sites on the GABAA and GABAB receptors, we further demonstrated that hydroxyfasudil could inhibit GABAergic interneuron phosphorylation triggered by the theta burst stimulation. In summary, our results indicated that the inactivation of Rho-kinase could enhance GABAA and GABAB expressions by different mechanisms to guarantee the induction of

  11. Developmental suppression of forebrain trkA receptors and attentional capacities in aging rats: A longitudinal study.

    Yegla, Brittney; Parikh, Vinay


    Basal forebrain (BF) cholinergic neurons innervating the cortex regulate cognitive, specifically attentional, processes. Cholinergic atrophy and cognitive decline occur at an accelerated pace in age-related neurodegenerative disorders such as Alzheimer's disease; however, the mechanism responsible for this phenomenon remains unknown. Here we hypothesized that developmental suppression of nerve growth factor signaling, mediated via tropomyosin-related kinase A (trkA) receptors, would escalate age-related attentional vulnerability. An adeno-associated viral vector expressing trkA shRNA (AAV-trkA) was utilized to knockdown trkA receptors in postnatal rats at an ontogenetic time point when cortical cholinergic inputs mature, and the impact of this manipulation on performance was assessed in animals maintained on an operant attention task throughout adulthood and until old (24 months) age. A within-subject comparison across different time points illustrated a gradual age-related decline in attentional capacities. However, the performance under baseline and distracted conditions did not differ between the AAV-trkA-infused and animals infused with a vector expressing shRNA against the control protein luciferase at any time point. Additional analysis of cholinergic measures conducted at 24 months showed that the capacity of cholinergic terminals to release acetylcholine following a depolarizing stimulus, cortical cholinergic fiber density and BF cholinergic cell size remained comparable between the two groups. Contrary to our predictions, these data indicate that developmental BF trkA disruption does not impact age-related changes in attentional functions. It is possible that life-long engagement in cognitive activity might have potentially rescued the developmental insults on the cholinergic system, thus preserving attentional capacities in advanced age. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. L-carnitine protects neurons from 1-methyl-4-phenylpyridinium-induced neuronal apoptosis in rat forebrain culture.

    Wang, C; Sadovova, N; Ali, H K; Duhart, H M; Fu, X; Zou, X; Patterson, T A; Binienda, Z K; Virmani, A; Paule, M G; Slikker, W; Ali, S F


    1-Methyl-4-phenylpyridinium ion (MPP+), an inhibitor of mitochondrial complex I, has been widely used as a neurotoxin because it elicits a severe Parkinson's disease-like syndrome with an elevation of intracellular reactive oxygen species (ROS) and apoptosis. L-carnitine plays an integral role in attenuating the brain injury associated with mitochondrial neurodegenerative disorders. The present study investigates the effects of L-carnitine against the toxicity of MPP+ in rat forebrain primary cultures. Cells in culture were treated for 24 h with 100, 250, 500 and 1000 microM MPP+ alone or co-incubated with L-carnitine. MPP+ produced a dose-related increase in DNA fragmentation as measured by cell death ELISA (enzyme-linked immunosorbent assay), an increase in the number of TUNEL (terminal dUTP nick-end labeling)-positive cells and a reduction in the mitochondrial metabolism of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). No significant effect was observed with the release of lactate dehydrogenase (LDH), indicating that cell death presumably occurred via apoptotic mechanisms. Co-incubation of MPP+ with L-carnitine significantly reduced MPP+-induced apoptosis. Western blot analyses showed that neurotoxic concentrations of MPP+ decreased the ratio of BCL-X(L) to Bax and decreased the protein levels of polysialic acid neural cell adhesion molecules (PSA-NCAM), a neuron specific marker. L-carnitine blocked these effects of MPP+ suggesting its potential therapeutic utility in degenerative disorders such as Parkinson's disease, Alzheimer's disease, ornithine transcarbamylase deficiency and other mitochondrial diseases.

  13. Forebrain medial septum region facilitates nociception in a rat formalin model of inflammatory pain.

    Lee, Andy Thiam-Huat; Ariffin, Mohammed Zacky; Zhou, Mingyi; Ye, Jenn Zhou; Moochhala, Shabbir M; Khanna, Sanjay


    The medial septum is anatomically and functionally linked to the hippocampus, a region implicated in nociception. However, the role of medial septum in nociception remains unclear. To investigate the role of the region in nociception in rats, muscimol, a GABA agonist, or zolpidem, a positive allosteric modulator of GABA(A) receptors, was microinjected into medial septum to attenuate the activity of neurons in the region. Electrophysiological studies in anesthetized rats indicated that muscimol evoked a stronger and longer-lasting suppression of medial septal-mediated activation of hippocampal theta field activity than zolpidem. Similarly, microinjection of muscimol (1 or 2 μg/0.5 μl) into the medial septum of awake rats suppressed both licking and flinching behaviors in the formalin test of inflammatory pain, whereas only the latter behavior was affected by zolpidem (8 or 12 μg/0.5 μl) administered into the medial septum. Interestingly, both drugs selectively attenuated nociceptive behaviors in the second phase of the formalin test that are partly driven by central plasticity. Indeed, muscimol reduced the second phase behaviors by 30% to 60%, which was comparable to the reduction seen with systemic administration of a moderate dose of the analgesic morphine. The reduction was accompanied by a decrease in formalin-induced expression of spinal c-Fos protein that serves as an index of spinal nociceptive processing. The drug effects on nociceptive behaviors were without overt sedation and were distinct from the effects observed after septal lateral microinjections. Taken together, these findings suggest that the activation of medial septum is pro-nociceptive and facilitates aspects of central neural processing underlying nociception.

  14. An Evolutionarily Conserved Network Mediates Development of the zona limitans intrathalamica, a Sonic Hedgehog-Secreting Caudal Forebrain Signaling Center

    Elena Sena


    Full Text Available Recent studies revealed new insights into the development of a unique caudal forebrain-signaling center: the zona limitans intrathalamica (zli. The zli is the last brain signaling center to form and the first forebrain compartment to be established. It is the only part of the dorsal neural tube expressing the morphogen Sonic Hedgehog (Shh whose activity participates in the survival, growth and patterning of neuronal progenitor subpopulations within the thalamic complex. Here, we review the gene regulatory network of transcription factors and cis-regulatory elements that underlies formation of a shh-expressing delimitated domain in the anterior brain. We discuss evidence that this network predates the origin of chordates. We highlight the contribution of Shh, Wnt and Notch signaling to zli development and discuss implications for the fact that the morphogen Shh relies on primary cilia for signal transduction. The network that underlies zli development also contributes to thalamus induction, and to its patterning once the zli has been set up. We present an overview of the brain malformations possibly associated with developmental defects in this gene regulatory network (GRN.

  15. Defects in GPI biosynthesis perturb Cripto signaling during forebrain development in two new mouse models of holoprosencephaly

    David M. McKean


    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.

  16. Estrogen receptor-beta colocalizes extensively with parvalbumin-labeled inhibitory neurons in the cortex, amygdala, basal forebrain, and hippocampal formation of intact and ovariectomized adult rats.

    Blurton-Jones, Mathew; Tuszynski, Mark H


    Estrogen has been reported to regulate the activity of gamma-aminobutyric acid (GABA)ergic interneurons within the hippocampus, basal forebrain, and hypothalamus of adult rodents. Although estrogen receptor-alpha bearing GABAergic interneurons have been identified previously, the neurotransmitter phenotype of cells that express the more recently characterized estrogen receptor-beta (ER-beta) has not been examined in vivo. We, therefore, have used fluorescent immunohistochemistry to further characterize the phenotype of ER-beta-bearing cells by double labeling for the GABAergic-associated calcium-binding protein, parvalbumin (PV). We find that a large proportion of ER-beta-immunoreactive cells within the cortex, amygdala, basal forebrain, and hippocampal formation of intact and ovariectomized (ovx) adult rats are PV-immunoreactive. Within the infralimbic, agranular insular, primary motor, parietal association, perirhinal, and lateral entorhinal cortices, an average of 95.6% +/- 0.8% (intact) and 94.5% +/- 1.4% (ovx) of all ER-beta-immunoreactive cells coexpress parvalbumin, and this proportion is strikingly similar across these diverse cortical regions. ER-beta/PV double-labeled cells represent 23.3% +/- 1.6% (intact) and 25.8% +/- 2.0% (ovx) of all PV-labeled cells within these regions. ER-beta/PV double-labeled cells are also observed within the lateral, accessory basal, and posterior cortical nuclei of the amygdala, and periamygdaloid cortex. Within the basal forebrain, 31.0% +/- 3.1% (intact) and 26.0% +/- 5.2 % (ovx) of ER-beta-immunoreactive cells coexpress PV. Almost all ER-beta-immunoreactive cells within the subiculum, a major output region of the hippocampal formation, double label for PV (intact = 97.2% +/- 2.8%; ovx = 100% +/- 0.0%). Thus, ER-beta exhibits extensive colocalization with a subclass of inhibitory neurons, suggesting a potential mechanism whereby estrogen can regulate neuronal excitability in diverse and broad brain regions by modulating

  17. The Role of Basal Forebrain in Rat Somatosensory Cortex: Impact on Cholinergic Innervation, Sensory Information Processing, and Tactile Discrimination


    noradrenergic neurons, as well as from the cholinergic neurons of the brainstem tegmentum (Jones and Cuello , 1989). This suggests that final control over...Jones, B. E., & Cuello , A. C. (1989). Afferents to the basal forebrain cholinergic cell area from pontomesencephalic- catecholamine, serotonin, and...organization in mouse barrel cortex. Brain Research, 165, 327-332. 160 Sofroniew, M. V., Eckenstein, Fo, Thoenen, Ho, & Cuello , A. C. (1982

  18. Low-Affinity Neurotrophin Receptor p75 Promotes the Transduction of Targeted Lentiviral Vectors to Cholinergic Neurons of Rat Basal Forebrain.

    Antyborzec, Inga; O'Leary, Valerie B; Dolly, James O; Ovsepian, Saak V


    Basal forebrain cholinergic neurons (BFCNs) are one of the most affected neuronal types in Alzheimer's disease (AD), with their extensive loss documented at late stages of the pathology. While discriminatory provision of neuroprotective agents and trophic factors to these cells is thought to be of substantial therapeutic potential, the intricate topography and structure of the forebrain cholinergic system imposes a major challenge. To overcome this, we took advantage of the physiological enrichment of BFCNs with a low-affinity p75 neurotrophin receptor (p75(NTR)) for their targeting by lentiviral vectors within the intact brain of adult rat. Herein, a method is described that affords selective and effective transduction of BFCNs with a green fluorescence protein (GFP) reporter, which combines streptavidin-biotin technology with anti-p75(NTR) antibody-coated lentiviral vectors. Specific GFP expression in cholinergic neurons was attained in the medial septum and nuclei of the diagonal band Broca after a single intraventricular administration of such targeted vectors. Bioelectrical activity of GFP-labeled neurons was proven to be unchanged. Thus, proof of principle is obtained for the utility of the low-affinity p75(NTR) for targeted transduction of vectors to BFCNs in vivo.

  19. Variations in daily expression of the circadian clock protein, PER2, in the rat limbic forebrain during stable entrainment to a long light cycle.

    Harbour, Valerie L; Robinson, Barry; Amir, Shimon


    The circadian clock in the mammalian suprachiasmatic nucleus (SCN) can be entrained by light cycles longer than the normal 24-h light/dark (LD) cycle, but little is known about the effect of such cycles on circadian clocks outside the SCN. Here we examined the effect of exposure to a 26-h T cycle (T26, 1 h:25 h LD) on patterns of expression of the clock protein, PERIOD2 (PER2), in the SCN and in four regions of the limbic forebrain known to exhibit robust circadian oscillations in PER2: the oval nucleus of the bed nucleus of the stria terminalis (BNSTov), central nucleus of the amygdala (CEA), basolateral amygdala (BLA), and dentate gyrus (DG). All rats showed stable entrainment of running wheel activity rhythms to the T26 cycle. As previously shown, PER2 expression in the SCN was stably entrained, peaking around the onset of locomotor activity. In contrast, exposure to the T26 cycle uncoupled the rhythms of PER2 expression in the BNSTov and CEA from that of the SCN, whereas PER2 rhythms in the BLA and DG were unaffected. These results show that exposure to long light cycles can uncouple circadian oscillators in select nuclei of the limbic forebrain from the SCN clock and suggest that such cycles may be used to study the functional consequences of coupling and uncoupling of brain circadian oscillators.

  20. Increased efficacy of the 6-hydroxydopamine lesion of the median forebrain bundle in small rats, by modification of the stereotaxic coordinates.

    Torres, E M; Lane, E L; Heuer, A; Smith, G A; Murphy, E; Dunnett, S B


    The 6-hydroxydopamine (6-OHDA) lesion is the most widely used rat model of Parkinson's disease. A single unilateral injection of 6-OHDA into the median forebrain bundle (MFB) selectively destroys dopamine neurons in the ipsilateral substantia nigra pars compacta (SNc) and ventral tegmental area (VTA), removing more than 95% of the dopamine innervation from target areas. The stereotaxic coordinates used to deliver 6-OHDA to the MFB have been used in our laboratory successfully for more than 25 years. However, in recent years we have observed a decline in the success rate of this lesion. Previously regular success rates of >80% of rats lesioned, have become progressively more variable, with rates as low as 20% recorded in some experiments. Having excluded variability of the neurotoxin and operator errors, we hypothesized that the change seen might be due to the use of smaller rats at the time of first surgery. An attempt to proportionally adjust the lesion coordinates base on head size did not increase lesion efficacy. However, in support of the small rat hypothesis it was observed that, using the standard coordinates, rat's heads had a "nose-up" position in the stereotaxic fame. Adjustment of the nose bar to obtain a flat head position during surgery improved lesion success, and subsequent adjustments of the lesion coordinates to account for smaller head size led to a greatly increased lesion efficacy (>90%) as assessed by amphetamine induced rotation.

  1. Induction of enhanced postnatal expression of immunoreactive calbindin-D28k in rat forebrain by the calcium antagonist nimodipine

    Luiten, Paul G.M.; Buwalda, Bauke; Traber, Jörg; Nyakas, Csaba


    The early postnatal development of immunoreactive calbindin-D28k (CaB-ir) containing neuronal systems in hippocampus and parietal cortex was studied in offspring of Wistar rats chronically treated with either the Ca2+-channel antagonist nimodipine or placebo food. The drug was applied to the mother

  2. Brain Barriers and a Subpopulation of Astroglial Progenitors of Developing Human Forebrain Are Immunostained for the Glycoprotein YKL-40

    Bjørnbak, Camilla; Brøchner, Christian B; Larsen, Lars A


    YKL-40, a glycoprotein involved in cell differentiation, has been associated with neurodevelopmental disorders, angiogenesis, neuroinflammation and glioblastomas. We evaluated YKL-40 protein distribution in the early human forebrain using double-labeling immunofluorescence and immunohistochemistry...

  3. Loss of BAF (mSWI/SNF Complexes Causes Global Transcriptional and Chromatin State Changes in Forebrain Development

    Ramanathan Narayanan


    Full Text Available BAF (Brg/Brm-associated factors complexes play important roles in development and are linked to chromatin plasticity at selected genomic loci. Nevertheless, a full understanding of their role in development and chromatin remodeling has been hindered by the absence of mutants completely lacking BAF complexes. Here, we report that the loss of BAF155/BAF170 in double-conditional knockout (dcKO mice eliminates all known BAF subunits, resulting in an overall reduction in active chromatin marks (H3K9Ac, a global increase in repressive marks (H3K27me2/3, and downregulation of gene expression. We demonstrate that BAF complexes interact with H3K27 demethylases (JMJD3 and UTX and potentiate their activity. Importantly, BAF complexes are indispensable for forebrain development, including proliferation, differentiation, and cell survival of neural progenitor cells. Our findings reveal a molecular mechanism mediated by BAF complexes that controls the global transcriptional program and chromatin state in development.

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

    Casey, Kenneth L.


    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.

  5. Responses of CA1 pyramidal neurons in rat hippocampus to transient forebrain ischemia: an in vivo intracellular recording study.

    Xu, Z C; Pulsinelli, W A


    The electrophysiological responses of CA1 pyramidal neurons to 5 min forebrain ischemia were studied with intracellular recording and staining techniques in vivo. The baseline membrane potential rapidly depolarized to approximately -20 mV about 3 min after the onset of ischemia and began to repolarize 1-3 min after recirculation. The amplitude of this ischemic depolarization (ID) was related directly to the severity of ischemia and its latency of onset was inversely related to brain temperature. Spontaneous synaptic activity ceased shortly after ischemia onset while the evoke synaptic potentials lasted until shortly before the onset of ID. Inhibitory postsynaptic potentials (IPSPs) disappeared earlier than excitatory postsynaptic potentials (EPSPs) and the membrane input resistance of CA1 neurons increased after the onset of ischemia.

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

    Tae-Ryong Riew

    Full Text Available 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.

  7. Effect of MDMA-Induced Axotomy on the Dorsal Raphe Forebrain Tract in Rats: An In Vivo Manganese-Enhanced Magnetic Resonance Imaging Study.

    Chuang-Hsin Chiu

    Full Text Available 3,4-Methylenedioxymethamphetamine (MDMA, also known as "Ecstasy", is a common recreational drug of abuse. Several previous studies have attributed the central serotonergic neurotoxicity of MDMA to distal axotomy, since only fine serotonergic axons ascending from the raphe nucleus are lost without apparent damage to their cell bodies. However, this axotomy has never been visualized directly in vivo. The present study examined the axonal integrity of the efferent projections from the midbrain raphe nucleus after MDMA exposure using in vivo manganese-enhanced magnetic resonance imaging (MEMRI. Rats were injected subcutaneously six times with MDMA (5 mg/kg or saline once daily. Eight days after the last injection, manganese ions (Mn2+ were injected stereotactically into the raphe nucleus, and a series of MEMRI images was acquired over a period of 38 h to monitor the evolution of Mn2+-induced signal enhancement across the ventral tegmental area, the medial forebrain bundle (MFB, and the striatum. The MDMA-induced loss of serotonin transporters was clearly evidenced by immunohistological staining consistent with the Mn2+-induced signal enhancement observed across the MFB and striatum. MEMRI successfully revealed the disruption of the serotonergic raphe-striatal projections and the variable effect of MDMA on the kinetics of Mn2+ accumulation in the MFB and striatum.

  8. 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

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


    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.

  9. The corpus callosum, the other great forebrain commissures, and the septum pellucidum: anatomy, development, and malformation

    Raybaud, Charles [Division of Neuroradiology, Hospital for Sick Children, Toronto, ON (Canada); University of Toronto, Division of Radiology, Toronto, ON (Canada)


    There are three telencephalic commissures which are paleocortical (the anterior commissure), archicortical (the hippocampal commissure), and neocortical. In non-placental mammals, the neocortical commissural fibers cross the midline together with the anterior and possibly the hippocampal commissure, across the lamina reuniens (joining plate) in the upper part of the lamina terminalis. In placental mammals, a phylogenetically new feature emerged, which is the corpus callosum: it results from an interhemispheric fusion line with specialized groups of mildline glial cells channeling the commissural axons through the interhemispheric meninges toward the contralateral hemispheres. This concerns the frontal lobe mainly however: commissural fibers from the temporo-occipital neocortex still use the anterior commissure to cross, and the posterior occipito-parietal fibers use the hippocampal commissure, forming the splenium in the process. The anterior callosum and the splenium fuse secondarily to form the complete commissural plate. Given the complexity of the processes involved, commissural ageneses are many and usually associated with other diverse defects. They may be due to a failure of the white matter to develop or to the commissural neurons to form or to migrate, to a global failure of the midline crossing processes or to a selective failure of commissuration affecting specific commissural sites (anterior or hippocampal commissures, anterior callosum), or specific sets of commissural axons (paleocortical, hippocampal, neocortical commissural axons). Severe hemispheric dysplasia may prevent the axons from reaching the midline on one or both sides. Besides the intrinsically neural defects, midline meningeal factors may prevent the commissuration as well (interhemispheric cysts or lipoma). As a consequence, commissural agenesis is a malformative feature, not a malformation by itself. Good knowledge of the modern embryological data may allow for a good understanding of a

  10. Changes in excitatory and inhibitory circuits of the rat hippocampus 12-14 months after complete forebrain ischemia.

    Arabadzisz, D; Freund, T F


    Changes in interneuron distribution and excitatory connectivity have been investigated in animals which had survived 12-14 months after complete forebrain ischemia, induced by four-vessel occlusion. Anterograde tracing with Phaseolus vulgaris leucoagglutinin revealed massive Schaffer collateral input even to those regions of the CA1 subfield where hardly any surviving pyramidal cells were found. Boutons of these Schaffer collaterals formed conventional synaptic contacts on dendritic spines and shafts, many of which likely belong to interneurons. Mossy fibres survived the ischemic challenge, however, large mossy terminals showed altered morphology, namely, the number of filopodiae on these terminals decreased significantly. The entorhinal input to the hippocampus did not show any morphological alterations. The distribution of interneurons was investigated by neurochemical markers known to label functionally distinct GABAergic cell populations. In the hilus, spiny interneurons showed a profound decrease in number. This phenomenon was not as obvious in CA3, but the spiny metabotropic glutamate receptor 1alpha-positive non-pyramidal cells, some of which contain calretinin or substance P receptor, disappeared from stratum lucidum of this area. In the CA1 region, somatostatin immunoreactivity disappeared from stratum oriens/lacunosum-moleculare-associated cells, while in metabotropic glutamate receptor 1alpha-stained sections these cells seemed unaffected in number. Other interneurons did not show an obvious decrease in number. In stratum radiatum of the CA1 subfield, some interneuron types had altered morphology: the substance P receptor-positive dendrites lost their characteristic radial orientation, and the metabotropic glutamate receptor 1alpha-expressing cells became extremely spiny. The loss of inhibitory interneurons at the first two stages of the trisynaptic loop coupled with a well-preserved excitatory connectivity among the subfields suggests that

  11. Spontaneous sleep-wake cycle and sleep deprivation differently induce Bdnf1, Bdnf4 and Bdnf9a DNA methylation and transcripts levels in the basal forebrain and frontal cortex in rats.

    Ventskovska, Olena; Porkka-Heiskanen, Tarja; Karpova, Nina N


    Brain-derived neurotrophic factor (Bdnf) regulates neuronal plasticity, slow wave activity and sleep homeostasis. Environmental stimuli control Bdnf expression through epigenetic mechanisms, but there are no data on epigenetic regulation of Bdnf by sleep or sleep deprivation. Here we investigated whether 5-methylcytosine (5mC) DNA modification at Bdnf promoters p1, p4 and p9 influences Bdnf1, Bdnf4 and Bdnf9a expression during the normal inactive phase or after sleep deprivation (SD) (3, 6 and 12 h, end-times being ZT3, ZT6 and ZT12) in rats in two brain areas involved in sleep regulation, the basal forebrain and cortex. We found a daytime variation in cortical Bdnf expression: Bdnf1 expression was highest at ZT6 and Bdnf4 lowest at ZT12. Such variation was not observed in the basal forebrain. Also Bdnf p1 and p9 methylation levels differed only in the cortex, while Bdnf p4 methylation did not vary in either area. Factorial analysis revealed that sleep deprivation significantly induced Bdnf1 and Bdnf4 with the similar pattern for Bdnf9a in both basal forebrain and cortex; 12 h of sleep deprivation decreased 5mC levels at the cortical Bdnf p4 and p9. Regression analysis between the 5mC promoter levels and the corresponding Bdnf transcript expression revealed significant negative correlations for the basal forebrain Bdnf1 and cortical Bdnf9a transcripts in only non-deprived rats, while these correlations were lost after sleep deprivation. Our results suggest that Bdnf transcription during the light phase of undisturbed sleep-wake cycle but not after SD is regulated at least partially by brain site-specific DNA methylation. © 2014 European Sleep Research Society.

  12. Expression of FOXP2 in the developing monkey forebrain: comparison with the expression of the genes FOXP1, PBX3, and MEIS2.

    Takahashi, Kaoru; Liu, Fu-Chin; Oishi, Takao; Mori, Takuma; Higo, Noriyuki; Hayashi, Motoharu; Hirokawa, Katsuiku; Takahashi, Hiroshi


    By using the developing monkey brain as a model for human development, we investigated the expression pattern of the FOXP2 gene, a member of the FOX family of transcription factors in the developing monkey brain, and compared its expression pattern with transcription factors PBX3, MEIS2, and FOXP1. We observed FOXP2 mRNA expression in several brain structures, including the striatum, the islands of Calleja and other basal forebrain regions, the cerebral cortex, and the thalamus. FOXP2 mRNA was preferentially expressed in striosomal compartments during striatal development. The striosomal expression was transient and developmentally down-regulated in a topographical order. Specifically, during the perinatal state, striosomal FOXP2 expression was detected in both the caudate nucleus and the putamen, although expression was more prominent in the caudate nucleus than in the putamen. Striosomal FOXP2 expression declined during the postnatal period, first in the putamen and later in the caudate nucleus. During the same period, we also detected PBX3 mRNA in the striosomal compartment of the developing monkey striatum. FOXP2, as well as PBX3 and MEIS2, was expressed in the islands of Calleja and other cell clusters of the basal forebrain. FOXP2, in combination with PBX3 and MEIS2, may play a pivotal role in the development of striosomal neurons of the striatum and the islands of Calleja.

  13. Postconditioning mitigates cell death following oxygen and glucose deprivation in PC12 cells and forebrain reperfusion injury in rats.

    Lin, Han-Chen; Narasimhan, Purnima; Liu, Shin-Yun; Chan, Pak H; Lai, I-Rue


    Postconditioning mitigates ischemia-induced cellular damage via a modified reperfusion procedure. Mitochondrial permeability transition (MPT) is an important pathophysiological change in reperfusion injury. This study explores the role of MPT modulation underlying hypoxic postconditioning (HPoC) in PC12 cells and studies the neuroprotective effects of ischemic postconditioning (IPoC) on rats. Oxygen-glucose deprivation (OGD) was performed for 10 hr on PC12 cells. HPoC was induced by three cycles of 10-min reoxygenation/10-min rehypoxia after OGD. The MPT inhibitor N-methyl-4-isoleucine cyclosporine (NIM811) and the MPT inducer carboxyatractyloside (CATR) were administered to selective groups before OGD. Cellular death was evaluated by flow cytometry and Western blot analysis. JC-1 fluorescence signal was used to estimate the mitochondrial membrane potential (△Ψm ). Transient global cerebral ischemia (tGCI) was induced via the two-vessel occlusion and hypotension method in male Sprague Dawley rats. IPoC was induced by three cycles of 10-sec reperfusion/10-sec reocclusion after index ischemia. HPoC and NIM811 administration attenuated cell death, cytochrome c release, and caspase-3 activity and maintained △Ψm of PC12 cells after OGD. The addition of CATR negated the protection conferred by HPoC. IPoC reduced neuronal degeneration and cytochrome c release and cleaved caspase-9 expression of hippocampal CA1 neurons in rats after tGCI. HPoC protected PC12 cells against OGD by modulating the MPT. IPoC attenuated degeneration of hippocampal neurons after cerebral ischemia.

  14. Bilateral projections from rat MI whisker cortex to the neostriatum, thalamus, and claustrum: forebrain circuits for modulating whisking behavior.

    Alloway, Kevin D; Smith, Jared B; Beauchemin, Kyle J; Olson, Michelle L


    In rats, whisking behavior is characterized by high-frequency synchronous movements and other stereotyped patterns of bilateral coordination that are rarely seen in the bilateral movements of the limbs. This suggests that the motor systems controlling whisker and limb movements must have qualitative or quantitative differences in their interhemispheric connections. To test this hypothesis, anterograde tracing methods were used to characterize the bilateral distribution of projections from the whisker and forepaw regions in the primary motor (MI) cortex. Unilateral tracer injections in the MI whisker or forepaw regions revealed robust projections to the corresponding MI cortical area in the contralateral hemisphere. Both MI regions project bilaterally to the neostriatum, but the corticostriatal projections from the whisker region are denser and more evenly distributed across both hemispheres than those from the MI forepaw region. The MI whisker region projects bilaterally to several nuclei in the thalamus, whereas the MI forepaw region projects almost exclusively to the ipsilateral thalamus. The MI whisker region sends dense projections to the contralateral claustrum, but those to the ipsilateral claustrum are less numerous. By contrast, the MI forepaw region sends few projections to the claustrum of either hemisphere. Bilateral deposits of different tracers in MI revealed overlapping projections to the neostriatum, thalamus, and claustrum when the whisker regions were injected, but not when the forepaw regions were injected. These results suggest that the bilateral coordination of the whiskers depends, in part, on MI projections to the contralateral neostriatum, thalamus, and claustrum. Copyright 2009 Wiley-Liss, Inc.

  15. Increased expression of Slit2 and its receptors Robo1 and Robo4 in reactive astrocytes of the rat hippocampus after transient forebrain ischemia.

    Park, Joo-Hee; Pak, Ha-Jin; Riew, Tae-Ryong; Shin, Yoo-Jin; Lee, Mun-Yong


    Slit2 is a secreted glycoprotein that was originally identified as a chemorepulsive factor in the developing brain; however, it was recently reported that Slit2 is associated with adult neuronal function including a variety of pathophysiological processes. To elucidate whether Slit2 is implicated in the pathophysiology of ischemic injury, we investigated the temporal changes and cellular localization of Slit2 and its predominant receptors, Robo1 and Robo4, for 28 days after transient forebrain ischemia. Slit2 and its receptors had similar overall expression patterns in the control and ischemic hippocampi. The ligand and receptors were constitutively expressed in hippocampal neurons in control animals; however, in animals with ischemic injury, their upregulation was detected in reactive astrocytes, but not in neurons or activated microglia, in the CA1 region. Astroglial induction of Slit2 and its receptors occurred by day 3 after reperfusion, and appeared to increase progressively until the final time point on day 28. Their temporal expression patterns overlapped with the time period in which reactive astrocytes undergo dynamic structural changes and appear hypertrophic in the ischemic hippocampus. The immunohistochemical data were consistent with the results of the immunoblot analyses, indicating that the expression of Slit2 and Robo increased progressively over the relatively long period of 28 days examined here. Collectively, these results suggest that Slit2/Robo signaling may be involved in regulating the astroglial reaction via autocrine or paracrine mechanisms in post-ischemic processes. Moreover, this may contribute to the dynamic morphological changes that occur in astrocytes in response to ischemic injury.

  16. Cloning and characterization of GRIPE, a novel interacting partner of the transcription factor E12 in developing mouse forebrain.

    Heng, Julian Ik Tsen; Tan, Seong-Seng


    The helix-loop-helix (HLH) family of transcription factors are key contributors to a wide array of developmental processes, including neurogenesis and hematopoiesis. These factors are thought to exert their regulatory influences by binding to cognate promoter-DNA sequences as dimers. Although studies in mice have convincingly demonstrated that neurogenic HLH proteins such as NeuroD are intimately involved in neuronal fate determination, the role of the ubiquitously expressed HLH protein, E12, in mammalian neurogenesis remains ambiguous. To address this, a yeast two-hybrid interaction screen was employed to identify dimerization partners to E12. Screening of an embryonic day 11.5 forebrain library resulted in the cloning of GRIPE, a novel GAP-related interacting protein to E12. GRIPE binds to the HLH region of E12 and may require E12 for nuclear import. Furthermore, GRIPE may negatively regulate E12-dependent target gene transcription. High levels of GRIPE and E12 mRNA were coincidentally detected during embryogenesis, but only GRIPE mRNA levels remained high in adult brain, particularly in neurons of the cortex and hippocampus. These observations were recapitulated through an in vitro model of neurogenesis. Taken together, these results indicate that GRIPE is a novel protein dimerization of which with E12 has important consequences for cells undergoing neuronal differentiation.

  17. Stress-induced changes in the expression of the clock protein PERIOD1 in the rat limbic forebrain and hypothalamus: role of stress type, time of day, and predictability.

    Sherin Al-Safadi

    Full Text Available Stressful events can disrupt circadian rhythms in mammals but mechanisms underlying this disruption remain largely unknown. One hypothesis is that stress alters circadian protein expression in the forebrain, leading to functional dysregulation of the brain circadian network and consequent disruption of circadian physiological and behavioral rhythms. Here we characterized the effects of several different stressors on the expression of the core clock protein, PER1 and the activity marker, FOS in select forebrain and hypothalamic nuclei in rats. We found that acute exposure to processive stressors, restraint and forced swim, elevated PER1 and FOS expression in the paraventricular and dorsomedial hypothalamic nuclei and piriform cortex but suppressed PER1 and FOS levels exclusively in the central nucleus of the amygdala (CEAl and oval nucleus of the bed nucleus of the stria terminalis (BNSTov. Conversely, systemic stressors, interleukin-1β and 2-Deoxy-D-glucose, increased PER1 and FOS levels in all regions studied, including the CEAl and BNSTov. PER1 levels in the suprachiasmatic nucleus (SCN, the master pacemaker, were unaffected by any of the stress manipulations. The effect of stress on PER1 and FOS was modulated by time of day and, in the case of daily restraint, by predictability. These results demonstrate that the expression of PER1 in the forebrain is modulated by stress, consistent with the hypothesis that PER1 serves as a link between stress and the brain circadian network. Furthermore, the results show that the mechanisms that control PER1 and FOS expression in CEAl and BNSTov are uniquely sensitive to differences in the type of stressor. Finally, the finding that the effect of stress on PER1 parallels its effect on FOS supports the idea that Per1 functions as an immediate-early gene. Our observations point to a novel role for PER1 as a key player in the interface between stress and circadian rhythms.

  18. Developmental specification of forebrain cholinergic neurons.

    Allaway, Kathryn C; Machold, Robert


    Striatal cholinergic interneurons and basal forebrain cholinergic projection neurons, which together comprise the forebrain cholinergic system, regulate attention, memory, reward pathways, and motor activity through the neuromodulation of multiple brain circuits. The importance of these neurons in the etiology of neurocognitive disorders has been well documented, but our understanding of their specification during embryogenesis is still incomplete. All forebrain cholinergic projection neurons and interneurons appear to share a common developmental origin in the embryonic ventral telencephalon, a region that also gives rise to GABAergic projection neurons and interneurons. Significant progress has been made in identifying the key intrinsic and extrinsic factors that promote a cholinergic fate in this precursor population. However, how cholinergic interneurons and projection neurons differentiate from one another during development, as well as how distinct developmental programs contribute to heterogeneity within those two classes, is not yet well understood. In this review we summarize the transcription factors and signaling molecules known to play a role in the specification and early development of striatal and basal forebrain cholinergic neurons. We also discuss the heterogeneity of these populations and its possible developmental origins. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Learning and the motivation to eat: forebrain circuitry.

    Petrovich, Gorica D


    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. Copyright © 2011 Elsevier Inc. All rights reserved.

  20. Outer brain barriers in rat and human development

    Brøchner, Christian B; Holst, Camilla Bjørnbak; Møllgård, Kjeld


    diffusion restriction between brain and subarachnoid CSF through an initial radial glial end feet layer covered with a pial surface layer. To further characterize these interfaces we examined embryonic rat brains from E10 to P0 and forebrains from human embryos and fetuses (6-21st weeks post...

  1. Forebrain neurogenesis: From embryo to adult

    Dennis, Daniel; Picketts, David; Slack, Ruth S.; Schuurmans, Carol


    A satellite symposium to the Canadian Developmental Biology Conference 2016 was held on March 16–17, 2016 in Banff, Alberta, Canada, entitled Forebrain Neurogenesis: From embryo to adult. The Forebrain Neurogenesis symposium was a focused, high-intensity meeting, bringing together the top Canadian and international researchers in the field. This symposium reported the latest breaking news, along with ‘state of the art’ techniques to answer fundamental questions in developmental neurobiology. Topics covered ranged from stem cell regulation to neurocircuitry development, culminating with a session focused on neuropsychiatric disorders. Understanding the underlying causes of neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD) is of great interest as diagnoses of these conditions are climbing at alarming rates. For instance, in 2012, the Centers for Disease Control reported that the prevalence rate of ASD in the U.S. was 1 in 88; while more recent data indicate that the number is as high as 1 in 68 (Centers for Disease Control and Prevention MMWR Surveillance Summaries. Vol. 63. No. 2). Similarly, the incidence of ASD is on the rise in Canada, increasing from 1 in 150 in 2000 to 1 in 63 in 2012 in southeastern Ontario (Centers for Disease Control and Prevention). Currently very little is known regarding the deficits underlying these neurodevelopmental conditions. Moreover, the development of effective therapies is further limited by major gaps in our understanding of the fundamental processes that regulate forebrain development and adult neurogenesis. The Forebrain Neurogenesis satellite symposium was thus timely, and it played a key role in advancing research in this important field, while also fostering collaborations between international leaders, and inspiring young researchers.

  2. Patterning of the chick forebrain anlage by the prechordal plate.

    Pera, E M; Kessel, M


    We analysed the role of the prechordal plate in forebrain development of chick embryos in vivo. After transplantation to uncommitted ectoderm a prechordal plate induces an ectopic, dorsoventrally patterned, forebrain-like vesicle. Grafting laterally under the anterior neural plate causes ventralization of the lateral side of the forebrain, as indicated by a second expression domain of the homeobox gene NKX2.1. Such a lateral ventralization cannot be induced by the secreted factor Sonic Hedgehog alone, as this is only able to distort the ventral forebrain medially. Removal of the prechordal plate does not reduce the rostrocaudal extent of the anterior neural tube, but leads to significant narrowing and cyclopia. Excision of the head process results in the caudal expansion of the NKX2.1 expression in the ventral part of the anterior neural tube, while PAX6 expression in the dorsal part remains unchanged. We suggest that there are three essential steps in early forebrain patterning, which culminate in the ventralization of the forebrain. First, anterior neuralization occurs at the primitive streak stage, when BMP-4-antagonizing factors emanate from the node and spread in a planar fashion to induce anterior neural ectoderm. Second, the anterior translocation of organizer-derived cells shifts the source of neuralizing factors anteriorly, where the relative concentration of BMP-4-antagonists is thus elevated, and the medial part of the prospective forebrain becomes competent to respond to ventralizing factors. Third, the forebrain anlage is ventralized by signals including Sonic Hedgehog, thereby creating a new identity, the prospective hypothalamus, which splits the eye anlage into two lateral domains.

  3. The role of sensory organs and the forebrain for the development of the craniofacial shape as revealed by Foxg1-cre-mediated microRNA loss.

    Kersigo, Jennifer; D'Angelo, Alex; Gray, Brian D; Soukup, Garrett A; Fritzsch, Bernd


    Cranial development is critically influenced by the relative growth of distinct elements. Previous studies have shown that the transcription factor Foxg1 is essential the for development of the telencephalon, olfactory epithelium, parts of the eye and the ear. Here we investigate the effects of a Foxg1-cre-mediated conditional deletion of Dicer1 and microRNA (miRNA) depletion on mouse embryos. We report the rapid and complete loss of the telencephalon and cerebellum as well as the severe reduction in the ears and loss of the anterior half of the eyes. These losses result in unexpectedly limited malformations of anterodorsal aspects of the skull. We investigated the progressive disappearance of these initially developing structures and found a specific miRNA of nervous tissue, miR-124, to disappear before reduction in growth of the specific neurosensory areas. Correlated with the absence of miR-124, these areas showed numerous apoptotic cells that stained positive for anticleaved caspase 3 and the phosphatidylserine stain PSVue® before the near or complete loss of those brain and sensory areas (forebrain, cerebellum, anterior retina, and ear). We conclude that Foxg1-cre-mediated conditional deletion of Dicer1 leads to the absence of functional miRNA followed by complete or nearly complete loss of neurons. Embryonic neurosensory development therefore depends critically on miRNA. Our data further suggest that loss of a given neuronal compartment can be triggered using early deletion of Dicer1 and thus provides a novel means to genetically remove specific neurosensory areas to investigate loss of their function on morphology (this study) or signal processing within the brain.

  4. Effect of anisodine on acute forebrain ischemia-reperfusion damage in rats%樟柳碱对大鼠脑缺血再灌注损伤的影响

    徐伟; 邓亦峰


    To study the protective effect of anisodine (Ani) on acute forebrain ischemia-reperfusion injury in rats. METHODS: Both vertebral arteries were occluded by electrocautery. Severe, but transient bilateral cerebral ischemia was produced by clamping both common carotid arteries in rats. Atomic absorption spectrophotometric and spectrophotometric methods were used to determine the contents of calcium and extravasated Evans blue (EB), respectively, remained in forebrain at 60-min recirculation after 30-min ischemia. RESULTS: At 60-min recirculation, the brain calcium contents were increased from 112 ± 6 μg/g brain dry weight in control (sham operation) group to 165 ± 7μg/g brain dry weight with marked increase of EB extravasation.and extravasated EB contents. CONCLUSION:Ani prevented the brain from ischemia insults through reducing intracellular calcium accumulation resulted from ischemia and reperfusion.%研究樟柳碱对大鼠急性脑缺血及再灌注损伤的影响.方法:电灼闭塞锥动脉并夹闭颈动脉,使大鼠前脑缺血30 min,放开双侧颈总动脉重灌60 min,并在重灌40 min时iv 2%伊文思蓝0.2 mL.分别用原子吸收分光光度法,分光光度法测定前脑钙含量和伊文思蓝含量.结果:缺血重灌后,大鼠脑钙含量由对照的112±6μg/g干重脑增加至165±7μg/g干重脑,伊文思蓝含量由对照的3.3±0.3μg/g湿重脑增加至6.7±0.5μg/g湿重脑,樟柳碱,东莨菪碱可使异常增高的脑钙含量以及伊文思蓝含量明显降低.结论:樟柳碱和东莨菪碱通过降低缺血及重灌引起的脑积累,减轻脑损伤改善脑功能.

  5. Dapper antagonist of catenin-1 cooperates with Dishevelled-1 during postsynaptic development in mouse forebrain GABAergic interneurons.

    Annie Arguello

    Full Text Available Synaptogenesis has been extensively studied along with dendritic spine development in glutamatergic pyramidal neurons, however synapse development in cortical interneurons, which are largely aspiny, is comparatively less well understood. Dact1, one of 3 paralogous Dact (Dapper/Frodo family members in mammals, is a scaffold protein implicated in both the Wnt/β-catenin and the Wnt/Planar Cell Polarity pathways. We show here that Dact1 is expressed in immature cortical interneurons. Although Dact1 is first expressed in interneuron precursors during proliferative and migratory stages, constitutive Dact1 mutant mice have no major defects in numbers or migration of these neurons. However, cultured cortical interneurons derived from these mice have reduced numbers of excitatory synapses on their dendrites. We selectively eliminated Dact1 from mouse cortical interneurons using a conditional knock-out strategy with a Dlx-I12b enhancer-Cre allele, and thereby demonstrate a cell-autonomous role for Dact1 during postsynaptic development. Confirming this cell-autonomous role, we show that synapse numbers in Dact1 deficient cortical interneurons are rescued by virally-mediated re-expression of Dact1 specifically targeted to these cells. Synapse numbers in these neurons are also rescued by similarly targeted expression of the Dact1 binding partner Dishevelled-1, and partially rescued by expression of Disrupted in Schizophrenia-1, a synaptic protein genetically implicated in susceptibility to several major mental illnesses. In sum, our results support a novel cell-autonomous postsynaptic role for Dact1, in cooperation with Dishevelled-1 and possibly Disrupted in Schizophrenia-1, in the formation of synapses on cortical interneuron dendrites.

  6. Cholinergic basal forebrain structures are involved in the mediation of the arousal effect of noradrenaline.

    Lelkes, Zoltán; Porkka-Heiskanen, Tarja; Stenberg, Dag


    Cholinergic basal forebrain structures are implicated in cortical arousal and regulation of the sleep-wake cycle. Cholinergic neurones are innervated by noradrenergic terminals, noradrenaline excites them via alpha-1 receptors and microinjection of noradrenaline into the basal forebrain enhances wakefulness. However, it is not known to what extent the cholinergic versus non-cholinergic basal forebrain projection neurones contribute to the arousing effects of noradrenaline. To elucidate the roles of cholinergic basal forebrain structures we administered methoxamine, an alpha-1-adrenergic agonist into the basal forebrain, in intact animals and again after selective destruction of the basal forebrain cholinergic cells by 192 IgG-saporin. In eight male Han-Wistar rats implanted with electroencephalogram/electromyogram electrodes, a microdialysis probe targeted into the basal forebrain was perfused with artificial cerebrospinal fluid for 6 h on a baseline day, and with cerebrospinal fluid in the first and with methoxamine in the second 3-h period of the subsequent day. The sleep-wake activity was recorded for 24 h on both days. Saporin was then injected into the basal forebrain and 2 weeks later the same experimental schedule (with cerebrospinal fluid and methoxamine) was repeated. In the intact animals, methoxamine exhibited a robust arousing effect and non-rapid eye movement (NREM) and REM sleep was suppressed. Lesioning of the basal forebrain cholinergic neurones abolished almost completely the NREM sleep-suppressing effect of methoxamine, whereas the REM sleep-suppressing effect remained intact. Thus, the basal forebrain cholinergic neurones mediate, at least in part, cortical arousal and non-REM sleep-suppression, but they are not involved in the REM sleep-suppressing effects of noradrenaline. © 2013 European Sleep Research Society.

  7. Adhesive/Repulsive Codes in Vertebrate Forebrain Morphogenesis

    Florencia Cavodeassi


    Full Text Available The last fifteen years have seen the identification of some of the mechanisms involved in anterior neural plate specification, patterning, and morphogenesis, which constitute the first stages in the formation of the forebrain. These studies have provided us with a glimpse into the molecular mechanisms that drive the development of an embryonic structure, and have resulted in the realization that cell segregation in the anterior neural plate is essential for the accurate progression of forebrain morphogenesis. This review summarizes the latest advances in our understanding of mechanisms of cell segregation during forebrain development, with and emphasis on the impact of this process on the morphogenesis of one of the anterior neural plate derivatives, the eyes.

  8. Medial Forebrain Bundle Deep Brain Stimulation has Symptom-specific Anti-depressant Effects in Rats and as Opposed to Ventromedial Prefrontal Cortex Stimulation Interacts With the Reward System.

    Edemann-Callesen, Henriette; Voget, Mareike; Empl, Laura; Vogel, Martin; Wieske, Franziska; Rummel, Julia; Heinz, Andreas; Mathé, Aleksander A; Hadar, Ravit; Winter, Christine


    In recent years, deep brain stimulation (DBS) has emerged as a promising treatment option for patients suffering from treatment-resistant depression (TRD). Several stimulation targets have successfully been tested in clinical settings, including the subgenual cingulum (Cg25) and the medial forebrain bundle (MFB). MFB-DBS has led to remarkable results, surpassing the effect of previous targets in terms of response latency and number of responders. However, the question remains as to which mechanisms underlie this difference. The aim of the present study was to thoroughly study the anti-depressant effect of MFB-DBS in the Flinders sensitive line (FSL) rat model of depression as well as to investigate whether MFB-DBS and Cg25-DBS operate through the same neurobiological circuits. FSL and control rats received bilateral high-frequency stimulation to the MFB at the level of the lateral hypothalamus, while being subjected to a variety of depression- and anxiety-related behavioral paradigms. To further compare the effects of MFB-DBS and Cg25-DBS on reward-related behavior, animals were stimulated in either the MFB or ventromedial prefrontal cortex (vmPFC, rodent analog to Cg25), while being tested in the intra-cranial self-stimulation paradigm. A marked symptom-specific anti-depressant effect of MFB-DBS was demonstrated. The ICSS-paradigm revealed that MFB-DBS, as opposed to vmPFC-DBS interacts with the reward system. Our data suggest that MFB-DBS and Cg25-DBS do not operate via the same neurobiological circuits. This differentiation might be of interest when selecting patients for either Cg25- or MFB-DBS. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Modelling of cerebral hyper-perfusion after chronic forebrain ischemia in rats%大鼠慢性前脑缺血解除后脑过度灌注模型的建立

    肖玮; 王天龙; 李俊发; 赵磊; 于培兰; 孔萃萃


    目的 建立大鼠慢性前脑缺血基础上的脑过度灌注模型.方法 选取雄性Wistar大鼠72只依随机数字表均分为两个模型建造组.缺血模型采用双侧颈总动脉结扎,随机数字表分为空白对照、假手术组、缺血2周组、缺血4周组,每组9只,结扎前后分别测定脑额叶血流、比较各组行为学评分、脑梗死面积.过度灌注模型是在缺血模型基础上,再灌注同时经尾静脉持续输注去氧肾上腺素4μg·kg-1·min-1,使再灌注后脑额叶血流超过基础值的200%.随机分为空白对照组、盐水组、过度灌注0.5 h组、过度灌注2 h组,每组9只,再灌注前后分别测定脑额叶血流,比较各组行为学评分、血脑屏障通透性、脑干湿重比值.结果 大鼠双侧颈动脉结扎后前脑血流减少可达67%±2%,脑过度灌注组与盐水输注组的脑血流变化值差异有统计学意义(P<0.01).缺血2周组的神经功能评分、脑梗死面积与正常对照组差异无统计学意义,缺血4周组的脑梗死面积与正常对照组差异有统计学意义.脑过度灌注2 h组的血脑屏障通透性改变有统计学意义(P<0.05).结论 结扎大鼠双侧颈总动脉2周后脑过度灌注2 h可较好地建立大鼠脑过度灌注综合征模型.%Objective To establish the cerebral hyper-perfusion model after chronic forebrain ischemia in rats. Methods A total of 72 male rats were equally randomized into 2 modeling groups. The ligation of bilateral common carotid artery could induce chronic forebrain ischemia. And 36 rats were randomly grouped by ischemia duration: control group ( n = 9 ), sham group ( n = 9 ), 2-wcek ischemia group ( n = 9 ) and 4-wcek ischemia group ( n = 9 ). The blood flow in frontal lobe was measured at pre- and post-ligation. The neurological score and cerebral infarction area were also compared among the groups. The min-1 via tail vein to produce cerebrally hyperperfused blood flow rate over 200% of baseline

  10. Bilateral lesions of the entorhinal cortex differentially modify haloperidol- and olanzapine-induced c-fos mRNA expression in the rat forebrain.

    Seillier, A; Coutureau, E; Thiriet, N; Herbeaux, K; Zwiller, J; Di Scala, G; Will, B; Majchrzak, M


    Lesions of the entorhinal cortex are now an accepted model for mimicking some of the neuropathological aspects of schizophrenia, since evidence has accumulated for the presence of cytoarchitectonic abnormalities within this cortex in schizophrenic patients. The present study was undertaken to address the functional consequences of bilateral entorhinal cortex lesions on antipsychotic-induced c-fos expression. After a 15-day recovery period, the effect of a typical antipsychotic, haloperidol (1 mg/kg), on c-fos mRNA expression was compared with that of an atypical one, olanzapine (10 mg/kg), in both sham-lesioned and entorhinal cortex-lesioned rats. In sham-lesioned rats, both haloperidol and olanzapine induced c-fos expression in the caudal cingulate cortex, dorsomedial and dorsolateral caudate-putamen, nucleus accumbens core and shell and lateral septum. In addition, olanzapine, but not haloperidol, increased c-fos expression within the central amygdala. In entorhinal cortex-lesioned rats, haloperidol-induced c-fos expression was markedly reduced in most areas. In contrast, the olanzapine-induced c-fos expression was not altered in the nucleus accumbens shell and lateral septum of the lesioned rats. These findings reveal that entorhinal cortex lesions affect c-fos expression in a compound- and regional-dependent manner. Our results further emphasize the importance of the exploration of the mechanisms of action of antipsychotic drugs in the context of an associated cortical pathology.

  11. Dynamic expression of MEIS1 homeoprotein in E14.5 forebrain and differentiated forebrain-derived neural stem cells.

    Barber, Benjamin A; Liyanage, Vichithra R B; Zachariah, Robby M; Olson, Carl O; Bailey, Melissa A G; Rastegar, Mojgan


    Central nervous system development is controlled by highly conserved homeoprotein transcription factors including HOX and TALE (Three Amino acid Loop Extension). TALE proteins are primarily known as HOX-cofactors and play key roles in cell proliferation, differentiation and organogenesis. MEIS1 is a TALE member with established expression in the developing central nervous system. MEIS1 is essential for embryonic development and Meis1 knockout mice dies at embryonic day (E) 14.5. However, Meis1/MEIS1 expression in the devolving forebrain, at this critical time-point has not been studied. Here, for the first time we characterize the region-specific expression of MEIS1 in E14.5 mouse forebrain, filling the gap of MEIS1 expression profile between E12.5 and E16.5. Previously, we reported MEIS1 transcriptional regulatory role in neuronal differentiation and established forebrain-derived neural stem cells (NSC) for gene therapy application of neuronal genes. Here, we show the dynamic expression of Meis1/MEIS1 during the differentiation of forebrain-derived NSC toward a glial lineage. Our results show that Meis1/MEIS1 expression is induced during NSC differentiation and is expressed in both differentiated neurons and astrocytes. Confirming these results, we detected MEIS1 expression in primary cultures of in vivo differentiated cortical neurons and astrocytes. We further demonstrate Meis1/MEIS1 expression relative to other TALE family members in the forebrain-derived NSC in the absence of Hox genes. Our data provide evidence that forebrain-derived NSC can be used as an accessible in vitro model to study the expression and function of TALE proteins, supporting their potential role in modulating NSC self-renewal and differentiation.

  12. Basal forebrain thermoregulatory mechanism modulates auto-regulated sleep

    Hruda N Mallick


    Full Text Available Regulation of body temperature and sleep are two physiological mechanisms that are vital for our survival. Interestingly neural structures implicated in both these functions are common. These areas include the medial preoptic area, the lateral preoptic area, the ventrolateral preoptic area, the median preoptic nucleus and the medial septum, which form part of the basal forebrain.When given a choice, rats prefer to stay at an ambient temperature of 270C, though the maximum sleep was observed when they were placed at 300C. Ambient temperature around 270C should be considered as the thermoneutral temperature for rats in all sleep studies. At this temperature the diurnal oscillations of sleep and body temperature are properly expressed. The warm sensitive neurons of the preoptic area mediate the increase in sleep at 300C. Promotion of sleep during the rise in ambient temperature from 270C to 300C, serve a thermoregulatory function. Autonomous thermoregulatory changes in core body temperature and skin temperature could act as an input signal to modulate neuronal activity in sleep-promoting brain areas. The studies presented here show that the neurons of the basal forebrain play a key role in regulating sleep. Basal forebrain thermoregulatory system is a part of the global homeostatic sleep regulatory mechanism, which is auto-regulated.

  13. Adult forebrain NMDA receptors gate social motivation and social memory.

    Jacobs, Stephanie; Tsien, Joe Z


    Motivation to engage in social interaction is critical to ensure normal social behaviors, whereas dysregulation in social motivation can contribute to psychiatric diseases such as schizophrenia, autism, social anxiety disorders and post-traumatic stress disorder (PTSD). While dopamine is well known to regulate motivation, its downstream targets are poorly understood. Given the fact that the dopamine 1 (D1) receptors are often physically coupled with the NMDA receptors, we hypothesize that the NMDA receptor activity in the adult forebrain principal neurons are crucial not only for learning and memory, but also for the proper gating of social motivation. Here, we tested this hypothesis by examining sociability and social memory in inducible forebrain-specific NR1 knockout mice. These mice are ideal for exploring the role of the NR1 subunit in social behavior because the NR1 subunit can be selectively knocked out after the critical developmental period, in which NR1 is required for normal development. We found that the inducible deletion of the NMDA receptors prior to behavioral assays impaired, not only object and social recognition memory tests, but also resulted in profound deficits in social motivation. Mice with ablated NR1 subunits in the forebrain demonstrated significant decreases in sociability compared to their wild type counterparts. These results suggest that in addition to its crucial role in learning and memory, the NMDA receptors in the adult forebrain principal neurons gate social motivation, independent of neuronal development. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Microinjection of the 5-HT7 receptor antagonist SB-269970 into the rat brainstem and basal forebrain: site-dependent effects on REM sleep.

    Monti, Jaime M; Leopoldo, Marcello; Jantos, Héctor; Lagos, Patricia


    The effects of SB-269970, a selective 5-HT7 receptor antagonist, on spontaneous sleep were studied in adult rats implanted for chronic sleep recordings. The 5-HT7 receptor ligand was microinjected into the horizontal limb of the diagonal band of Broca (HDB) and the laterodorsal tegmental nucleus (LDT) during the light period of the 12-h light/12-h dark cycle. For comparative purposes the compound was administered systemically and, in addition, injected directly into the dorsal raphe nucleus (DRN). Microinjection of SB-269970 into the HDB and the DRN induced a significant reduction of rapid-eye-movement sleep (REMS). Similar effects were observed after systemic administration of the 5-HT7 receptor antagonist. On the other hand, local infusion of the compound into the LDT provoked the opposite effect. It is proposed that the deactivation of GABAergic cells located in the HDB, DRN and LDT is responsible for the changes induced by SB-269970 on REM sleep values. It is suggested that the antidepressant effect of the 5-HT7 receptor antagonist could partly depend on the involvement of neuronal systems located in the DRN and the HDB.

  15. Forebrain GABAergic projections to locus coeruleus in mouse.

    Dimitrov, Eugene L; Yanagawa, Yuchio; Usdin, Ted B


    The noradrenergic locus coeruleus (LC) regulates arousal, memory, sympathetic nervous system activity, and pain. Forebrain projections to LC have been characterized in rat, cat, and primates, but not systematically in mouse. We surveyed mouse forebrain LC-projecting neurons by examining retrogradely labeled cells following LC iontophoresis of Fluoro-Gold and anterograde LC labeling after forebrain injection of biotinylated dextran amine or viral tracer. Similar to other species, the central amygdalar nucleus (CAmy), anterior hypothalamus, paraventricular nucleus, and posterior lateral hypothalamic area (PLH) provide major LC inputs. By using mice expressing green fluorescent protein in γ-aminobutyric acid (GABA)ergic neurons, we found that more than one-third of LC-projecting CAmy and PLH neurons are GABAergic. LC colocalization of biotinylated dextran amine, following CAmy or PLH injection, with either green fluorescent protein or glutamic acid decarboxylase (GAD)65/67 immunoreactivity confirmed these GABAergic projections. CAmy injection of adeno-associated virus encoding channelrhodopsin-2-Venus showed similar fiber labeling and association with GAD65/67-immunoreactive (ir) and tyrosine hydroxylase (TH)-ir neurons. CAmy and PLH projections were densest in a pericoerulear zone, but many fibers entered the LC proper. Close apposition between CAmy GABAergic projections and TH-ir processes suggests that CAmy GABAergic neurons may directly inhibit noradrenergic principal neurons. Direct LC neuron targeting was confirmed by anterograde transneuronal labeling of LC TH-ir neurons following CAmy or PLH injection of a herpes virus that expresses red fluorescent protein following activation by Cre recombinase in mice that express Cre recombinase in GABAergic neurons. This description of GABAergic projections from the CAmy and PLH to the LC clarifies important forebrain sources of inhibitory control of central nervous system noradrenergic activity.

  16. Early effects of lipopolysaccharide-induced inflammation on foetal brain development in rat

    Cristina A Ghiani


    Full Text Available Studies in humans and animal models link maternal infection and imbalanced levels of inflammatory mediators in the foetal brain to the aetiology of neuropsychiatric disorders. In a number of animal models, it was shown that exposure to viral or bacterial agents during a period that corresponds to the second trimester in human gestation triggers brain and behavioural abnormalities in the offspring. However, little is known about the early cellular and molecular events elicited by inflammation in the foetal brain shortly after maternal infection has occurred. In this study, maternal infection was mimicked by two consecutive intraperitoneal injections of 200 μg of LPS (lipopolysaccharide/kg to timed-pregnant rats at GD15 (gestational day 15 and GD16. Increased thickness of the CP (cortical plate and hippocampus together with abnormal distribution of immature neuronal markers and decreased expression of markers for neural progenitors were observed in the LPS-exposed foetal forebrains at GD18. Such effects were accompanied by decreased levels of reelin and the radial glial marker GLAST (glial glutamate transporter, and elevated levels of pro-inflammatory cytokines in maternal serum and foetal forebrains. Foetal inflammation elicited by maternal injections of LPS has discrete detrimental effects on brain development. The early biochemical and morphological changes described in this work begin to explain the sequelae of early events that underlie the neurobehavioural deficits reported in humans and animals exposed to prenatal insults.

  17. Early Effects of Lipopolysaccharide-Induced Inflammation on Foetal Brain Development in Rat

    Cristina A Ghiani


    Full Text Available Studies in humans and animal models link maternal infection and imbalanced levels of inflammatory mediators in the foetal brain to the aetiology of neuropsychiatric disorders. In a number of animal models, it was shown that exposure to viral or bacterial agents during a period that corresponds to the second trimester in human gestation triggers brain and behavioural abnormalities in the offspring. However, little is known about the early cellular and molecular events elicited by inflammation in the foetal brain shortly after maternal infection has occurred. In this study, maternal infection was mimicked by two consecutive intraperitoneal injections of 200 μg of LPS (lipopolysaccharide/kg to timed-pregnant rats at GD15 (gestational day 15 and GD16. Increased thickness of the CP (cortical plate and hippocampus together with abnormal distribution of immature neuronal markers and decreased expression of markers for neural progenitors were observed in the LPS-exposed foetal forebrains at GD18. Such effects were accompanied by decreased levels of reelin and the radial glial marker GLAST (glial glutamate transporter, and elevated levels of pro-inflammatory cytokines in maternal serum and foetal forebrains. Foetal inflammation elicited by maternal injections of LPS has discrete detrimental effects on brain development. The early biochemical and morphological changes described in this work begin to explain the sequelae of early events that underlie the neurobehavioural deficits reported in humans and animals exposed to prenatal insults.

  18. Age-related intraneuronal elevation of αII-spectrin breakdown product SBDP120 in rodent forebrain accelerates in 3×Tg-AD mice.

    Cai, Yan; Zhu, Hai-Xia; Li, Jian-Ming; Luo, Xue-Gang; Patrylo, Peter R; Rose, Gregory M; Streeter, Jackson; Hayes, Ron; Wang, Kevin K W; Yan, Xiao-Xin; Jeromin, Andreas


    Spectrins line the intracellular surface of plasmalemma and play a critical role in supporting cytoskeletal stability and flexibility. Spectrins can be proteolytically degraded by calpains and caspases, yielding breakdown products (SBDPs) of various molecular sizes, with SBDP120 being largely derived from caspase-3 cleavage. SBDPs are putative biomarkers for traumatic brain injury. The levels of SBDPs also elevate in the brain during aging and perhaps in Alzheimer's disease (AD), although the cellular basis for this change is currently unclear. Here we examined age-related SBDP120 alteration in forebrain neurons in rats and in the triple transgenic model of AD (3×Tg-AD) relative to non-transgenic controls. SBDP120 immunoreactivity (IR) was found in cortical neuronal somata in aged rats, and was prominent in the proximal dendrites of the olfactory bulb mitral cells. Western blot and densitometric analyses in wild-type mice revealed an age-related elevation of intraneuronal SBDP120 in the forebrain which was more robust in their 3×Tg-AD counterparts. The intraneuronal SBDP120 occurrence was not spatiotemporally correlated with transgenic amyloid precursor protein (APP) expression, β-amyloid plaque development, or phosphorylated tau expression over various forebrain regions or lamina. No microscopically detectable in situ activated caspase-3 was found in the nuclei of SBDP120-containing neurons. The present study demonstrates the age-dependent intraneuronal presence of an αII-spectrin cleavage fragment in mammalian forebrain which is exacerbated in a transgenic model of AD. This novel neuronal alteration indicates that impairments in membrane protein metabolism, possibly due to neuronal calcium mishandling and/or enhancement of calcium sensitive proteolysis, occur during aging and in transgenic AD mice.

  19. Age-related intraneuronal elevation of αII-spectrin breakdown product SBDP120 in rodent forebrain accelerates in 3×Tg-AD mice.

    Yan Cai

    Full Text Available Spectrins line the intracellular surface of plasmalemma and play a critical role in supporting cytoskeletal stability and flexibility. Spectrins can be proteolytically degraded by calpains and caspases, yielding breakdown products (SBDPs of various molecular sizes, with SBDP120 being largely derived from caspase-3 cleavage. SBDPs are putative biomarkers for traumatic brain injury. The levels of SBDPs also elevate in the brain during aging and perhaps in Alzheimer's disease (AD, although the cellular basis for this change is currently unclear. Here we examined age-related SBDP120 alteration in forebrain neurons in rats and in the triple transgenic model of AD (3×Tg-AD relative to non-transgenic controls. SBDP120 immunoreactivity (IR was found in cortical neuronal somata in aged rats, and was prominent in the proximal dendrites of the olfactory bulb mitral cells. Western blot and densitometric analyses in wild-type mice revealed an age-related elevation of intraneuronal SBDP120 in the forebrain which was more robust in their 3×Tg-AD counterparts. The intraneuronal SBDP120 occurrence was not spatiotemporally correlated with transgenic amyloid precursor protein (APP expression, β-amyloid plaque development, or phosphorylated tau expression over various forebrain regions or lamina. No microscopically detectable in situ activated caspase-3 was found in the nuclei of SBDP120-containing neurons. The present study demonstrates the age-dependent intraneuronal presence of an αII-spectrin cleavage fragment in mammalian forebrain which is exacerbated in a transgenic model of AD. This novel neuronal alteration indicates that impairments in membrane protein metabolism, possibly due to neuronal calcium mishandling and/or enhancement of calcium sensitive proteolysis, occur during aging and in transgenic AD mice.

  20. In vivo labeling of rabbit cholinergic basal forebrain neurons with fluorochromated antibodies

    Hartig, W; Varga, C; Kacza, J; Grosche, J; Seeger, J; Luiten, PGM; Brauer, K; Harkany, T; Härtig, Wolfgang


    Cholinergic basal forebrain neurons (CBFN) expressing the low-affinity neurotrophin receptor p75 (p75(NTR)) were previously selectively labeled in vivo with carbocyanine 3 (Cy3)-tagged anti-p75(NTR), but the applied 192IgG-conjugates recognized p75(NTR) only in rat The antibody ME 20.4 raised agains

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

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


    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.

  2. Neurodevelopment genes in lampreys reveal trends for forebrain evolution in craniates.

    Adèle Guérin

    Full Text Available 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.

  3. Age-dependent consequences of seizures and the development of temporal lobe epilepsy in the rat.

    Dubé, C; da Silva Fernandes, M J; Nehlig, A


    The age-related functional changes underlying epileptogenesis remain to be clarified. In the present study, we explored the correlation between metabolic changes, neuronal damage and epileptogenesis during the acute, silent and chronic phases following status epilepticus (SE) induced by lithium-pilocarpine (Li-Pilo) in 10- (P10), 21-day-old (P21) and adult rats. Local cerebral metabolic rates for glucose (LCMRglcs) were measured by the [14C]2-deoxyglucose method during SE, the silent period and the interictal phase of the chronic period. Neurodegeneration was assessed by cresyl violet staining. During SE, LCMRglcs dramatically increased at all ages mainly in forebrain vulnerable regions. During the silent phase, in P21 and adult rats, metabolic decreases were recorded in damaged forebrain regions involved in the genesis and propagation of seizures 14 days after SE. At the end of the silent phase, P21 and adult rats exhibited metabolic increases in intact brainstem areas involved in the remote control of epilepsy. During the interictal phase of the chronic period, LCMRglcs decreased in damaged forebrain areas of adult and P21 rats that were not spontaneously epileptic, while LCMRglcs were similar to control levels in epileptic P21 rats. In P10 rats, there was no damage and no metabolic consequences at any time after SE. In conclusion, the process of epileptogenesis and its functional consequences differ in P21 and adult rats. The factors underlying these age-related differences remain to be explored. Copyright 2001 S. Karger AG, Basel

  4. Effect of postnatal lead exposure on the development of sympathetic innervation of the heart. [Rats

    Abreu, M.E.


    To determine possible mechanisms for this Pb-induced cardiotoxicity, several neutrochemical parameters indicative of cardiac sympathetic innervation were measured in developing rats. Presynaptic indices of nerve terminal development which were studied included steady-state levels of norepinephrine, neuronal uptake and vesicular storage of /sup 3/H-norepinephrine. Analysis of postsynaptic development was accomplished by quantitating the density of ..beta..-adrenergic receptors and by measuring the activity of adenylate cyclase. Rat pups were exposed to Pb from birth to weaning (21 days) via the milk of dams whose drinking water contained 0.2% Pb acetate. This method and level of Pb treatment had no effect on body or heart weight development, however, it did result in a seven-fold increase in the blood Pb content (70-75 of the treated pups during the period of exposure. Pb exposure accelerated the development of sympathetic innervation of the heart as detected by significant increases in the vesicular uptake of /sup 3/H-norepinephrine and the steady-state concentration of norepinephrine measured at postnatal day 4. On the other hand, ontogeny of the neutronal uptake of /sup 3/H-norepinephrine in the heart and in the forebrain was not affected by Pb treatment. The apparent premature development of sympathetic innervation induced by Pb treatment was not reflected in significant alterations in either the density or the affinity of ..beta..-adrenergic receptor sites determined by the binding kinetics of /sup 3/H-dihydroalprenolol.

  5. Fgf16 is required for specification of GABAergic neurons and oligodendrocytes in the zebrafish forebrain.

    Ayumi Miyake

    Full Text Available 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 (GABAergic 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.

  6. Expressional changes in cerebrovascular receptors after experimental transient forebrain ischemia

    Johansson, Sara; Povlsen, Gro Klitgaard; Edvinsson, Lars


    of vasoconstrictive endothelin and 5-hydroxytryptamine receptors in cerebral arteries. Experimental transient forebrain ischemia of varying durations was induced in male wistar rats, followed by reperfusion for 48 hours. Neurological function was assessed daily by three different tests and cerebrovascular expression......Global ischemic stroke is one of the most prominent consequences of cardiac arrest, since the diminished blood flow to the brain results in cell damage and sometimes permanently impaired neurological function. The post-arrest period is often characterised by cerebral hypoperfusion due to subacute...... the insult, a phenomenon that leads to increased contraction of cerebral arteries, reduced perfusion of the affected area and worsened ischemic damage. Based on these findings, the aim of the present study was to investigate if transient global cerebral ischemia is associated with upregulation...

  7. Motor development after vestibular deprivation in rats

    Geisler, HC; Gramsbergen, A


    This review summarizes the postural development in the rat and the influences of vestibular deprivation from the 5th postnatal day on this development. Vestibular deprivation leads to a delay in motor development. Most probably this delay is caused by a delay in the development of postural control,

  8. Spatiotemporal distribution of PAX6 and MEIS2 expression and total cell numbers in the ganglionic eminence in the early developing human forebrain

    Larsen, Karen B; Lutterodt, Melissa C; Laursen, Henning


    in the same time window. We demonstrate by in situ hybridization and immunohistochemistry that the two homeobox genes are expressed during early fetal brain development in humans. PAX6 mRNA and protein were located in the proliferative zones of the neocortex and in single cells in the cortical preplate at 7...

  9. 黑质致密部和内侧前脑束注射6-OHDA 制备的帕金森病大鼠模型纹状体中 DA 含量比较%Effects of 6-OHDA-lesioned Parkinson’s disease rat model in substantia nigra compacta and medial forebrain bundle on DA level in the striatum

    韩玲娜; 常永丽; 郭晓姝; 张翠英


    Objective:To study the effects of substantia nigra compacta (SNc)lesioned and medial forebrain bundle (MFB)lesion Parkinson’s disease(PD)rat models by 6-hydroxydopamine (6-OHDA)on the dopamine (DA)level in the striatum.Methods:Rats were randomly divided into sham-operated (n = 12),SNc-lesioned(n = 1 5 )and MFB-lesioned (n =14)groups.Changes of the DA level in the striatum were observed by the high performance liquid chromatography with elec-trochemical detection in 3 groups rats.Results:Compared to sham-operated rats,the DA levels of the SNc-lesioned and MFB-lesioned rats decreased significantly.And compared to the SNc-lesioned rats,the degree of DA levels in the MFB-lesioned rats docreased more serious (P =0.005).Conclusion:The lesioned range of DA neurons of MFB-lesioned PD rat model is wider than that of SNc-lesion,which provides a theory basis for the choice of modeling methods in different researches.%目的::比较黑质致密部(SNc)损毁和内侧前脑束(MFB)损毁2种方法制备的帕金森病(PD)大鼠模型对纹状体中多巴胺(DA)递质含量的影响。方法:将大鼠随机分为假手术组(n=12)、SNc 损毁组(n=15)和 MFB 损毁组(n=14)。采用高效液相色谱-电化学检测法,观察3组大鼠损毁侧纹状体中 DA的含量。结果:与假手术组相比较,SNc 损毁组(P <0.001)和 MFB 损毁组(P <0.001)大鼠纹状体中 DA含量均显著降低,与 SNc 损毁组相比较,MFB 损毁组大鼠纹状体中 DA 含量下降更为显著(P =0.005)。结论:MFB 损毁制备的 PD 大鼠模型对 DA 能神经元的损伤范围较 SNc 损毁有所扩大,为不同研究选择制备模型的方法提供一定的理论依据。

  10. Chlordiazepoxide-induced released responding in extinction and punishment-conflict procedures is not altered by neonatal forebrain norepinephrine depletion.

    Bialik, R J; Pappas, B A; Pusztay, W


    The effects of chlordiazepoxide (CDZ) in extinction and punishment-conflict tasks were examined in rats after neonatal systemic administration of 6-hydroxydopamine (6-OHDA) to deplete forebrain norepinephrine (NE). At about 70 days of age the rats were water deprived and trained for three days to drink in a novel apparatus. On the fourth day (test day) drinking was either extinguished by elimination of water from the drinking tube or punished by lick-contingent shock. Just prior to this test session half of the vehicle and half of the 6-OHDA treated rats were given an injection of CDZ (8 mg/kg IP). Both the injection of CDZ and forebrain NE depletion prolonged responding during extinction and reduced the suppressant effects of punishment in male rats, and these effects were of similar magnitude. Furthermore, CDZ was as effective in neonatal 6-OHDA treated male rats as in vehicle treated rats indicating that decreased transmission is ascending NE fibers caused by CDZ is not solely responsible for its behavioral effects in extinction and conflict tasks. Rather, these effects may involve cooperative mediation by both noradrenergic and serotonergic forebrain terminals. Unexpectedly, CDZ's anti-extinction effect was absent in female rats and its anti-conflict effect observed only in NE depleted females.

  11. Microglia Modulate Wiring of the Embryonic Forebrain

    Paola Squarzoni


    Full Text Available Dysfunction of microglia, the tissue macrophages of the brain, has been associated with the etiology of several neuropsychiatric disorders. Consistently, microglia have been shown to regulate neurogenesis and synaptic maturation at perinatal and postnatal stages. However, microglia invade the brain during mid-embryogenesis and thus could play an earlier prenatal role. Here, we show that embryonic microglia, which display a transiently uneven distribution, regulate the wiring of forebrain circuits. Using multiple mouse models, including cell-depletion approaches and cx3cr1−/−, CR3−/−, and DAP12−/− mutants, we find that perturbing microglial activity affects the outgrowth of dopaminergic axons in the forebrain and the laminar positioning of subsets of neocortical interneurons. Since defects in both dopamine innervation and cortical networks have been linked to neuropsychiatric diseases, our study provides insights into how microglial dysfunction can impact forebrain connectivity and reveals roles for immune cells during normal assembly of brain circuits.

  12. Excitatory Hindbrain-Forebrain Communication Is Required for Cisplatin-Induced Anorexia and Weight Loss.

    Alhadeff, Amber L; Holland, Ruby A; Zheng, Huiyuan; Rinaman, Linda; Grill, Harvey J; De Jonghe, Bart C


    characterize the excitatory nature of neural projections activated by cisplatin in rats and reveal the necessity of specific hindbrain-forebrain projections for cisplatin-induced anorexia and weight loss. Together, these findings help to characterize the neural mechanisms mediating cisplatin-induced anorexia, advancing opportunities to develop better-tolerated chemotherapies and adjuvant therapies to prevent anorexia and concurrent nutritional deficiencies during cancer treatment. Copyright © 2017 the authors 0270-6474/17/370362-09$15.00/0.

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

    Phillips, H.S.; Hains, J.M.; Laramee, G.R.; Rosenthal, A.; Winslow, J.W. (Genentech, San Francisco, CA (USA))


    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.

  14. Dcc regulates asymmetric outgrowth of forebrain neurons in zebrafish.

    Jingxia Gao

    Full Text Available The guidance receptor DCC (deleted in colorectal cancer ortholog UNC-40 regulates neuronal asymmetry development in Caenorhabditis elegans, but it is not known whether DCC plays a role in the specification of neuronal polarity in vertebrates. To examine the roles of DCC in neuronal asymmetry regulation in vertebrates, we studied zebrafish anterior dorsal telencephalon (ADt neuronal axons. We generated transgenic zebrafish animals expressing the photo-convertible fluorescent protein Kaede in ADt neurons and then photo-converted Kaede to label specifically the ADt neuron axons. We found that ADt axons normally project ventrally. Knock down of Dcc function by injecting antisense morpholino oligonucleotides caused the ADt neurons to project axons dorsally. To examine the axon projection pattern of individual ADt neurons, we labeled single ADt neurons using a forebrain-specific promoter to drive fluorescent protein expression. We found that individual ADt neurons projected axons dorsally or formed multiple processes after morpholino knock down of Dcc function. We further found that knock down of the Dcc ligand, Netrin1, also caused ADt neurons to project axons dorsally. Knockdown of Neogenin1, a guidance receptor closely related to Dcc, enhanced the formation of aberrant dorsal axons in embryos injected with Dcc morpholino. These experiments provide the first evidence that Dcc regulates polarized axon initiation and asymmetric outgrowth of forebrain neurons in vertebrates.

  15. Role of tissue plasminogen activator/plasmin cascade in delayed neuronal death after transient forebrain ischemia.

    Takahashi, Hiroshi; Nagai, Nobuo; Urano, Tetsumei

    We studied the possible involvement of the tissue plasminogen activator (t-PA)/plasmin system on both delayed neuronal death in the hippocampus and the associated enhancement of locomotor activity in rats, after transient forebrain ischemia induced by a four-vessel occlusion (FVO). Seven days after FVO, locomotor activity was abnormally increased and, after 10 days, pyramidal cells were degraded in the CA1 region of the hippocampus. FVO increased the t-PA antigen level and its activity in the hippocampus, which peaked at 4 h. Both the enhanced locomotor activity and the degradation of pyramidal cells were significantly suppressed by intracerebroventricular injection of aprotinin, a plasmin inhibitor, at 4 h but not during FVO. These results suggest the importance of the t-PA/plasmin cascade during the early pathological stages of delayed neuronal death in the hippocampus following transient forebrain ischemia.

  16. Regional distribution of putative NPY Y*U1 receptors and neurons expressing Y*U1 mRNA in forebrain areas of the rat central nervous system

    Larsen, Philip J.; Sheikh, Søren P.; Jakobsen, Cherine R.


    Anatomi, neurobiologi, neuropeptide Y, NPY analogues, receptor autoradiography, in situ hybridization histochemistry, Y*U1 mRNA, Y*U1 andY*U2 receptors, rat......Anatomi, neurobiologi, neuropeptide Y, NPY analogues, receptor autoradiography, in situ hybridization histochemistry, Y*U1 mRNA, Y*U1 andY*U2 receptors, rat...

  17. The non-opioid KOR agonist Salovinorin A reducing brain edema in rats with forebrain ischemia and reperfusion%非阿片类药物KOR激动剂Salvinorin A减轻前脑缺血再灌注大鼠脑水肿的作用

    张燕; 王震虹; 何振洲; 忻纪华


    Objective To discuss the mechanism of Kappa opioid receptor (KOR) agonist Salvinorin A (SA) on decreas-ing brain edema after forebrain ischemia-reperfusion (I/R) injury in rats. Methods Male Sprague-Dawley rats were di-vided into 5 groups (n=10): sham operation group, I/R group, DMSO (vehicle) group, SA group and Norbinaltorphimine (nor-BIN, KOR antagonist) +SA group. Forebrain ischemia was performed by low artery pressure with bilateral carotid artery occlusion for 10 minutes. Intervenes (DMSO, SA, nor-BIN+SA) were performed after forebrain ischemia instantly. The animals were sacrificed 24 hours after reperfusion. The hippocampus was taken for pathology, and TdT-mediated dUTP nick end labeling (TUNEL) and immunohistochemical test were used for AQP4 detection. The wet-dry weight method was used to assess brain water content. Results Compared with sham operation group, hippocampus water con-tent increased in I/R group (P< 0.01). Hippocampus water content was significantly lower in SA group than that in I/R group (P<0.01). Hippocampus water content was significantly higher in nor-BIN+SA group than that in SA group (P<0.05). Compared with I/R and DMSO groups, hippocampus neurosis and apoptosis were alleviated significantly with treatment of SA 24 h after forebrain I/R (P<0.01), which effect was blunted by nor-BIN. Compared with sham opera-tion group, AQP4 expressed in hippocampus was promoted by I/R (P < 0.01). Compared with I/R group, AQP4 ex-pressed was depressed in SA group (P< 0.01). The expression of AQP4 increased significantly with treatment of nor-BIN+SA compared with SA (P< 0.05). Conclusion SA can reduce cerebral edema after forebrain ischemia and brain damage by inhibition of AQP4. Its mechanism may be correlated with KOR.%目的:探讨大鼠前脑缺血再灌注(I/R)损伤后,Kappa阿片受体(KOR)激动剂Salvinorin A(SA)减轻脑水肿的机制。方法成年健康雄性Sprague-Dawley(SD)大鼠随机分为5组(n=10):假手术组、I/R组、DMSO

  18. Construction of the human forebrain.

    Jernigan, Terry L; Stiles, Joan


    The adult human brain is arguably the most complex of biological systems. It contains 86 billion neurons (the information processing cells of the brain) and many more support cells. The neurons, with the assistance of the support cells, form trillions of connections creating complex, interconnected neural networks that support all human thought, feeling, and action. A challenge for modern neuroscience is to provide a model that accounts for this exquisitely complex and dynamic system. One fundamental part of this model is an account of how the human brain develops. This essay describes two important aspects of this developmental story. The first part of the story focuses on the remarkable and dynamic set of events that unfold during the prenatal period to give rise to cell lineage that form the essential substance of the brain, particularly the structures of the cerebral hemispheres. The second part of the story focuses on the formation of the major brain pathways of the cerebrum, the intricate fiber bundles that connect different populations of neurons to form the information processing systems that support all human thought and action. These two aspects of early brain development provide an essential foundation for understanding how the structure, organization, and functioning of the human brain emerge. WIREs Cogn Sci 2017, 8:e1409. doi: 10.1002/wcs.1409 For further resources related to this article, please visit the WIREs website.

  19. Forebrain substrates of reward and motivation.

    Wise, Roy A


    Electrical stimulation of the medial forebrain bundle can reward arbitrary acts or motivate biologically primitive, species-typical behaviors like feeding or copulation. The subsystems involved in these behaviors are only partially characterized, but they appear to transsynaptically activate the mesocorticolimbic dopamine system. Basal function of the dopamine system is essential for arousal and motor function; phasic activation of this system is rewarding and can potentiate the effectiveness of reward-predictors that guide learned behaviors. This system is phasically activated by most drugs of abuse and such activation contributes to the habit-forming actions of these drugs.

  20. Microarray Analysis of the Developing Rat Mandible

    Hideo KABURAGI; Naoyuki SUGANO; Maiko OSHIKAWA; Ryosuke KOSHI; Naoki SENDA; Kazuhiro KAWAMOTO; Koichi ITO


    To analyze the molecular events that occur in the developing mandible, we examined the expression of 8803 genes from samples taken at different time points during rat postnatal mandible development.Total RNA was extracted from the mandibles of 1-day-old, 1-week-old, and 2-week-old rats. Complementary RNA (cRNA) was synthesized from cDNA and biotinylated. Fragmented cRNA was hybridized to RGU34A GeneChip arrays. Among the 8803 genes tested, 4344 were detectable. We identified 148 genes with significantly increased expression, and 19 genes with significantly decreased expression. A comprehensive analysis appears to be an effective method of studying the complex process of development.

  1. Efficient in vivo electroporation of the postnatal rodent forebrain.

    Camille Boutin

    Full Text Available Functional gene analysis in vivo represents still a major challenge in biomedical research. Here we present a new method for the efficient introduction of nucleic acids into the postnatal mouse forebrain. We show that intraventricular injection of DNA followed by electroporation induces strong expression of transgenes in radial glia, neuronal precursors and neurons of the olfactory system. We present two proof-of-principle experiments to validate our approach. First, we show that expression of a human isoform of the neural cell adhesion molecule (hNCAM-140 in radial glia cells induces their differentiation into cells showing a neural precursor phenotype. Second, we demonstrate that p21 acts as a cell cycle inhibitor for postnatal neural stem cells. This approach will represent an important tool for future studies of postnatal neurogenesis and of neural development in general.

  2. Regional cerebral blood flow and glucose metabolism following transient forebrain ischemia.

    Pulsinelli, W A; Levy, D E; Duffy, T E


    Progressive brain damage after transient cerebral ischemia may be related to changes in postischemic cerebral blood flow and metabolism. Regional cerebral blood flow (rCBF) and cerebral glucose utilization (rCGU) were measured in adult rats prior to, during (only rCBF), and serially after transient forebrain ischemia. Animals were subjected to 30 minutes of forebrain ischemia by occluding both common carotid arteries 24 hours after cauterizing the vertebral arteries. Regional CBF was measured by the indicator-fractionation technique using 4-iodo-[14C]-antipyrine. Regional CGU was measured by the 2-[14C]deoxyglucose method. The results were correlated with the distribution and progression of ischemic neuronal damage in animals subjected to an identical ischemic insult. Cerebral blood flow to forebrain after 30 minutes of moderate to severe ischemia (less than 10% control CBF) was characterized by 5 to 15 minutes of hyperemia; rCBF then fell below normal and remained low for as long as 24 hours. Post-ischemic glucose utilization in the forebrain, except in the hippocampus, was depressed below control values at 1 hour and either remained low (neocortex, striatum) or gradually rose to normal (white matter) by 48 hours. In the hippocampus, glucose utilization equaled the control value at 1 hour and fell below control between 24 and 48 hours. The appearance of moderate to severe morphological damage in striatum and hippocampus coincided with a late rise of rCBF above normal and with a fall of rCGU; the late depression of rCGU was usually preceded by a period during which metabolism was increased relative to adjacent tissue. Further refinement of these studies may help identify salvageable brain after ischemia and define ways to manipulate CBF and metabolism in the treatment of stroke.

  3. Patterns of cell death in the perinatal mouse forebrain.

    Mosley, Morgan; Shah, Charisma; Morse, Kiriana A; Miloro, Stephen A; Holmes, Melissa M; Ahern, Todd H; Forger, Nancy G


    The importance of cell death in brain development has long been appreciated, but many basic questions remain, such as what initiates or terminates the cell death period. One obstacle has been the lack of quantitative data defining exactly when cell death occurs. We recently created a "cell death atlas," using the detection of activated caspase-3 (AC3) to quantify apoptosis in the postnatal mouse ventral forebrain and hypothalamus, and found that the highest rates of cell death were seen at the earliest postnatal ages in most regions. Here we have extended these analyses to prenatal ages and additional brain regions. We quantified cell death in 16 forebrain regions across nine perinatal ages from embryonic day (E) 17 to postnatal day (P) 11 and found that cell death peaks just after birth in most regions. We found greater cell death in several regions in offspring delivered vaginally on the day of parturition compared with those of the same postconception age but still in utero at the time of collection. We also found massive cell death in the oriens layer of the hippocampus on P1 and in regions surrounding the anterior crossing of the corpus callosum on E18 as well as the persistence of large numbers of cells in those regions in adult mice lacking the pro-death Bax gene. Together these findings suggest that birth may be an important trigger of neuronal cell death and identify transient cell groups that may undergo wholesale elimination perinatally. J. Comp. Neurol. 525:47-64, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  4. Tolerance of nestin+ cholinergic neurons in the basal forebrain against colchicine-induced cytotoxicity

    Jing Yu; Kaihua Guo; Dongpei Li; Jinhai Duan; Juntao Zou; Junhua Yang; Zhibin Yao


    In the present study we injected colchicine into the lateral ventricle of Sprague-Dawley rats to investigate the effects of colchicine on the number of different-type neurons in the basal forebrain and to search for neurons resistant to injury. After colchicine injection, the number of nestin+ cholinergic neurons was decreased at 1 day, but increased at 3 days and peaked at 14-28 days. The quantity of nestin- cholinergic neurons, parvalbumin-positive neurons and choline acetyl transferase-positive neurons decreased gradually. Our results indicate that nestin+ cholinergic neurons possess better tolerance to colchicine-induced neurotoxicity.

  5. Testicular development and reproductivity in rats

    Bing, Wang; Masahiro, Murakami; Kiyomi, Eguchi-Kasai; Kumie, Nojima; Yi, Shang; Kaoru, Tanaka; Kazuko, Fujita [National Institute of Radiological Sciences, Inage-ku, Chiba (Japan); Coffigny, H. [CEA Fontenay-aux-Roses, Dir. des Sciences du Vivant, 92 (France)


    Effects on gonads in prenatal male fetuses, and on the postnatal testicular development and reproductivity of male offspring were studied following exposure of pregnant Wistar rats to either accelerated carbon-ion beans with a Let value of about 13 keV/L]m or neon-ion beams with a Let value of about 30 keV/I Im at a dose range from 0.1 Gy to 2.0 Gy on gestation day 15. Induction of apoptosis in fetal gonocytes was evaluated pathologically in male gonads. Mean number of pups, pre-weaning mortality, and the age for testis descent in offspring were examined. Testis weight and the ratio of it to body weight were measured on postnatal days 30, 60 and 90, respectively. Development of testicular tubules was analyzed histologically. In addition, in the male offspring, the successful mating rates with non-irradiated female rats, the mean number of pups descended, and, the weaning rates of the pups were investigated. The effects of X-rays at 200 kVp estimated for the same biological end points were studied for comparison. For heavy ions, a dose of 2.0 Gy caused 100% pre-weaning mortality. For some endpoints, such as pre-weaning mortality, testis weight, and ratio of testis weight to body weight, significant alteration was observed in offspring prenatally received only 0.1 Gy of accelerated neon ions; while for the most endpoints regarding the effects from carbon ions or X rays, a significant alteration could be observed only when a dose was at 0.5 Gy or more. In this dose range, apoptosis in gonocytes of fetal gonads was significantly induced in a dose-dependent manner with a peak at around 12 to 18 hr after irradiation; in the prenatally irradiated pups, statistical significances for increased prenatal death, delayed accomplishment in testis descent, low testis weight, changed ratios of testis weight to body weight, and increased malformed testicular tubules were recorded. When the dose was at 1.0 Gy or 1.5 Gy, marked decrease in successful mating rates was also observed

  6. Injury effects of advanced glycation end products on the cultured primary rat basal forebrain cholinergic neurons%糖基化终末产物对大鼠基底前脑胆碱能神经元的损伤作用

    殷青青; 刘雪平; 董传芳; 董雪丽; 李艳菊; 罗鼎真; 侯训尧


    目的 研究糖基化终末产物(AGE-BSA)对原代培养的基底前脑胆碱能神经元形态、生存率、凋亡率、胆碱乙酰转移酶(ChAT)与乙酰胆碱酯酶(AchE)活性的影响.在体外水平研究AGEs在阿尔茨海默病(Alzheimer's disease,AD)神经元缺失发生中的作用及其可能机制.方法 原代培养大鼠基底前脑胆碱能神经元,观察细胞生长变化,进行免疫荧光细胞化学鉴定;用300 μg/mLAGE-BSA以及糖基化终末产物受体(RAGE)中和抗体阻断处理原代培养的基底前脑胆碱能神经元,作用不同时间后置于倒置显微镜下观察细胞形态变化;采用MTT法检测神经元的存活率;采用流式细胞术检测神经元的凋亡率;经比色法检测ChAT和AchE的活性变化.结果 AGEBSA干预胆碱能神经元72 h后,细胞形态发生明显损伤性变化,细胞存活率明显降低,凋亡率增高,ChAT活性明显下降,AchE活性明显升高;RAGE中和抗体阻断组72 h较之AGE-BSA组,细胞形态损伤变化较轻,生存率偏高,凋亡率较低,ChAT活性较高,AchE活性偏低,但比空白对照组生存率降低,凋亡率增高,ChAT活性明显下降,AchE活性明显升高.结论 糖基化终末产物作用72 h可以引起胆碱能神经元的损伤,并造成ChAT活性下降和AchE活性明显升高,部分阻断其与特异性受体RAGE的结合可以减弱其损伤作用,提示糖基化终末产物通过其受体参与了对胆碱能神经元的损伤作用.%Objective To investigate effects of advanced glycation end products (AGEs) on the cell morphology, survival rate, apoptosis rate, choline acetyltransfesterase (ChAT) activity and acetylcholine( AchE) activity of the cultured primary rat basal forebrain cholinergic neurons. To explore the effect and the possible mechanism of AGEs in Alzheimer's disease( AD) at the cell level. Methods Cultured primary rat basal forebrain cholinergic neurons were intervened by AGE-BSA and the RAGE neutralizing antibody, then the cell

  7. Effect of propofol on rat forebrain ischemia reperfusion induced mitochondrial damage and uncoupling protein 2 expression%丙泊酚对大鼠前脑缺血/再灌注诱导线粒体损伤及解耦联蛋白2表达的影响

    戚思华; 王晓东; 李军; 王毅; 李文志


    Objective To investigate the effect of propofol on rat forebrain ischemia reperfusion induced mitochondrial damage and uncoupling protein 2 (UCP 2)expression. Methods 45 male Wistar rats weighing 250 g-300 g were randomly divided into three groups (n= 15):control group (C) ;ischemia reperfusion group (I/R) ;propofol group (P). Forebrain cerebral ischemia reperfusion was produced by 2-vessel occlusion method. Bilateral carotid arteries were released after 10 min cerebral ischemia. Normal saline 1 mg/kg and propofol 1 mg/kg were separately injected into the lateral cerebral ventricle by micro syringe in group I/R and group P. The animals were decapitated at the end of 24 h reperfusion and the hippocampal were separated.The mitochondria of hippocampal in each group were isolated. The mitochondria in three groups were incubated by CaCl2for 5 min at 37℃. Morphological changes of mitoehondria were observed by using electron microscopy (n=3). Mitochondrial permeability transition pore (MPTP)opening were detected by ultravioletvisible absorption spectroscopy(n=6). The expression of UCP2 in each group were determined by western blotting method (n=6). Results Group C showed normal mitochondrial ultrastructure;Significant mitochondrial swelling, disrupted cristae and membrane rupture were showed in group I/R;Morphological changes of mitechondria in group P were between group C and group I/R. Absorbance values of mitochondrial decreased in group C, group I/R and group P. Compared with group C, absorbance values of mitochondrial were lower in group I/R and group P (P<0.05). The decrease of absorbance values of mitochondria was reduced in group P(0.017 ± 0.007)compared with that in group I/R (0.028 ± 0.007)(P<0.05). The expression of UCP2 in hippocampus was significantly up-regnlated in group I/R (0.88 ± 0.14) and group P (1.32 + 0. 10)(P<0.05). Compared with group I/R, the expression of UCP2 were higher in group P (P<0.05). Conclusion Propofol improve mitochondrial

  8. Temporal changes in glial fibrillary acidic protein messenger RNA and [{sup 3}H]PK11195 binding in relation to imidazoline-I{sub 2}-receptor and {alpha}{sub 2}-adrenoceptor binding in the hippocampus following transient global forebrain ischaemia in the rat

    Craven, J.A.; Gundlach, A.L.; Conway, E.L. [The University of Melbourne, Clinical Pharmacology and Therapeutics Unit (Australia); Department of Medicine, Austin and Repatriation Medical Centre (Australia)


    Immunohistochemical studies have demonstrated that following global forebrain ischaemia the selective neuronal loss that occurs in the CA1 pyramidal cell layer of the hippocampus is accompanied by a reactive astrocytosis, characterized by increases in glial fibrillary acidic protein, and activation of microglia. In this study the spatial changes in glial fibrillary acidic protein messenger RNA levels in the hippocampus have been mapped four, eight, 12, 16 and 20 days following 10 min of global forebrain ischaemia in the rat and related to changes in [{sup 3}H]PK11195 binding to peripheral benzodiazepine receptors, a putative marker of activated microglia. Recent studies have suggested that the imidazoline-I{sub 2}-receptor, one of a class of non-adrenergic receptors related to, but structurally and functionally distinct from {alpha}{sub 2}-adrenoceptors, may have a functional role in controlling the expression of glial fibrillary acidic protein. To explore this possibility further we have also mapped changes in imidazoline-I{sub 2}-receptor and {alpha}{sub 2}-adrenoceptor binding sites. Following transient ischaemia there was a marked, biphasic increase in glial fibrillary acidic protein messenger RNA levels throughout the vulnerable CA1 region of the hippocampus, peaking four days after ischaemia and then increasing gradually during the remainder of the study period. There was also a sustained increase in [{sup 3}H]PK11195 binding, however, in contrast to the initial increase in glial fibrillary acidic protein messenger RNA levels that peaked four days after ischaemia the density of [{sup 3}H]PK11195 binding increased rapidly in all strata of the CA1 region over the first eight days and then increased more slowly throughout days 12 to 20. Despite the marked increase in glial fibrillary acidic protein messenger RNA levels there was no concomitant alteration in imidazoline-I{sub 2}-receptor binding sites detected using the specific radioligand, [{sup 3}H]2

  9. [Development of the habenulointerpeduncular tract in rats].

    Klepukov, A A; Makarenko, I G


    Development of the habenulointerpeduncular tract has been carried out on fixed brain preparations obtained from 21 day rat embryos and from neonatal animals on the 0 and 9 days of postnatal development by diffusion oflipophilic fluorescent carbocyanine dye DiI (1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate) through neuron membranes. The marker was introduced into the nuclei of the habenula, the interpeduncular nucleus, and into the area of raphe nuclei. Neurons and fibers that contained Dil were identified on vibratome sections by fluorescent and confocal microscopy. we have found that reciprocal links between the lateral habenula nucleus and raphe nuclei are formed in the prenatal period by stage E21. Raphe nuclei innervating neurons were located in dorso- and ventrocaudal parts of the lateral habenula nucleus. Projections of the medial habenula nucleus onto interpeduncular nucleus were found only in the postnatal P2 period. Neurons that provide a source of these projections form characteristic assemblies inside the medial habenula nucleus. Therefore, the present study for the first time describes heterogenic formation of different projection systems that are involved in the habenulointerpeduncular tract of rats at perinatal ontogenesis.

  10. Mosaic Subventricular Origins of Forebrain Oligodendrogenesis

    Azim, Kasum; Berninger, Benedikt; Raineteau, Olivier


    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

  11. Mosaic subventricular origins of forebrain oligodendroglia

    Kasum eAzim


    Full Text Available 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 Wnt 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.

  12. Temporal profile of neuronal damage in a model of transient forebrain ischemia.

    Pulsinelli, W A; Brierley, J B; Plum, F


    This study examined the temporal profile of ischemic neuronal damage following transient bilateral forebrain ischemia in the rat model of four-vessel occlusion. Wistar rats were subjected to transient but severe forebrain ischemia by permanently occluding the vertebral arteries and 24 hours later temporarily occluding the common carotid arteries for 10, 20, or 30 minutes. Carotid artery blood flow was restored and the rats were killed by perfusion-fixation after 3, 6, 24, and 72 hours. Rats with postischemic convulsions were discarded. Ischemic neuronal damage was graded in accordance with conventional neuropathological criteria. Ten minutes of four-vessel occlusion produced scattered ischemic cell change in the cerebral hemispheres of most rats. The time to onset of visible neuronal damage varied among brain regions and in some regions progressively worsened with time. After 30 minutes of ischemia, small to medium-sized striatal neurons were damaged early while the initiation of visible damage to hippocampal neurons in the h1 zone was delayed for 3 to 6 hours. The number of damaged neurons in neocortex (layer 3, layers 5 and 6, or both) and hippocampus (h1, h3-5, paramedian zone) increased significantly (p less than 0.01) between 24 and 72 hours. The unique delay in onset of ischemic cell change and the protracted increase in its incidence between 24 and 72 hours could reflect either delayed appearance of ischemic change in previously killed neurons or a delayed insult that continued to jeopardize compromised but otherwise viable neurons during the postischemic period.

  13. Temporal and spatial distribution of metabotropic glutamate receptor 5 during development in the rat cortex and hippocampus

    Xinli Xiao; Ming Hu; Pengbo Yang; Lin Zhang; Xinlin Chen; Yong Liu


    Metabotropic glutamate receptor 5 (mGluR5) is expressed by neurons in zones of active neurogenesis and is involved in the development of neural stem cells in vivo and in vitro. We examined the expression of mGluR5 in the cortex and hippocampus of rats during various prenatal and postnatal periods using immunohistochemistry. During prenatal development, mGluR5 was primarily localized to neuronal somas in the forebrain. During early postnatal periods, the receptor was mainly present on somas in the cortex. mGluR5 immunostaining was visible in apical dendrites and in the neuropil of neurons and persisted throughout postnatal development. During this period, pyramidal neurons were strongly labeled for the receptor. In the hippocampal CA1 region, mGluR5 immunoreactivity was more intense in the stratum oriens, stratum radiatum, and lacunosum moleculare at P0, P5 and P10 relative to P60. mGluR5 expression increased significantly in the molecular layer and decreased significantly in the granule cell layer of the dentate gyrus at P5, P10 and P60 in comparison with P0. Furthermore, some mGluR5-positive cells were also bromodeoxyuridine- or NeuroD-positive in the dentate gyrus at P14. These results demonstrate that mGluR5 has a differential expression pattern in the cortex and hippocampus during early growth, suggesting a role for this receptor in the control of domain specific brain developmental events.

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

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


    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.

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

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


    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.

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

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


    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

  17. Forebrain neuroanatomy of the neonatal and juvenile dolphin (T. truncatus & S. coeruloalba

    Roberta eParolisi


    Full Text Available 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/grey 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 analysis 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.

  18. Transient forebrain ischemia-induced neuronal degeneration in fascia dentata transplants.

    Tønder, N; Aznar, S; Johansen, F F


    Fascia dentata tissue blocks from newborn rats were grafted into one-week-old, ibotenic acid-induced lesions of the fascia dentata, or the normal fascia dentata of adult rats. After at least 2 months survival the recipient rats were subjected to 10 min of forebrain ischemia (4-vessel occlusion), and examined 2 or 4 days later for neuronal degeneration in the host hippocampi and the transplants, by silver staining and immunohistochemistry. Transplants survived well in both normal and lesioned host brains, with easily recognizable subfields and layers and presence of normal types of principal and non-principal neurons. As expected, argyrophilic, degenerating neurons were present in the pyramidal cell layer of CAl and CA3c of the non-grafted contralateral host hippocampus and in the contralateral dentate hilus (CA4). In the hilus the degeneration corresponded to the loss of somatostatin-immunoreactive neurons, while parvalbumin-immunoreactive neurons were spared. In the dentate transplants degenerating neurons were observed in the granule cell layer, the hilus and the adjacent CA3 pyramidal cell layer. There was no obvious loss of either somatostatin- or parvalbumin-immunoreactive neurons. The degeneration varied considerably between transplants, from a few to large groups of silver stained neurons, but this difference did not display any obvious relation to grafting into normal or lesioned hosts, the exact location of the grafts or the general organization and distribution of intrinsic or extrinsic host afferents in the grafts. The results demonstrate that both ischemia-susceptible and -resistant types of neurons grafted to normal and lesioned adult rat brains are susceptible to transient forebrain ischemia after transplantation. In spite of an extensive reorganization of transplant nerve connections, the physiologicalbiochemical mechanisms necessary for the induction of ischemic cell death were accordingly present in the transplants.

  19. Effects of Ketogenic Diet on Expresslon of Plasticity-Related Gene 1 in Rat Forebrain Following Recurrent Neonatal Seizures%生酮饮食对反复惊厥新生大鼠前脑可塑性相关基因-1表达的影响

    张雪媛; 倪宏; 任守芸; 陈情情


    目的 探讨新生大鼠反复惊厥前脑可塑性相关基因-1( PRG-1)的表达及生酮饮食(KD)对其表达的影响.方法 日龄7d(P7)的SD大鼠24只.随机分为对照组(CON组)和惊厥组(RS组),每组各12只.适应性喂养1d后,RS组大鼠吸入三氟乙醚诱导惊厥发作,反复诱导惊厥持续30 min,每日1次,同样方法连续诱导8d;对照组同样操作,但不吸入三氟乙醚.在P21依据是否给予KD,每组大鼠再随机分为2组,即未惊厥普通饮食组(CON+ ND)、未惊厥KD组(CON+ KD)、惊厥普通饮食组(RS+ND)、惊厥KD组(RS+KD),每组各6只.CON+ ND组和RS+ND组大鼠给予普通饮食,CON+KD组和RS +KD组大鼠给予KD,饮食干预3周.P42大鼠断头取大脑皮质及海马,用免疫印迹法检测各组大鼠脑组织皮质及海马PRG-1的表达.结果 与CON+ ND组比较,RS +ND组皮质及海马PRG-1表达均显著增高(Pa<0.05);与RS+ND组比较,RS+KD组皮质及海马PRG-1表达均明显降低(Pa<0.05);与CON+ ND组比较,CON+ KD组皮质及海马PRG-1的表达均无统计学差异(Pa>0.05).结论 新生大鼠反复惊厥远期PRG-1的表达增高,提示其参与发育期惊厥性脑损伤的病理生理机制.而KD可能通过下调惊厥组大鼠PRG-1表达,参与发育期惊厥性脑损伤的修复.%Objective To detect the long - term expression of plasticity - related gene 1 ( PRG - 1) in rat forebrain following recurrent neonatal seizures and the effect of ketogenic diet on PRC - 1 expression level. Methods Twenty - four Sprague - Dawley neonatal rats( postnatal days 7,P7)were randomly divided into control group (CON group) and recurrent - seizure group ( RS group) ,and each group had 12 rats. Rats were adapted to the environment for 1 day. From P8,rats in RS group were subjected to recurrent seizures induced by inhalant flu-rolhyl 30 min once day for consecutive 8 days,while rats in CON group were treated in the same way except for exposing them to flurothyl. At the day of P21, each group

  20. Chick homeobox gene cDlx expression demarcates the forebrain anlage, indicating the onset of forebrain regional specification at gastrulation.

    Borghjid, S; Siddiqui, M A


    Here we describe the isolation and characterization of a chick homeobox-containing gene, cDlx, which shows greater than 85% homology to the homeodomain of other vertebrate Distal-less genes. Northern blot analysis and in situ hybridization studies reveal that cDlx expression is developmentally regulated and is tissue specific. In particular, the developmental expression pattern is characterized by an early appearance of cDlx transcript in the prospective forebrain region of gastrulating embryos. During neurulation, cDlx is consistently expressed in a spatially restricted domain in the presumptive ventral forebrain region of the neural plate that will give rise to the hypothalamus and the adenohypophysis. Our data support the notion that members of the Dlx gene family are part of a homeobox gene code in forebrain pattern formation and suggest that regional specification of the forebrain occurs at much earlier stages than previously thought. The homeobox gene cDlx may thus play a role in defining forebrain regional identity as early as gastrulation.


    高殿帅; 张凤真; 王德广; 周长福


    In order to investigate the chemical and morphornetrical properties of the neuronal precursor cells derived from thesubventricular zone(SVZ) of the postnatal rat forebrain in vitro. The cell-type specific antibodies were used for the immunocy-tochemical staining ,and the morphometric parameters which were the mean soma diameter and the ellipticity index (i. e. , thesmallest soma diameter divided by the largest soma diameter) of every SVZ-derived cell were measured for identifying the pheno-types of the SVZ cells in vitro. The experiment animals were SD rats (weights: 100~ 150 g), the SVZ cells derived from thepostnatal rats were cultured on poly-D-lysine-coated 24-well glass chamber slides in the Neurobasal Medium supplemented withB27 in 5% CO2 at 37 C. The following results were obtained.. At 1 day in vitro, almost all SVZ cells (〉90%) from the postna-tal rat forebrain expressed Tujl, an antibody that recognizes neuron-specific tubulin. Likewise, the preponderance of the SVZcells expressed the polysialylated neural cell adhesion molecule (PSA-N-CAM) ; The majority of the SVZ Tujl-positive cells cul-tured were the cells that had oval-shaped bodies with two short, unbranched processes protruded from every two poles, theirmean soma diameter were 8.42±1.03μm and their ellipticity index were 0.57±0.12. Meanwhile, there were approximately20% of the SVZ cells in culture that were sphere-shaped cells with mean soma diameter 7.20±l.04 μm , and it might be observed that these cells connected with one another. As the time in culture went on, these sphere-shaped SVZ-derived cells alsotransformed to oval-shaped ones as described above, but it could be observed that the cells were still connected in the processesof them. By 3 and 5 days in culture, the SVZ cells had larger cell somas (average diameter 9. 07±1.07 μm), and often consider-ably longer processes but still with few branches. Immunocytochemical staining revealed that the majority of the SVZ cells in cul

  2. File list: His.Neu.10.AllAg.Forebrain [Chip-atlas[Archive

    Full Text Available His.Neu.10.AllAg.Forebrain mm9 Histone Neural Forebrain SRX093315,SRX377672,SRX3776...70,SRX377678,SRX377676,SRX093314,SRX377674 ...

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  6. File list: His.Neu.20.AllAg.Forebrain [Chip-atlas[Archive

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  10. File list: InP.Neu.50.AllAg.Forebrain [Chip-atlas[Archive

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  11. File list: ALL.Neu.05.AllAg.Forebrain [Chip-atlas[Archive

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  12. File list: ALL.Neu.20.AllAg.Forebrain [Chip-atlas[Archive

    Full Text Available ALL.Neu.20.AllAg.Forebrain mm9 All antigens Neural Forebrain SRX093315,SRX377672,SR...SRX377674,SRX317036,SRX377671 ...

  13. File list: InP.Neu.20.AllAg.Forebrain [Chip-atlas[Archive

    Full Text Available InP.Neu.20.AllAg.Forebrain mm9 Input control Neural Forebrain SRX377677,SRX377675,S...RX377679,SRX377673,SRX669236,SRX377671 ...

  14. Rat embryonic stem cells create new era in development of genetically manipulated rat models

    Kazushi; Kawaharada; Masaki; Kawamata; Takahiro; Ochiya


    Embryonic stem(ES) cells are isolated from theinner cell mass of a blastocyst, and are used for the generation of gene-modified animals. In mice, the transplantation of gene-modified ES cells into recipient blastocysts leads to the creation of gene-targeted mice such as knock-in and knock-out mice; these gene-targeted mice contribute greatly to scientific development. Although the rat is considered a useful laboratory animal alongside the mouse, fewer genemodified rats have been produced due to the lack of robust establishment methods for rat ES cells. A new method for establishing rat ES cells using signaling inhibitors was reported in 2008. By considering the characteristics of rat ES cells, recent research has made progress in improving conditions for the stable culture of rat ES cells in order to generate gene-modified rats efficiently. In this review, we summarize several advanced methods to maintain rat ES cells and generate gene-targeted rats.

  15. Effects of Afobazole on Postnatal Development of Rat Offspring.

    Bugaeva, L I; Denisova, T D; Sergeeva, S A; Morozova, Yu A; Kharlamov, I V


    Physical development, development of sensory and motor reflexes, behavioral and mnestic patterns were studied infantile and juvenile rat pups born by female rats receiving Afobazole during pregnancy. Physical development and development of sensory and motor reflexes in rats were completed without pathologies by the age of 2 months. During the infantile period, the rat pups demonstrated reduced body weight gain, delayed eye opening and pupillary response formation, decreased muscle force, and suppressed motor behavior. During the juvenile period, body weight gain and development of motor behavior were intensified. Females demonstrated later vagina opening and poorer mnestic responses. In males, the terms of sexual maturation were unchanged and processes of learning and memory retrieval were not impaired.

  16. Grafts of fetal locus coeruleus neurons in rat amygdala-piriform cortex suppress seizure development in hippocampal kindling.

    Barry, D I; Wanscher, B; Kragh, J; Bolwig, T G; Kokaia, M; Brundin, P; Björklund, A; Lindvall, O


    Hippocampal kindling was investigated in rats with a 6-hydroxydopamine-induced lesion of the forebrain catecholamine system after implantation of neural tissue from the fetal locus coeruleus region either bilaterally into the amygdala-piriform cortex (i.e., distant to the kindling site) or unilaterally into the hippocampus (close to the kindling site). Lesioned animals with either sham grafts or control grafts consisting of fetal striatal tissue showed a kindling rate much faster than that of normal controls. In contrast, in rats with bilateral locus coeruleus grafts in the amygdala-piriform cortex (implanted at three sites) the development of seizures was similar to that of controls and significantly slower than that in lesioned animals with sham grafts. All these animals had bilateral surviving grafts with a mean of 125 noradrenergic cells per implantation site. In the animals with locus coeruleus grafts in the stimulated hippocampus the kindling rate did not differ from that in the lesioned animals with control grafts. Most of these animals had large surviving grafts and showed a dense noradrenergic reinnervation of the implanted hippocampus. The present findings indicate that grafting of fetal pontine tissue (rich in noradrenergic neurons) to a site distant to the stimulation focus, but important for the generalization and spread of seizures, can retard the development of seizures in hippocampal kindling. Together with the data of our previous report this study also indicates that noradrenergic reinnervation of both hippocampi is important for the seizure-suppressant action in hippocampal kindling of locus coeruleus grafts implanted in the hippocampus.

  17. Development of a Rat Model of Hypothermia


    general measure of activity, since it can not distinguish the type of locomotor action. Dataloggers are 1.5 cm diameter x 0.5 cm thick cylinders...rat Tc when challenged by cold. Small mammals employ BAT to generate heat to sustain body temperature during cold exposure (1). Moreover, blood...water swims in rats. Physiol. Behav. 54:1081-1084, 1993. 12. Ricco, D.C., E.A. MacArdy and S.C. Kissinger. Association processes in adaptation

  18. Association of basal forebrain volumes and cognition in normal aging.

    Wolf, D; Grothe, M; Fischer, F U; Heinsen, H; Kilimann, I; Teipel, S; Fellgiebel, A


    The basal forebrain cholinergic system (BFCS) is known to undergo moderate neurodegenerative alterations during normal aging and severe atrophy in Alzheimer's disease (AD). It has been suggested that functional and structural alterations of the BFCS mediate cognitive performance in normal aging and AD. But, it is still unclear to what extend age-associated cognitive decline can be related to BFCS in normal aging. We analyzed the relationship between BFCS volume and cognition using MRI and a comprehensive neuropsychological test battery in a cohort of 43 healthy elderly subjects spanning the age range from 60 to 85 years. Most notably, we found significant associations between general intelligence and BFCS volumes, specifically within areas corresponding to posterior nuclei of the nucleus basalis of Meynert (Ch4p) and the nucleus subputaminalis (NSP). Associations between specific cognitive domains and BFCS volumes were less pronounced. Supplementary analyses demonstrated that especially the volume of NSP but also the volume of Ch4p was related to the volume of widespread temporal, frontal, and parietal gray and white matter regions. Volumes of these gray and white matter regions were also related to general intelligence. Higher volumes of Ch4p and NSP may enhance the effectiveness of acetylcholine supply in related gray and white matter regions underlying general intelligence and hence explain the observed association between the volume of Ch4p as well as NSP and general intelligence. Since general intelligence is known to attenuate the degree of age-associated cognitive decline and the risk of developing late-onset AD, the BFCS might, besides the specific contribution to the pathophysiology in AD, constitute a mechanism of brain resilience in normal aging.

  19. Functional conservation of a forebrain enhancer from the elephant shark (Callorhinchus milii in zebrafish and mice

    Tay Boon-Hui


    Full Text Available Abstract Background The phylogenetic position of the elephant shark (Callorhinchus milii is particularly relevant to study the evolution of genes and gene regulation in vertebrates. Here we examine the evolution of Dlx homeobox gene regulation during vertebrate embryonic development with a particular focus on the forebrain. We first identified the elephant shark sequence orthologous to the URE2 cis -regulatory element of the mouse Dlx1/Dlx2 locus (herein named CmURE2. We then conducted a comparative study of the sequence and enhancer activity of CmURE2 with that of orthologous regulatory sequences from zebrafish and mouse. Results The CmURE2 sequence shows a high percentage of identity with its mouse and zebrafish counterparts but is overall more similar to mouse URE2 (MmURE2 than to zebrafish URE2 (DrURE2. In transgenic zebrafish and mouse embryos, CmURE2 displayed enhancer activity in the forebrain that overlapped with that of DrURE2 and MmURE2. However, we detected notable differences in the activity of the three sequences in the diencephalon. Outside of the forebrain, CmURE2 shows enhancer activity in areas such as the pharyngeal arches and dorsal root ganglia where its' counterparts are also active. Conclusions Our transgenic assays show that part of the URE2 enhancer activity is conserved throughout jawed vertebrates but also that new characteristics have evolved in the different groups. Our study demonstrates that the elephant shark is a useful outgroup to study the evolution of regulatory mechanisms in vertebrates and to address how changes in the sequence of cis -regulatory elements translate into changes in their regulatory activity.

  20. Cell death atlas of the postnatal mouse ventral forebrain and hypothalamus: effects of age and sex.

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


    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. Copyright © 2013 Wiley Periodicals, Inc.

  1. Origins of serotonin innervation of forebrain structures

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


    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.

  2. Expression and localization of paxillin in rat pancreas during development

    Jing Guo; Li-Jie Liu; Li Yuan; Ning Wang; Wei De


    AIM: To investigate the expression and localization of paxillin in rat pancreas during development. METHODS: Pancreata from Sprague Dawley rat fetuses, embryos, young animals, and adult animals were used in this study. Expression levels of paxillin in pancreata of different development stages were detected by reverse transcription polymerase chain reaction and Western blotting. To identify the cell location of paxillin in the developing rat pancreas, immunohistochemistry and double-immunofluorescent staining were performed using antibodies for specific cell markers and paxillin, respectively. RESULTS: The highest paxillin mRNA level was detected at E15.5 (embryo day 15.5) following a decrease in the later developmental periods (P < 0.05 vs E18.5, P0 and adult, respectively), and a progressively increased paxillin protein expression through the transition from E15.5 to adult was detected. The paxillin positive staining was mainly localized in rat islets of Langerhans at each stage tested during pancreas development. CONCLUSION: The dynamic expression of paxillin in rat pancreas from different stages indicates that paxillin might be involved in some aspects of pancreatic development.

  3. Development of sensory motor reflexes in 2 G exposed rats.

    Wubbels, Réne; Bouët, Valentine; de Jong, Herman; Gramsbergen, Albert


    During gestation and early postnatal development, the animal's size and weight rapidly increase. Within that period, gravity affects sensory and motor development. We studied age-dependent modifications of several types of motor reflexes in 5 groups of rats conceived, born and reared in hypergravity (HG; 2 g). These rats were transferred to normal gravity (NG; 1 g) at various postnatal days, and their behavioral reflexes were compared with a control group which was constantly kept under NG. HG induced a retarded development of vestibular dependent reflexes. Other types of motor behavior were not delayed.

  4. Forebrain activation in REM sleep: an FDG PET study.

    Nofzinger, E A; Mintun, M A; Wiseman, M; Kupfer, D J; Moore, R Y


    Rapid eye movement (REM) sleep is a behavioral state characterized by cerebral cortical activation with dreaming as an associated behavior. The brainstem mechanisms involved in the generation of REM sleep are well-known, but the forebrain mechanisms that might distinguish it from waking are not well understood. We report here a positron emission tomography (PET) study of regional cerebral glucose utilization in the human forebrain during REM sleep in comparison to waking in six healthy adult females using the 18F-deoxyglucose method. In REM sleep, there is relative activation, shown by increased glucose utilization, in phylogenetically old limbic and paralimbic regions which include the lateral hypothalamic area, amygdaloid complex, septal-ventral striatal areas, and infralimbic, prelimbic, orbitofrontal, cingulate, entorhinal and insular cortices. The largest area of activation is a bilateral, confluent paramedian zone which extends from the septal area into ventral striatum, infralimbic, prelimbic, orbitofrontal and anterior cingulate cortex. There are only small and scattered areas of apparent deactivation. These data suggest that an important function of REM sleep is the integration of neocortical function with basal forebrain-hypothalamic motivational and reward mechanisms. This is in accordance with views that alterations in REM sleep in psychiatric disorders, such as depression, may reflect dysregulation in limbic and paralimbic structures.

  5. Posture and locomotion in the rat : Independent or interdependent development?

    Gramsbergen, A

    In this essay, recent research into the relation between postural control and the development of walking in the rat is reviewed. The adult-like walking pattern develops at the 15th to 16th day (P15-P16). Until this age, postural control, as indicated by EMG activity in the longissimus muscle in the

  6. Posture and locomotion in the rat : Independent or interdependent development?

    Gramsbergen, A


    In this essay, recent research into the relation between postural control and the development of walking in the rat is reviewed. The adult-like walking pattern develops at the 15th to 16th day (P15-P16). Until this age, postural control, as indicated by EMG activity in the longissimus muscle in the

  7. Adolescent social isolation influences cognitive function in adult rats

    Feng Shao; Xiao Han; Shuang Shao; Weiwen Wang


    Adolescence is a critical period for neurodevelopment. Evidence from animal studies suggests that isolated rearing can exert negative effects on behavioral and brain development. The present study aimed to investigate the effects of adolescent social isolation on latent inhibition and brain-derived neurotrophic factor levels in the forebrain of adult rats. Male Wistar rats were randomly divided into adolescent isolation (isolated housing, 38–51 days of age) and social groups. Latent inhibition was tested at adulthood. Brain-derived neurotrophic factor levels were measured in the medial prefrontal cortex and nucleus accumbens by an enzyme-linked immunosorbent assay. Adolescent social isolation impaired latent inhibition and increased brain-derived neurotrophic factor levels in the medial prefrontal cortex of young adult rats. These data suggest that adolescent social isolation has a profound effect on cognitive function and neurotrophin levels in adult rats and may be used as an animal model of neurodevelopmental disorders.

  8. Postnatal morphine administration alters hippocampal development in rats.

    Traudt, Christopher M; Tkac, Ivan; Ennis, Kathleen M; Sutton, Leah M; Mammel, Daniel M; Rao, Raghavendra


    Morphine is frequently used as an analgesic and sedative in preterm infants. Adult rats exposed to morphine have an altered hippocampal neurochemical profile and decreased neurogenesis in the dentate gyrus of the hippocampus. To evaluate whether neonatal rats are similarly affected, rat pups were injected twice daily with 2 mg/kg morphine or normal saline from postnatal days 3 to 7. On postnatal day 8, the hippocampal neurochemical profile was determined using in vivo (1)H NMR spectroscopy. The mRNA and protein concentrations of specific analytes were measured in hippocampus, and cell division in dentate gyrus was assessed using bromodeoxyuridine. The concentrations of γ-aminobutyric acid (GABA), taurine, and myo-insotol were decreased, whereas concentrations of glutathione, phosphoethanolamine, and choline-containing compounds were increased in morphine-exposed rats relative to control rats. Morphine decreased glutamic acid decarboxylase enzyme levels and myelin basic protein mRNA expression in the hippocampus. Bromodeoxyuridine labeling in the dentate gyrus was decreased by 60-70% in morphine-exposed rats. These results suggest that recurrent morphine administration during brain development alters hippocampal structure.

  9. Basal forebrain degeneration precedes and predicts the cortical spread of Alzheimer's pathology

    Schmitz, Taylor W.; Nathan Spreng, R.; Weiner, Michael W.; Aisen, Paul; Petersen, Ronald; Jack, Clifford R; Jagust, William; Trojanowki, John Q.; Toga, Arthur W; Beckett, Laurel; Green, Robert C.; Saykin, Andrew J.; Morris, John; Leslie M Shaw; Khachaturian, Zaven


    There is considerable debate whether Alzheimer's disease (AD) originates in basal forebrain or entorhinal cortex. Here we examined whether longitudinal decreases in basal forebrain and entorhinal cortex grey matter volume were interdependent and sequential. In a large cohort of age-matched older adults ranging from cognitively normal to AD, we demonstrate that basal forebrain volume predicts longitudinal entorhinal degeneration. Models of parallel degeneration or entorhinal origin received ne...

  10. Slit-Robo signals regulate pioneer axon pathfinding of the tract of the postoptic commissure in the mammalian forebrain.

    Ricaño-Cornejo, Itzel; Altick, Amy L; García-Peña, Claudia M; Nural, Hikmet Feyza; Echevarría, Diego; Miquelajáuregui, Amaya; Mastick, Grant S; Varela-Echavarría, Alfredo


    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.

  11. Loss of MeCP2 From Forebrain Excitatory Neurons Leads to Cortical Hyperexcitation and Seizures

    Zhang, Wen; Peterson, Matthew; Beyer, Barbara; Frankel, Wayne N.


    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

  12. Polyneural innervation in the psoas muscle of the developing rat

    Ijkema-Paassen, J; Gramsbergen, A


    Polyneural innervation was studied in the psoas muscle in developing rats from P4 till P25 and at adult age, with the combined silver-acetylcholinesterase technique. Nerve endings were counted, and endplates were measured. These data were compared with such data in the human. The end of polyneural i


    This study used confocal laser scanning microscopy (CLSM) to study follicular development in millimeter pieces of rat ovary. To use this technology, it is essential to stain the tissue before laser excitation with the confocal microscope. Various fluorescent stains (Yo-Pro, Bo-Pr...

  14. Developing a Speaker Identification System for the DARPA RATS Project

    Plchot, O; Matsoukas, S; Matejka, P


    This paper describes the speaker identification (SID) system developed by the Patrol team for the first phase of the DARPA RATS (Robust Automatic Transcription of Speech) program, which seeks to advance state of the art detection capabilities on audio from highly degraded communication channels. ...

  15. Long-lasting novelty-induced neuronal reverberation during slow-wave sleep in multiple forebrain areas.

    Sidarta Ribeiro


    Full Text Available The discovery of experience-dependent brain reactivation during both slow-wave (SW and rapid eye-movement (REM sleep led to the notion that the consolidation of recently acquired memory traces requires neural replay during sleep. To date, however, several observations continue to undermine this hypothesis. To address some of these objections, we investigated the effects of a transient novel experience on the long-term evolution of ongoing neuronal activity in the rat forebrain. We observed that spatiotemporal patterns of neuronal ensemble activity originally produced by the tactile exploration of novel objects recurred for up to 48 h in the cerebral cortex, hippocampus, putamen, and thalamus. This novelty-induced recurrence was characterized by low but significant correlations values. Nearly identical results were found for neuronal activity sampled when animals were moving between objects without touching them. In contrast, negligible recurrence was observed for neuronal patterns obtained when animals explored a familiar environment. While the reverberation of past patterns of neuronal activity was strongest during SW sleep, waking was correlated with a decrease of neuronal reverberation. REM sleep showed more variable results across animals. In contrast with data from hippocampal place cells, we found no evidence of time compression or expansion of neuronal reverberation in any of the sampled forebrain areas. Our results indicate that persistent experience-dependent neuronal reverberation is a general property of multiple forebrain structures. It does not consist of an exact replay of previous activity, but instead it defines a mild and consistent bias towards salient neural ensemble firing patterns. These results are compatible with a slow and progressive process of memory consolidation, reflecting novelty-related neuronal ensemble relationships that seem to be context- rather than stimulus-specific. Based on our current and previous results

  16. Hormone induced changes in lactase glycosylation in developing rat intestine.

    Chaudhry, Kamaljit Kaur; Mahmood, Safrun; Mahmood, Akhtar


    Lactase exists in both soluble and membrane-bound forms in suckling rat intestine. The distribution of lactase and its glycosylated isoforms in response to thyroxine or cortisone administration has been studied in suckling rats. 75% of lactase activity was detected, associated with brush borders, compared to 24% in the soluble fraction of 8-day-old rats. Thyroxine treatment enhanced soluble lactase activity to 34%, whereas particulate fraction was reduced to 67% compared to controls. Cortisone administration reduced soluble lactase activity from 24% in controls to 12% with a concomitant increase in membrane-bound activity to 89%. Western blot analysis revealed lactase signal, corresponding to 220 kDa in both the soluble and membrane fractions, which corroborated the enzyme activity data. The elution pattern of papain solubilized lactase from agarose-Wheat Germ agglutinin, or Concanavalin A or Jacalin agglutinin columns was different in the suckling and adult rat intestines. Also the elution profile of lactase activity from agarose-lectin columns was modulated in cortisone, thyroxine, and insulin injected pups, which suggests differences in glycosylated isoforms of lactase under these conditions. These findings suggest the role of these hormones in inducing changes in lactase glycosylation during postnatal development of intestine, which may contribute to adult-type hypolactasia in rats.

  17. Postnatal development of plasma amino acids in hyperphagic rats.

    Salvadó, M J; Segués, T; Arola, L


    The effect of feeding a highly palatable high-energy cafeteria diet on individual amino acid levels in plasma during postnatal development of the rat has been evaluated and compared to chow-fed controls. The cafeteria diet selected by the rats was hypercaloric and hyperlipidic, with practically the same amount of carbohydrate as the control diet, and slightly hyperproteic. In response to cafeteria feeding, significant decreases were observed in plasma serine and cysteine along the period studied. Significant changes with age during the growth period were shown by cafeteria-fed animals, which were not observed in control rats. Citrulline levels were lower on days 10 and 14 in cafeteria pups than in chow pups. Methionine was highest on day 30. Threonine was also higher at days 20 and 30, as was valine but with a nadir at day 10. Lysine showed maximal values on days 14 and 30.

  18. Effects of hindlimb unloading on neuromuscular development of neonatal rats

    Huckstorf, B. L.; Slocum, G. R.; Bain, J. L.; Reiser, P. M.; Sedlak, F. R.; Wong-Riley, M. T.; Riley, D. A.


    We hypothesized that hindlimb suspension unloading of 8-day-old neonatal rats would disrupt the normal development of muscle fiber types and the motor innervation of the antigravity (weightbearing) soleus muscles but not extensor digitorum longus (EDL) muscles. Five rats were suspended 4.5 h and returned 1.5 h to the dam for nursing on a 24 h cycle for 9 days. To control for isolation from the dam, the remaining five littermates were removed on the same schedule but not suspended. Another litter of 10 rats housed in the same room provided a vivarium control. Fibers were typed by myofibrillar ATPase histochemistry and immunostaining for embryonic, slow, fast IIA and fast IIB isomyosins. The percentage of multiple innervation and the complexity of singly-innervated motor terminal endings were assessed in silver/cholinesterase stained sections. Unique to the soleus, unloading accelerated production of fast IIA myosin, delayed expression of slow myosin and retarded increases in standardized muscle weight and fiber size. Loss of multiple innervation was not delayed. However, fewer than normal motor nerve endings achieved complexity. Suspended rats continued unloaded hindlimb movements. These findings suggest that motor neurons resolve multiple innervation through nerve impulse activity, whereas the postsynaptic element (muscle fiber) controls endplate size, which regulates motor terminal arborization. Unexpectedly, in the EDL of unloaded rats, transition from embryonic to fast myosin expression was retarded. Suspension-related foot drop, which stretches and chronically loads EDL, may have prevented fast fiber differentiation. These results demonstrate that neuromuscular development of both weightbearing and non-weightbearing muscles in rats is dependent upon and modulated by hindlimb loading.

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

    Ardian eHana


    Full Text Available 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 in 15 consecutive patients between 2012 and 2015. Men and women of all ages were included. There were 6 women and 9 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 6 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 x 200 mm², slice thickness 2 mm, and an acquisition matrix of 96 x 96 yielding nearly isotropic voxels of 2 x 2 x 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 less than 9 minutes. We were able to visualize the medial forebrain bundle in 12 of our patients bilaterally and in the remaining 3 patients we depicted the medial forebrain bundle on one side. It was the contralateral side of the lesion. These were 2 meningiomas and one metastasis. Portrayal of the medial forebrain bundle 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. Furthermore it might explain at a certain extent character changes in patients with lesions in the frontal lobe. Surgery in this part of the brain should always take the preservation of this white matter tract into account.

  20. Basal Forebrain Cholinergic System and Orexin Neurons: Effects on Attention

    Villano, Ines; Messina, Antonietta; Valenzano, Anna; Moscatelli, Fiorenzo; Esposito, Teresa; Monda, Vincenzo; Esposito, Maria; Precenzano, Francesco; Carotenuto, Marco; Viggiano, Andrea; Chieffi, Sergio; Cibelli, Giuseppe; Monda, Marcellino; Messina, Giovanni


    The basal forebrain (BF) cholinergic system has an important role in attentive functions. The cholinergic system can be activated by different inputs, and in particular, by orexin neurons, whose cell bodies are located within the postero-lateral hypothalamus. Recently the orexin-producing neurons have been proved to promote arousal and attention through their projections to the BF. The aim of this review article is to summarize the evidence showing that the orexin system contributes to attentional processing by an increase in cortical acetylcholine release and in cortical neurons activity. PMID:28197081

  1. Reduced-folate carrier (RFC is expressed in placenta and yolk sac, as well as in cells of the developing forebrain, hindbrain, neural tube, craniofacial region, eye, limb buds and heart

    Prasad Puttur


    Full Text Available Abstract Background Folate is essential for cellular proliferation and tissue regeneration. As mammalian cells cannot synthesize folates de novo, tightly regulated cellular uptake processes have evolved to sustain sufficient levels of intracellular tetrahydrofolate cofactors to support biosynthesis of purines, pyrimidines, and some amino acids (serine, methionine. Though reduced-folate carrier (RFC is one of the major proteins mediating folate transport, knowledge of the developmental expression of RFC is lacking. We utilized in situ hybridization and immunolocalization to determine the developmental distribution of RFC message and protein, respectively. Results In the mouse, RFC transcripts and protein are expressed in the E10.0 placenta and yolk sac. In the E9.0 to E11.5 mouse embryo RFC is widely detectable, with intense signal localized to cell populations in the neural tube, craniofacial region, limb buds and heart. During early development, RFC is expressed throughout the eye, but by E12.5, RFC protein becomes localized to the retinal pigment epithelium (RPE. Conclusions Clinical studies show a statistical decrease in the number of neural tube defects, craniofacial abnormalities, cardiovascular defects and limb abnormalities detected in offspring of female patients given supplementary folate during pregnancy. The mechanism, however, by which folate supplementation ameliorates the occurrence of developmental defects is unclear. The present work demonstrates that RFC is present in placenta and yolk sac and provides the first evidence that it is expressed in the neural tube, craniofacial region, limb buds and heart during organogenesis. These findings suggest that rapidly dividing cells in the developing neural tube, craniofacial region, limb buds and heart may be particularly susceptible to folate deficiency.

  2. Rabbit Forebrain cholinergic system : Morphological characterization of nuclei and distribution of cholinergic terminals in the cerebral cortex and hippocampus

    Varga, C; Hartig, W; Grosche, J; Luiten, PGM; Seeger, J; Brauer, K; Harkany, T; Härtig, Wolfgang; Keijser, Jan N.


    Although the rabbit brain, in particular the basal forebrain cholinergic system, has become a common model for neuropathological changes associated with Alzheimer's disease, detailed neuroanatomical studies on the morphological organization of basal forebrain cholinergic nuclei and on their output p

  3. developing cerebellum of wistar rat (Rattus Novergicus)

    Histoinorphometric studies on the effect of cyanide consumption of the developing cerebellum of .... most of the plant sources of food consumed in the trop- ics'. Cyanide poisoning ... to be affected by substances such as caffeine, theobro- mine ...

  4. Estradiol selectively enhances auditory function in avian forebrain neurons.

    Caras, Melissa L; O'Brien, Matthew; Brenowitz, Eliot A; Rubel, Edwin W


    Sex steroids modulate vertebrate sensory processing, but the impact of circulating hormone levels on forebrain function remains unclear. We tested the hypothesis that circulating sex steroids modulate single-unit responses in the avian telencephalic auditory nucleus, field L. We mimicked breeding or nonbreeding conditions by manipulating plasma 17β-estradiol levels in wild-caught female Gambel's white-crowned sparrows (Zonotrichia leucophrys gambelii). Extracellular responses of single neurons to tones and conspecific songs presented over a range of intensities revealed that estradiol selectively enhanced auditory function in cells that exhibited monotonic rate level functions to pure tones. In these cells, estradiol treatment increased spontaneous and maximum evoked firing rates, increased pure tone response strengths and sensitivity, and expanded the range of intensities over which conspecific song stimuli elicited significant responses. Estradiol did not significantly alter the sensitivity or dynamic ranges of cells that exhibited non-monotonic rate level functions. Notably, there was a robust correlation between plasma estradiol concentrations in individual birds and physiological response properties in monotonic, but not non-monotonic neurons. These findings demonstrate that functionally distinct classes of anatomically overlapping forebrain neurons are differentially regulated by sex steroid hormones in a dose-dependent manner.

  5. Characterization of rat apical tissues in different root development stage.

    Xu, Lin; Yang, Zhenhua; Jin, Fang; Duan, Yinzhong; Jin, Yan


    In this study, we try to compare the histological characteristics and the odontogenic capability of apical tissues (AT) at different root development stages of rat molar teeth. AT of mandibular first molars from 8-day-old, 21-day-old, and 35-day-old Sprague-Dawley rats were selected as being representative of root-initiating, root-forming, and root-completing stages, respectively. Cell counting, flow cytometry assays, alkaline phosphatase activity, alizarin red staining, and reverse transcription polymerase chain reaction were performed to assess the proliferation and mineralization potential of apical tissue cells at different stages of root development in vitro. In vivo transplantation of apical tissue cells combined with ceramic bovine bone was used to characterize the differentiation capacity. It was shown that there was a structurally and functionally dynamic change in the apical tissue of developing tooth root of rats, of which the unique developmental potential will reduce gradually with the ending up of root development. The AT of root-initiating and root-forming stage exhibited much higher proliferation and tissue-regenerative capacity than those of root-completing stage. Our present results indicate that the apical tissue, with the sustainable developmental ability throughout almost the whole process of tooth development, can yet be regarded as a competent candidate source for root/periodontal tissues regeneration.

  6. Behavioural consequences of hypergravity in developing rats

    Bouet, [No Value; Wubbels, RJ; de Jong, HAA; Gramsbergen, A


    Gravity represents a stable reference for the nervous system. When the individual is increasing in size and weight, gravity may influence several aspects of the sensory and motor developments. To clarify this role, we studied age-dependent modifications of several exteroceptive and proprioceptive

  7. Behavioural consequences of hypergravity in developing rats

    Bouet, [No Value; Wubbels, RJ; de Jong, HAA; Gramsbergen, A


    Gravity represents a stable reference for the nervous system. When the individual is increasing in size and weight, gravity may influence several aspects of the sensory and motor developments. To clarify this role, we studied age-dependent modifications of several exteroceptive and proprioceptive re

  8. Radiation-induced apoptosis in developing fetal rat cerebral cortex

    Chung, Woong Ki; Nam, Taek Keun; Lee, Min Cheol; Ahn, Sung Ja; Song, Ju Young; Park, Seung Jin; Nah, Byung Sik [College of Medicine, Chonnam National Univ., Gwangju (Korea, Republic of)


    The study was performed to investigate apoptosis by radiation in the developing fetal rat brain. Fetal brains were irradiated in utero between the 17th and 19th days of fetal life(E17-19) by linear accelerator. A dose of irradiation ranging from 1 Gy to 4 Gy was used to evaluate dose dependency. To test time dependency the rats were irradiated with 2 Gy and then the fetal brain specimens were removed at variable time course; 1, 3, 6, 12 and 24 hours after the onset of irradiation. Immunohistochemical staining using in situ TdT-mediated dUTP nick end labelling (TUNEL) technique was used for apoptotic cells. The cerebral cortex, including three zones of cortical zone (CZ), intermediate zone (IZ), and ventricular zone (VZ), was examined. TUNEL positive cells revealed typical features of apoptotic cells under light microscope in the fetal rat cerebral cortex. Apoptotic cells were not found in the cerebral cortex of non-irradiated fetal rats, but did appear in the entire cerebral cortex after 1 Gy irradiation, and were more extensive at the ventricular and intermediate zones than at the cortical zone. The extent of apoptosis was increased with increasing doses of radiation. Apoptosis reached the peak at 6 hours after the onset of 2 Gy irradiation and persisted until 24 hours. Typical morphologic features of apoptosis by irradiation were observed in the developing fetal rat cerebral cortex. It was more extensive at the ventricular and intermediate zones than at the cortical zone, which suggested that stem cells or early differentiating cells are more radiosensitive than differentiated cells of the cortical zone.

  9. Shh and Gli3 regulate formation of the telencephalic-diencephalic junction and suppress an isthmus-like signaling source in the forebrain.

    Rash, Brian G; Grove, Elizabeth A


    In human holoprosencephaly (HPE), the forebrain does not separate fully into two hemispheres. Further, the border between the telencephalon and diencephalon, the telencephalic/diencephalic junction (TDJ), is often indistinct, and the ventricular system can be blocked at the third ventricle, creating a forebrain 'holosphere'. Mice deficient in Sonic Hedgehog (Shh) have previously been described to show HPE and associated cyclopia. Here we report that the third ventricle is blocked in Shh null mutants, similar to human HPE, and that characteristic telencephalic and diencephalic signaling centers, the cortical hem and zona limitans intrathalamica (ZLI), are merged, obliterating the TDJ. The resulting forebrain holosphere comprises Foxg1-positive telencephalic- and Foxg1-negative diencephalic territories. Loss of one functional copy of Gli3 in Shh nulls rescues ventricular collapse and substantially restores the TDJ. Characteristic regional gene expression patterns are rescued on the telencephalic side of the TDJ but not in the diencephalon. Further analysis of compound Shh;Gli3 mutants revealed an unexpected type of signaling center deregulation. In Shh;Gli3 mutants, adjacent rings of Fgf8 and Wnt3a expression are induced in the diencephalon at the ZLI, reminiscent of the Fgf8/Wnt1-expressing isthmic organizer. Neither Shh nor Gli3 single mutants show this forebrain double ring of Fgf/Wnt expression; thus both Shh and Gli3 are independently required to suppress it. Adjacent tissue is not respecified to a midbrain/hindbrain fate, but shows overgrowth, consistent with ectopic mitogen expression. Our observations indicate that the separation of the telencephalon and diencephalon depends on interactions between Shh and Gli3, and, moreover, demonstrate that both Shh and Gli3 suppress a potential Fgf/Wnt signaling source in the forebrain. That optional signaling centers are actively repressed in normal development is a striking new insight into the processes of vertebrate

  10. Variations in dietary iron alter behavior in developing rats.

    Piñero, D; Jones, B; Beard, J


    Iron deficiency in children is associated with retardation in growth and cognitive development, and the effects on cognition may be irreversible, even with treatment. Excessive iron has also been associated with neurological disease, especially in reference to the increased iron content in the brains of Alzheimer's disease and Parkinson's disease patients. This study evaluated the effects of dietary iron deficiency and excess iron on physical activity in rats. The animal model used is developmentally sensitive and permits control of the timing as well as the duration of the nutritional insult. Hence, to study the effects of early, late and long-term iron deficiency or excess iron (supplementation), rats were either made iron deficient or supplemented on postnatal day (PND) 10-21, PND 21-35 and PND 10-35. Some iron-deficient rats were iron repleted between PND 21-35. Different measures of motor activity were taken at PND 14, 17, 20, 27 and 34. Iron-deficient and iron-supplemented rats showed decreased activity and stereotypic behavior; this was apparent for any onset and duration of the nutritional insult. Recovery from iron deficiency did not normalize these functional variables, showing that the deleterious effects of early iron deficiency persist despite subsequent adequate treatment. This study demonstrates that iron deficiency in early life leads to irreversible behavioral changes. The biological bases for these behavioral alterations are not readily apparent, because iron therapy rapidly reverses the iron losses in all brain regions.

  11. Changes of the nitric oxide synthase-positive and nestin-positive neurons in the basal forebrain of castrated adult male rats following androgen replacement therapy%雄激素替代治疗后去势成年雄性大鼠基底前脑一氧化氮合酶及巢蛋白阳性神经元的变化

    郭灵; 汪华侨; 袁群芳; 姚志彬


    BACKGROUND: The neurons in the medial septum (MS), vertical and horizontal limbs of diagonal band of Broca (vDB and hDB) in the basal forebrain contain rich androgen receptors (ARs) and estrogen receptors (ERs) by which androgen and estrogen can act dramatically on the neurons in the basal forebrain, subsequently affecting learning and memory processes.OBJECTIVE: To qualitatively and quantitatively investigate the effects of androgen replacement therapy on the nitric oxide synthase (NOS)-positive and nestin-positive neurons in the MS, vDB and hDB of castrated adult male rats.DESIGN: A randomly controlled study on experimental animals.SETTING: Department of Anatomy and Brain Research Laboratory of Zhngshan Medical College of Sun Yat-sen University.MATERIALS: The experiment was performed at Department of Anatomy and Brain Research Laboratory of Zhongshan Medical College of Sun Yatsen University from June 2001 to June 2002. Totally twenty-eight adult male Sprague-Dawley rats were randomly divided into four groups with seven rats in each group: androgen replacement therapy for 4 weeks following 24 hours of castration (ART1), androgen replacement therapy for 2 weeks following 2 weeks of castration (ART2), vehicle replacement therapy for 4weeks following 24 hours of castration (VRT), sham-operated group (Sham).INTERVENTIONS: ① ART1 group: The castrated rats received subcutaneous injection of testosterone proprionate (25 mg/kg) dissolved in 100 μL of sterile sesame oil every other day from 10:30 am to 11:00 am for 14 times (4 weeks). ② ART2 group: The castrated rats received subcutaneous injection of testosterone proprionate with the same dosage and method as ART1 group for 7 times (2 weeks). ③ The rats in VRT group received subcutaneous injection of 100μL of sterile sesame oil for 14 times (4 weeks) by the same regime as described above. ④ Rats in Sham group only received sham-operated treatments, and testes were intact and lived for 4 weeks.MAIN OUTCOME

  12. Postnatal development of aminopeptidase (arylamidase) activity in rat brain.

    de Gandarias, J M; Ramírez, M; Zulaica, J; Iribar, C; Casis, L


    Changes in the activities of Leu- and Arg-arylamidase in rat frontal and parietal cortices and the subcortical area (including thalamus, hypothalamus, and striatum) were examined in the 2nd, 4th, 8th, 12th, and 24th weeks of life. Average levels found in the subcortical region were greater than those in the cortical areas. The most marked changes in enzymatic activity in the course of brain development were found in the subcortical structure. Leu-arylamidase activity increased from the 2nd week up to the 8th week, returning to the 2nd week level at the 12th and 24th weeks. The maximum levels of Arg-arylamidase activity were found at the 4th and 8th weeks. These data suggest that proteolytic activity is involved in the postnatal development of rat brain.

  13. Development of the adrenal axis in the neonatal rat

    Guillet, Ronnie [Univ. of Rochester, NY (United States)


    Plasma corticosterone and ACTH concentrations were determined in neonatal rats 1, 7, 14, and 21 days old, under a variety of experimental conditions, to obtain more information on the postnatal development of the rat hypothalamo-adrenal (HHA) axis. The results indicate that: (1) there is a diminution followed by an increase in responsiveness of the adrenal gland, but the pituitary response to direct hormonal stimulation is unchanged during the first three postnatal weeks; (2) continued stimulation of the adrenal by ACTH or of the central nervous system (CNS) or hypothalamus by corticosterone is necessary during early postnatal development to allow normal maturation of the HHA axis; and (3) feedback inhibition is operative by birth, at least to a moderate degree. Taken together, the studies suggest that both the adrenal and pituitary glands are potentially functional at birth, but that the hypothalamic and CNS mediators of the stress response are not mature until at least the second or third postnatal week. (ERB)

  14. Whole-Brain Monosynaptic Afferent Inputs to Basal Forebrain Cholinergic System

    Hu, Rongfeng; Jin, Sen; He, Xiaobin; Xu, Fuqiang; Hu, Ji


    The basal forebrain cholinergic system (BFCS) robustly modulates many important behaviors, such as arousal, attention, learning and memory, through heavy projections to cortex and hippocampus. However, the presynaptic partners governing BFCS activity still remain poorly understood. Here, we utilized a recently developed rabies virus-based cell-type-specific retrograde tracing system to map the whole-brain afferent inputs of the BFCS. We found that the BFCS receives inputs from multiple cortical areas, such as orbital frontal cortex, motor cortex, and insular cortex, and that the BFCS also receives dense inputs from several subcortical nuclei related to motivation and stress, including lateral septum, central amygdala, paraventricular nucleus of hypothalamus, dorsal raphe, and parabrachial nucleus. Interestingly, we found that the BFCS receives inputs from the olfactory areas and the entorhinal–hippocampal system. These results greatly expand our knowledge about the connectivity of the mouse BFCS and provided important preliminary indications for future exploration of circuit function. PMID:27777554

  15. GRK5 Deficiency Leads to Selective Basal Forebrain Cholinergic Neuronal Vulnerability.

    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


    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.

  16. Expression of AT2 receptors in the developing rat fetus.

    Grady, E F; Sechi, L. A.; Griffin, C A; Schambelan, M.; Kalinyak, J E


    Angiotensin II is known primarily for its effects on blood pressure and electrolyte homeostasis, but recent studies suggest that angiotensin II may play a role in the regulation of cellular growth. This study was undertaken to identify the angiotensin II receptor subtypes expressed during fetal and neonatal development and to characterize their cellular localization. Using an in situ receptor binding assay on sagittal frozen sections of fetal and neonatal rats, bound 125I-[Sar1,Ile8]-angioten...


    ZHANG Qian-shen; CHANG Li-wen; LIU Han-chu; RONG Zhi-hu; CHEN Hong-bing


    Objective To investigate the temporal expression of Notch receptors in developing lungs of rats and to explore the regulating role of Notch in lung development. Methods We studied the expression of Notch1,2,3 isforms in embryonic days 18,20,21 and postnatal days 1,4,7,14, 21 rat lungs. Six rats of each group were used to assess lung histologic changes by HE staining and expression of Notch in lungs by immunohistochemistry. Total RNA was extracted by Trizol reagent from the frozen lung tissues. mRNA levels of Notch were measured by reverse transcription polymerase chain reaction (RT-PCR). Results It is showed that Notch1-3 mainly localized in the airway surface epithelium、alveolar epithelium during the psdueoglandular stage, and reached the peaks at canalicular period. The expression patterns of Notch1-3 were changed with the fetal age. Conclusion These results support multiple roles for Notch1,2,and 3 receptor activation during lung development, probably not only modulating the process of branching morphogenesis but also involved in determining the cell differentiation fate in fetal alveolar epithelium.

  18. Passive stiffness of rat skeletal muscle undernourished during fetal development

    Ana Elisa Toscano


    Full Text Available OBJECTIVES: The aim of the study was to investigate the effect of fetal undernutrition on the passive mechanical properties of skeletal muscle of weaned and young adult rats. INTRODUCTION: A poor nutrition supply during fetal development affects physiological functions of the fetus. From a mechanical point of view, skeletal muscle can be also characterized by its resistance to passive stretch. METHODS: Male Wistar rats were divided into two groups according to their mother's diet during pregnancy: a control group (mothers fed a 17% protein diet and an isocaloric low-protein group (mothers fed a 7.8% protein diet. At birth, all mothers received a standardized meal ad libitum. At the age of 25 and 90 days, the soleus muscle and extensor digitorum longus (EDL muscles were removed in order to test the passive mechanical properties. A first mechanical test consisted of an incremental stepwise extension test using fast velocity stretching (500 mm/s enabling us to measure, for each extension stepwise, the dynamic stress (σd and the steady stress (σs. A second test consisted of a slow velocity stretch in order to calculate normalized stiffness and tangent modulus from the stress-strain relationship. RESULTS: The results for the mechanical properties showed an important increase in passive stiffness in both the soleus and EDL muscles in weaned rat. In contrast, no modification was observed in young adult rats. CONCLUSIONS: The increase in passive stiffness in skeletal muscle of weaned rat submitted to intrauterine undernutrition it is most likely due to changes in muscle passive stiffness.

  19. Influence of age and immunization on development of gingivitis in rats

    Lekic, P; Klausen, B; Friis-Hasché, E


    To study the effect of age and antigenic priming on the development of gingivitis, 33 healthy rats were placed in contact with Streptococcus mutans, Actinomyces viscosus, Fusobacterium nucleatum, and Bacteroides gingivalis. On days 0, 3, 7, and 14 after inoculation, the gingival condition...... was judged clinically and histologically, and serum antibody titers against the bacteria were measured. The rats were divided into three groups: 1 month old, 3 months old, and 3 months old immunized. None of the young rats developed gingivitis during the experiment, whereas half of the adult and all...... of the adult immunized rats bled on probing on days 7 and 14. In general, antibody titers against the bacteria were low in young rats, moderate in adult rats, and high in adult immunized rats. These results indicate that adult rats react stronger to plaque antigens than young rats and that previous contact...

  20. Development of neuropeptide Y-mediated heart innervation in rats.

    Masliukov, Petr M; Moiseev, Konstantin; Emanuilov, Andrey I; Anikina, Tatyana A; Zverev, Alexey A; Nozdrachev, Alexandr D


    Neuropeptide Y (NPY) plays a trophic role in the nervous and vascular systems and in cardiac hypertrophy. However, there is no report concerning the expression of NPY and its receptors in the heart during postnatal development. In the current study, immunohistochemistry and Western blot analysis was used to label NPY, and Y1R, Y2R, and Y5R receptors in the heart tissue and intramural cardiac ganglia from rats of different ages (newborn, 10 days old, 20 days old, 30 days old, 60 days old, 1 year old, and 2 years old).The obtained data suggest age-dependent changes of NPY-mediated heart innervation. The density of NPY-immunoreactive (IR) fibers was the least in newborn animals and increased in the first 20 days of life. In the atria of newborn and 10-day-old rats, NPY-IR fibers were more abundant compared with the ventricles. The vast majority of NPY-IR fibers also contained tyrosine hydroxylase, a key enzyme in catecholamine synthesis.The expression of Y1R increased between 10 and 20 days of life. Faint Y2R immunoreactivity was observed in the atria and ventricles of 20-day-old and older rats. In contrast, the highest level of the expression of Y5R was found in newborn pups comparing with more adult rats. All intramural ganglionic neurons were also Y1R-IR and Y5R-IR and Y2R-negative in all studied animals.Thus, the increasing of density of NPY-containing nerve fibers accompanies changes in relation of different subtypes of NPY receptors in the heart during development.


    This work describes the development of a physiologically based pharmacokinetic (PBPK) model of deltamethrin, a type II pyrethroid, in the developing male Sprague-Dawley rat. Generalized Michaelis-Menten equations were used to calculate metabolic rate constants and organ weights ...

  2. Immunohistochemical evidence of Muc1 expression during rat embryonic development

    E. Lacunza


    Full Text Available During embryonic development, studies on mouse and human embryos have established that Muc1/MUC1 expression coincides with the onset of epithelial sheet and glandular formation. This study aimed therefore at evaluating the temporal and spatial expression of Muc1 at different stages of rat development. In this experiment, 80 animals were included: 64 rat foetuses at 13, 14, 15, 16, 17, 18, 19 and 20 days of gestation from pregnant females (WKAH/Hok, 8 embryos each stage. Standard immunohistochemistry was performed using anti-MUC1 cytoplasmic tail polyclonal antibody (CT33. The reaction was considered positive when more than 5% of the cells were stained; reaction patterns were: L = linear, membrane, C = cytoplasmic and M = mixed; nuclear staining was also recorded. Intensity was graded as negative (-, low (+, moderate (++ and strong (+++. Muc1 expression was observed with a low intensity on 13th day (13 d in the stomach, lung and kidney; at 14 d, small intestine and pancreas were also reactive; at 16 d, liver and esophagus and at 18 d, trachea and salivary glands. During the development, intensity increased while the pattern of expression changed: at the first days of gestation, it was predominantly linear and apical while during further development an increase in cytoplasmic expression was observed. Trachea, stomach, kidney and lung epithelia were the more reactive tissues. In specimens belonging to neonates and adults, all tissues analyzed showed similar Muc1 expression. The findings of this study assess that Muc1 is highly expressed in the epithelial rat embryonic development.

  3. Intestinal lactase synthesis during postnatal development in the rat

    Jonas, M.M.; Montgomery, R.K.; Grand, R.J.


    To elucidate the mechanism of the developmental decline in intestinal lactase activity at the weaning, the authors examined lactase synthesis in suckling and adult rats. Lactase was purified to homogeneity from pooled intestines of newborn rats and used to raise a monospecific antibody. Using this antibody, they developed a quantitative immunoprecipitation assay for lactase. Intestinal microvillus membrane proteins were labeled in 15-day and adult rats by intraluminal pulse-chase with TH-leucine, and newly synthesized lactase quantified by immunoprecipitation. When lactase synthesis was expressed as the quantity of microvillus membrane lactase synthesized relative to total microvillus membrane protein synthesized, a significantly greater proportion of TH-leucine incorporation into lactase was demonstrated in the suckling animals. No structural differences between newly synthesized suckling and adult lactase were observed when they were compared by SDS-polyacrylamide gel electrophoresis and fluorography. These data suggest that a change in the rate of lactase synthesis plays a role in the postweaning decline in enzyme activity.

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

    Irene eAvila


    Full Text Available 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.

  5. Development of diabetes-induced acidosis in the rat retina.

    Dmitriev, Andrey V; Henderson, Desmond; Linsenmeier, Robert A


    We hypothesized that the retina of diabetic animals would be unusually acidic due to increased glycolytic metabolism. Acidosis in tumors and isolated retina has been shown to lead to increased VEGF. To test the hypothesis we have measured the transretinal distribution of extracellular H(+) concentration (H(+)-profiles) in retinae of control and diabetic dark-adapted intact Long-Evans rats with ion-selective electrodes. Diabetes was induced by intraperitoneal injection of streptozotocin. Intact rat retinae are normally more acidic than blood with a peak of [H(+)]o in the outer nuclear layer (ONL) that averages 30 nM higher than H(+) in the choroid. Profiles in diabetic animals were similar in shape, but diabetic retinae began to be considerably more acidic after 5 weeks of diabetes. In retinae of 1-3 month diabetics the difference between the ONL and choroid was almost twice as great as in controls. At later times, up to 6 months, some diabetics still demonstrated abnormally high levels of [H(+)]o, but others were even less acidic than controls, so that the average level of acidosis was not different. Greater variability in H(+)-profiles (both between animals and between profiles recorded in one animal) distinguished the diabetic retinae from controls. Within animals, this variability was not random, but exhibited regions of higher and lower H(+). We conclude that retinal acidosis begins to develop at an early stage of diabetes (1-3 months) in rats. However, it does not progress, and the acidity of diabetic rat retina was diminished at later stages (3-6 months). Also the diabetes-induced acidosis has a strongly expressed local character. As result, the diabetic retinas show much wider variability in [H(+)] distribution than controls. pH influences metabolic and neural processes, and these results suggest that local acidosis could play a role in the pathogenesis of diabetic retinopathy. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Convulsions and inhibition of glutamate decarboxylase by pyridoxal phosphate-gamma-glutamyl hydrazone in the developing rat.

    Massieu, L; Rivera, A; Tapia, R


    We have previously shown that in the adult rat the inhibition of brain glutamate decarboxylase (GAD) activity by pyridoxal phosphate-gamma-glutamyl hydrazone (PLPGH) administration does not result in convulsions, whereas in the adult mouse intense convulsions invariably occur. In the present study we report that, surprisingly, immature rats from 2 to 20 days of age treated with PLPGH (80 mg/kg) showed generalized tonic-clonic convulsions, whereas no convulsions at all were present in 30 days-old or older rats. GAD activity, measured by enzymic determination of GABA formed in forebrain homogenates, was inhibited by about 60% at the time of convulsions in 15 days-old and younger rats, whereas the inhibition was between 40 and 50% in older animals. The addition of the coenzyme pyridoxal 5'-phosphate to the incubation medium completely reversed this inhibition. In all treated animals GABA levels were lower compared to controls. The results indicate that the susceptibility of GAD in vivo to a diminished cofactor concentration decreases with age. It seems possible that changes in the expression of enzyme forms are reflected in developmental variations in the susceptibility to seizures induced by vitamin B6 depletion, but alterations of other B6-dependent biochemical pathways cannot be discarded.

  7. Effect of lead acetate on neurobehavioral development of rats

    Mello C.F.


    Full Text Available We investigated the effects of lead exposure during the pre- and postnatal period on the neurobehavioral development of female Wistar rats (70-75 days of age, 120-150 g using a protocol of lead intoxication that does not affect weight gain. Wistar rats were submitted to lead acetate intoxication by giving their dams 1.0 mM lead acetate. Control dams received deionized water. Growth and neuromotor development were assessed by monitoring daily the following parameters in 20 litters: body weight, ear unfolding, incisor eruption, eye opening, righting, palmar grasp, negative geotaxis, cliff avoidance and startle reflex. Spontaneous alternation was assessed on postnatal day 17 using a T maze. The animals' ability to equilibrate on a beaker rim was measured on postnatal day 19. Lead intoxication was confirmed by measuring renal, hepatic and cerebral lead concentration in dams and litters. Lead treatment hastened the day of appearance of the following parameters: eye opening (control: 13.5 ± 0.6, N = 88; lead: 12.9 ± 0.6, N = 72; P<0.05, startle reflex (control: 13.0 ± 0.8, N = 88; lead: 12.0 ± 0.7, N = 72; P<0.05 and negative geotaxis. On the other hand, spontaneous alternation performance was hindered in lead-exposed animals (control: 37.6 ± 19.7; lead: 57.5 ± 28.3% of alternating animals; P<0.05. These results suggest that lead exposure without concomitant undernutrition alters rat development, affecting specific subsets of motor skills.

  8. Development of heart failure assessed by tissue Doppler imaging in hypertensive Dahl rats

    宮田, 聖子||ミヤタ, セイコ||Miyata, Seiko; 山田, 亜紀||ヤマダ, アキ||Yamada, Aki||Iwami Yamada, Aki; 橋本, 克徳||ハシモト, カツノリ||Hashimoto, Katsunori; 黒木, 祥子||クロキ, ショウコ||Kuroki, Shoko; 岩本, 隆司||イワモト, タカシ||Iwamoto, Takashi; 野田, 明子||ノダ, アキコ||Noda, Akiko


    Objective: Tissue Doppler imaging (TDI) has been recognized as a useful tool to assess regional myocardial function. The purpose of this study was to evaluate the development of heart failure in hypertensive Dahl rats using echocardiography with TDI. Methods: Dahl salt-sensitive (DS) rats were placed on 8% NaCl diet from 7 weeks old. As an age-matched control, DS rats were consistently placed on normal diet. In these rats, echocardiography was performed successively. We evaluated interventric...

  9. Ovarian innervation develops before initiation of folliculogenesis in the rat.

    Malamed, S; Gibney, J A; Ojeda, S R


    Sympathetic neurotransmitters have been shown to be present in the ovary of the rat during early postnatal development and to affect steroidogenesis before the ovary becomes responsive to gonadotropins, and before the first primordial follicles are formed. This study was undertaken to determine if development of the ovarian innervation is an event that antedates the initiation of folliculogenesis in the rat, Rattus norvegicus. Serial sections of postnatal ovaries revealed a negligible frequency of follicles 24 h after birth (about 1 primordial follicle per ovary). Twelve hours later there were about 500 follicles per ovary, a number that more than doubled to about 1300 during the subsequent 12 h, indicating that an explosive period of follicular differentiation occurs between the end of postnatal days 1 and 2. Electron microscopy demonstrated that before birth the ovaries are already innervated by fibers containing clear and dense-core vesicles. Immunohistochemistry performed on either fetal (day 19) or newborn (less than 15h after birth) ovaries showed the presence of catecholaminergic nerves, identified by their content of immunoreactive tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis. While some of these fibers innervate blood vessels, others are associated with primordial ovarian cells, thereby suggesting their participation in non-vascular functions. Since prefollicular ovaries are insensitive to gonadotropins, the results suggest that the developing ovary becomes subjected to direct neurogenic influences before it acquires responsiveness to gonadotropins.

  10. Lesions of the basal forebrain cholinergic system in mice disrupt idiothetic navigation.

    Adam S Hamlin

    Full Text Available 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.

  11. Forebrain commissures and visual memory: a new approach.

    Doty, R W; Ringo, J L; Lewine, J D


    The primary purpose of these exploratory experiments was to determine: (1) whether the forebrain commissures can provide full accessibility of the mnemonic store to either hemisphere when the taks involves memory for 'events' (images) rather than, as in essentially all previous tests on split-brain animals, memory for 'rules' (discrimination habits); and (2) whether the anterior commissure (AC) alone is capable of such function. Macaques, with optic chiasm transected to allow limitation of direct visual input to one or the other hemisphere, were trained on tasks requiring recognition of previously viewed photographic slides. For one task, delayed-matching-to-sample (DMTS), the animal was presented with a 'sample' image, and then 0-15s later was required to choose that image in preference to a second image concurrently displayed. On the other task, running recognition (RR), a series of images was presented, some of which were repetitions of images previously seen in that session, and the animal was required to signal its recognition of these repetitions. For either task the initial presentation could be made to one eye and hemisphere, and subsequent recognition required of the other. In such circumstance, if all forebrain commissures were divided, such interhemispheric recognition was no longer possible. For the DMTS task if either the AC or 5 mm of the splenium of the corpus callosum were available, interhemispheric recognition was basically equivalent to that using the same eye and hemisphere. However, interhemispheric accuracy with the RR task, while well above chance levels, was consistently inferior to that achieved intrahemispherically when complex scenes or objects were viewed. This is probably a consequence mostly of the differing visual fields of the two eyes, since interhemispheric accuracy was greatly improved by use of images having approximately identical right and left halves. No consistent hemispheric specialization nor difference in direction of

  12. Wistar-Kyoto Female Rats Are More Susceptible to Develop Sugar Binging: A Comparison with Wistar Rats.

    Papacostas-Quintanilla, Helena; Ortiz-Ortega, Víctor Manuel; López-Rubalcava, Carolina


    The hedonic component of the feeding behavior involves the mesolimbic reward system and resembles addictions. Nowadays, the excessive consumption of sucrose is considered addictive. The Wistar-Kyoto (WKY) rat strain is prone to develop anxiety and addiction-like behavior; nevertheless, a lack of information regarding their vulnerability to develop sugar binging-like behavior (SBLB) and how it affects the reward system persist. Therefore, the first aim of the present study was to compare the different predisposition of two rat strains, Wistar (W) and WKY to develop the SBLB in female and male rats. Also, we studied if the SBLB-inducing protocol produces changes in anxiety-like behavior using the plus-maze test (PMT) and, analyzed serotonin (5-HT) and noradrenaline (NA) concentrations in brain areas related to anxiety and ingestive behavior (brain stem, hypothalamus, nucleus accumbens, and amygdala). Finally, we evaluated whether fluoxetine, a drug that has been effective in reducing the binge-eating frequency, body weight, and severity of binge eating disorder, could also block this behavior. Briefly, WKY and W female rats were exposed to 30% sucrose solution (2 h, 3 days/week for 4 weeks), and fed up ad libitum. PMT was performed between the last two test periods. Immediately after the last test where sucrose access was available, rats were decapitated and brain areas extracted for high-performance liquid chromatography analysis. The results showed that both W and WKY female and male rats developed the SBLB. WKY rats consumed more calories and ingested a bigger amount of sucrose solution than their W counterpart. This behavior was reversed by using fluoxetine, rats exposed to the SBLB-inducing protocol presented a rebound effect during the washout period. On female rats, the SBLB-inducing protocol induced changes in NA concentrations on WKY, but not on W rats. No changes were found in 5-HT levels. Finally, animals that developed SBLB showed increased anxiety

  13. Keratoepithelioplasty in rat: development of a model and histological study.

    Amano, S; Sawa, M; Ishii, Y


    A model for keratoepithelioplasty (KEP) was developed using the Lewis rat, and histological studies were performed using this model. The entire corneal epithelium was removed mechanically and a 1.5-mm width of the conjunctiva including the limbus was excised. An oval corneal lamellar graft (3 x 1.5 mm) with an intact epithelium taken from another Lewis rat was transplanted on the denuded limbus. Biomicroscopic observations showed much less vascular invasion in the part of the cornea adjacent to the lenticule than in other parts of the cornea, and the cornea remained clear adjacent to the lenticule. Histologically, a few vessels were observed in the corneal stroma under the lenticule. Epithelial cells on the lenticule specimens showed histological characteristics of the corneal epithelium. These findings indicate that one of the functions of KEP is to block neovascularization in the newly developing corneal epithelium by transplanting the lenticule between the corneal epithelium and conjunctival vessels. The present study also confirmed that this model is useful in the research of the pathophysiological mechanism of KEP.

  14. Neurobehavioral Assessment of Rats Exposed to Yttrium Nitrate during Development

    LI Chen Xi; MA Chuan; FANG Hai Qin; ZHI Yuan; YU Zhou; XU Hai Bin; JIA Xu Dong


    Objective The aim of this study was to assess the effects of yttrium nitrate on neurobehavioral development in Sprague-Dawley rats. Methods Dams were orally exposed to 0, 5, 15, or 45 mg/kg daily of yttrium nitrate from gestation day (GD) 6 to postnatal day (PND) 21. Body weight and food consumption were monitored weekly. Neurobehavior was assessed by developmental landmarks and reflexes, motor activity, hot plate, Rota-rod and cognitive tests. Additionally, brain weights were measured on PND 21 and 70. Results No significant difference was noted among all groups for maternal body weight and food consumption. All yttrium-exposed offspring showed an increase in body weight on PND 21;however, no significant difference in body weight for exposed pups versus controls was observed 2 weeks or more after the yttrium solution was discontinued. The groups given 5 mg/kg daily decreased significantly in the duration of female forelime grip strength and ambulation on PND 13. There was no significant difference between yttrium-exposed offspring and controls with respect to other behavioral ontogeny parameters and postnatal behavioral test results. Conclusion Exposure of rats to yttrium nitrate in concentrations up to 45 mg/kg daily had no adverse effects on their neurobehavioral development.

  15. Splenotoxic effect of radiographic developer effluent on Wistar rats

    Anthony C. Ugwu


    Results: Normal spleen histology was observed in the control group. In contrast, tissue degeneration and necrosis; lymphocytic infiltration as well as reduction of splenic follicles were observed in some of the test groups (IIA, IIB and IIIA. Interestingly, the toxic effects of the developer effluent on group IIIB administered with higher dose for a longer period of 28 days were not as severe as observed in the other test groups. Conclusions: The present study which indicated adverse effects of exposures to sub-lethal doses of developer effluent on Wistar rats' spleen tissues suggests the need for proper management and disposal of radiographic effluents. [Int J Res Med Sci 2016; 4(5.000: 1625-1631

  16. Retake the Center Stage——New Development of Rat Genetics

    Sushuang Zheng; Kindiya Geghman; Sushila Shenoy; Chenjian Li


    The rat is a powerful model for the study of human physiology and diseases,and is preferred by physiologists,neuroscientists and toxicologists.However,the lack of robust genetic modification tools has severely limited the generation of rat genetic models over the last two decades.In the last few years,several gene-targeting strategies have been developed in rats using N-ethyl-N-nitrosourea (ENU),transposons,zinc-finger nucleases (ZFNs),bacterial artificial chromosome (BAC) mediated transgenesis,and recently established rat embryonic stem (ES) cells.The development and improvement of these approaches to genetic manipulation have created a bright future for the use of genetic rat models in investigations of gene function and human diseases.Here,we summarize the strategies used for rat genetic manipulation in current research.We also discuss BAC transgenesis as a potential tool in rat transgenic models.

  17. Interstrain Differences in the Development of Pyometra after Estrogen Treatment of Rats

    Brossia, Lisa Jane; Roberts, Christopher Sean; Lopez, Jennifer T; Bigsby, Robert M; Dynlacht, Joseph R


    This case report describes the unanticipated development of pyometra in Brown Norway rats after treatment with estrogen. Sprague Dawley and Brown Norway rats were ovariectomized and randomly assigned to treatment groups (subcutaneous implantation of either a capsule containing 20 mg 17β-estradiol or an empty capsule, as a control). After irradiation of only the right eye, the rats were followed for several months in an attempt to determine the effects of estrogen on radiation cataractogenesis and investigate potential strain differences in this phenomenon. However, all Brown Norway rats that received estradiol treatment developed pyometra, whereas none the Sprague Dawley or control Brown Norway rats did. This case demonstrates the potential adverse effects of exogenous estrogen therapy, which are strain-specific in the rat. Caution should be taken when designing estrogen-related experiments involving Brown Norway rats and other potentially sensitive strains. PMID:19807973

  18. Probing forebrain to hindbrain circuit functions in Xenopus.

    Kelley, Darcy B; Elliott, Taffeta M; Evans, Ben J; Hall, Ian C; Leininger, Elizabeth C; Rhodes, Heather J; Yamaguchi, Ayako; Zornik, Erik


    The vertebrate hindbrain includes neural circuits that govern essential functions including breathing, blood pressure and heart rate. Hindbrain circuits also participate in generating rhythmic motor patterns for vocalization. In most tetrapods, sound production is powered by expiration and the circuitry underlying vocalization and respiration must be linked. Perception and arousal are also linked; acoustic features of social communication sounds-for example, a baby's cry-can drive autonomic responses. The close links between autonomic functions that are essential for life and vocal expression have been a major in vivo experimental challenge. Xenopus provides an opportunity to address this challenge using an ex vivo preparation: an isolated brain that generates vocal and breathing patterns. The isolated brain allows identification and manipulation of hindbrain vocal circuits as well as their activation by forebrain circuits that receive sensory input, initiate motor patterns and control arousal. Advances in imaging technologies, coupled to the production of Xenopus lines expressing genetically encoded calcium sensors, provide powerful tools for imaging neuronal patterns in the entire fictively behaving brain, a goal of the BRAIN Initiative. Comparisons of neural circuit activity across species (comparative neuromics) with distinctive vocal patterns can identify conserved features, and thereby reveal essential functional components.

  19. A Basal Forebrain Site Coordinates the Modulation of Endocrine and Behavioral Stress Responses via Divergent Neural Pathways

    Johnson, Shane B.; Emmons, Eric B.; Anderson, Rachel M.; Glanz, Ryan M.; Romig-Martin, Sara A.; Narayanan, Nandakumar S.; LaLumiere, Ryan T.


    The bed nuclei of the stria terminalis (BST) are critically important for integrating stress-related signals between the limbic forebrain and hypothalamo-pituitary-adrenal (HPA) effector neurons in the paraventricular hypothalamus (PVH). Nevertheless, the circuitry underlying BST control over the stress axis and its role in depression-related behaviors has remained obscure. Utilizing optogenetic approaches in rats, we have identified a novel role for the anteroventral subdivision of BST in the coordinated inhibition of both HPA output and passive coping behaviors during acute inescapable (tail suspension, TS) stress. Follow-up experiments probed axonal pathways emanating from the anteroventral BST which accounted for separable endocrine and behavioral functions subserved by this cell group. The PVH and ventrolateral periaqueductal gray were recipients of GABAergic outputs from the anteroventral BST that were necessary to restrain stress-induced HPA activation and passive coping behavior, respectively, during TS and forced swim tests. In contrast to other BST subdivisions implicated in anxiety-like responses, these results direct attention to the anteroventral BST as a nodal point in a stress-modulatory network for coordinating neuroendocrine and behavioral coping responses, wherein impairment could account for core features of stress-related mood disorders. SIGNIFICANCE STATEMENT Dysregulation of the neural pathways modulating stress-adaptive behaviors is implicated in stress-related psychiatric illness. While aversive situations activate a network of limbic forebrain regions thought to mediate such changes, little is known about how this information is integrated to orchestrate complex stress responses. Here we identify novel roles for the anteroventral bed nuclei of the stria terminalis in inhibiting both stress hormone output and passive coping behavior via divergent projections to regions of the hypothalamus and midbrain. Inhibition of these projections

  20. Sleep-wake sensitive mechanisms of adenosine release in the basal forebrain of rodents: an in vitro study.

    Robert Edward Sims

    Full Text Available 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.

  1. Development of exoskeletal robotic limbs for a rat controlled by neural signals based on a vehicular neuro-robotic platform RatCar.

    Fukayama, Osamu; Otsuka, Hiroshi; Hashimoto, Ryuta; Suzuki, Takafumi; Mabuchi, Kunihiko


    A pair of exoskeletal limbs for a rat has been developed based on a vehicular Brain-Machine Interface "Rat-Car". The "RatCar" is a whole-body motor prosthesis system for a rat developed by the authors, estimating locomotion velocity according to neural signals pattern to move the rat body by the vehicle instead of its original limbs. In this paper, exoskeletal limbs have displaced the wheels for more natural modality of body control. The system was tested by applying peripheral nerve signals from a behaving rat.

  2. Noradrenaline neuron degeneration contributes to motor impairments and development of L-DOPA-induced dyskinesia in a rat model of Parkinson's disease.

    Shin, Eunju; Rogers, James R.; Devoto, Paola; Björklund, Anders; Carta, Manolo


    Parkinson's disease (PD) is characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra. However, studies of post-mortem PD brains have shown that not only DA neurons but also the noradrenergic (NA) neurons in the locus coeruleus degenerate, and that the NA neurodegeneration may be as profound, and also precede degeneration of the midbrain DA neurons. Previous studies in animal models of PD have suggested that loss of forebrain NA will add to the development of ...

  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.

    Bagga, V; Dunnett, S B; Fricker, R A


    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.

  4. Deletion of forebrain glycine transporter 1 enhances conditioned freezing to a reliable, but not an ambiguous, cue for threat in a conditioned freezing paradigm.

    Dubroqua, Sylvain; Singer, Philipp; Yee, Benjamin K


    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 (GlyT1) 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.

  5. The activation of cannabinoid receptors during early postnatal development reduces the expression of cell adhesion molecule L1 in the rat brain.

    Gómez, María; Hernández, Mariluz; Fernández-Ruiz, Javier


    Cannabinoid CB(1) receptors and their ligands emerge early in brain development and are abundantly expressed in certain brain regions that play key roles in processes related to cell proliferation and migration, neuritic elongation and guidance, and synaptogenesis. This would support the notion that the cannabinoid system might play a modulatory role in the regulation of these processes. We have recently presented preliminary in vivo evidence showing that this modulatory action might be exerted, among others, through regulating the levels of several key elements in these processes, such as the L1 protein. This was observed in various white matter areas of the rat forebrain. Because these preliminary in vivo experiments focused only in fetal ages, we concentrated now in the period of early postnatal development. To this end, we analyzed the effects of the cannabinoid agonist Delta(9)-tetrahydrocannabinol (Delta(9)-THC) daily administered since the 5th day of gestation on mRNA levels for L1 in different brain structures of rat neonates at different postnatal ages (PND1, PND5 and PND12). Our results revealed that Delta(9)-THC exposure affected the levels of L1 transcripts in specific brain structures only in PND1, these effects disappearing during further days. Thus, we found reduced L1-mRNA levels in grey matter regions, such as the cerebral cortex, septum nuclei, striatum, dentate gyrus and CA3 subfield of the Ammon horn. White matter areas and subventricular zones were, however, more resistant to Delta(9)-THC exposure at this postnatal age in contrast with the previous data obtained in the fetal brain. Importantly, the effects were influenced by gender of animals, since the reductions were always more marked in females than males, also in contrast with the data reported for the fetal brain. In summary, the cannabinoid system seems to modulate the levels of L1 in several brain structures during specific periods of development [late gestation (previous data) and very

  6. Electrophysiological changes of CA3 neurons and dentate granule cells following transient forebrain ischemia.

    Howard, E M; Gao, T M; Pulsinelli, W A; Xu, Z C


    The electrophysiological responses of CA3 pyramidal neurons and dentate granule (DG) cells in rat hippocampus were studied after transient forebrain ischemia using intracellular recording and staining techniques in vivo. Approximately 5 min of ischemic depolarization was induced using 4-vessel occlusion method. The spike threshold and rheobase of CA3 neurons remained unchanged up to 12 h following reperfusion. No significant change in spike threshold was observed in DG cells but the rheobase transiently increased 6-9 h after ischemia. The input resistance and time constant of CA3 neurons increased 0-3 h after ischemia and returned to control ranges at later time periods. The spontaneous firing rate in CA3 neurons transiently decreased shortly following reperfusion, while that of DG cells progressively decreased after ischemia. In CA3 neurons, the amplitude and slope of excitatory postsynaptic potentials (EPSPs) transiently decreased 0-3 h after reperfusion, and the stimulus intensity threshold for EPSPs transiently increased at the same time. No significant changes in amplitude and slope of EPSPs were observed in DG cells, but the stimulus intensity threshold for EPSPs slightly increased shortly after reperfusion. The present study demonstrates that the excitability of CA3 pyramidal neurons and DG cells after 5 min ischemic depolarization is about the same as control levels, whereas the synaptic transmission to these cells was transiently suppressed after the ischemic insult. These results suggest that synaptic transmission is more sensitive to ischemia than membrane properties, and the depression of synaptic transmission may be a protective mechanism against ischemic insults.

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

    Avila, Irene; Lin, Shih-Chieh


    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.


    Kalinchuk, Anna V.; Porkka-Heiskanen, Tarja; McCarley, Robert W.; Basheer, Radhika


    The tight coordination of biochemical and electrophysiological mechanisms underlies the homeostatic sleep pressure (HSP) produced by sleep deprivation (SD). We have reported that during SD the levels of inducible nitric oxide synthase (iNOS), extracellular nitric oxide (NO), adenosine [AD]ex, lactate [Lac]ex and pyruvate [Pyr]ex increase in the basal forebrain (BF). However, it is not clear whether all of them contribute to HSP leading to increased electroencephalogram (EEG) delta activity during non-rapid eye movement (NREM) recovery sleep (RS) following SD. Previously, we showed that NREM delta increase evident during RS depends on the presence of BF cholinergic (ChBF) neurons. Here, we investigated the role of ChBF cells in coordination of biochemical and EEG changes seen during SD and RS in the rat. Increases in low theta power (5–7Hz), but not high theta (7–9Hz), during SD correlated with the increase in NREM delta power during RS, and with the changes in nitrate/nitrite [NOx]ex and [AD]ex. Lesions of ChBF cells using IgG 192-saporin prevented increases in [NOx]ex, [AD]ex and low theta activity, during SD, but did not prevent increases in [Lac]ex and [Pyr]ex. Infusion of NO donor DETA NONOate into the saporin-treated BF failed to increase NREM RS and delta power, suggesting ChBF cells are important for mediating NO homeostatic effects. Finally, SD-induced iNOS was mostly expressed in ChBF cells, and the intensity of iNOS induction correlated with the increase in low theta activity. Together, our data indicate ChBF cells are important in regulating the biochemical and EEG mechanisms that contribute to HSP. PMID:25369989

  9. Genetic interplay between the transcription factors Sp8 and Emx2 in the patterning of the forebrain

    Stoykova Anastasia


    Full Text Available Abstract Background The forebrain consists of multiple structures necessary to achieve elaborate functions. Proper patterning is, therefore, a prerequisite for the generation of optimal functional areas. Only a few factors have been shown to control the genetic networks that establish early forebrain patterning. Results and conclusion Using conditional inactivation, we show that the transcription factor Sp8 has an essential role in the molecular and functional patterning of the developing telencephalon along the anteroposterior axis by modulating the expression gradients of Emx2 and Pax6. Moreover, Sp8 is essential for the maintenance of ventral cell identity in the septum and medial ganglionic eminence (MGE. This is probably mediated through a positive regulatory interaction with Fgf8 in the medial wall, and Nkx2.1 in the rostral MGE anlage, and independent of SHH and WNT signaling. Furthermore, Sp8 is required during corticogenesis to sustain a normal progenitor pool, and to control preplate splitting, as well as the specification of cellular diversity within distinct cortical layers.

  10. Oral Morphine Consumption Reduces Lens Development in Rat Embryos

    Hossein Bahadoran


    Full Text Available Objective: Consumption of morphine, during pregnancy, in addition to inducing defects in the mother’s nervous system function, caused defects or delays in the formation and evolution of embryonic visual system. In the present study, changes in lens development was assessed in embryos exposed in utero to morphine. Material and Methods: Female Wistar rats (250-300 g were mated with male rats and pregnancy was determined by sperm observation in vaginal smear. This day was considered as embryonic day zero (E0. The females were then divided randomly into the experimental and the control groups. The control group received tap water and the experimental group received morphine (0.05 mg/ml in their water. On embryonic day 13 ( E13, blood samples were collected from the retro-orbital sinus of all animals for plasma corticosterone detection. On embryonic day 17(E17, the animals were killed by an overdose of chloroform and the embryos were taken out surgically. The embryos were fixed in 10% formalin for 30 days. At this time, the head of the embryos were removed for tissue processing and Hematoxylin- Eosin (H&E staining. The samples were evaluated using light microscope and MOTIC software. Results: Our data indicated that plasma corticosterone level was dramatically increased and the lens was thinner in the experimental group. (Although the proliferation of lens cells increased in the experiment group but that lens had delay in removing the proliferated and elongation cells with abnormal density in the lateral part of the lens in compare with control group. I have no idea what the authors are stating here. Moreover, the opening of the eyelids was delayed in the off springs of the mothers who received morphine. Conclusions: This study showed that morphine consumption during pregnancy leads to defects in fetal visual system development, particularly in the lens, and eyelids.

  11. Spectral analysis of the electroencephalogram in the developing rat.

    Bronzino, J D; Siok, C J; Austin, K; Austin-Lafrance, R J; Morgane, P J


    Power spectral measures of the EEG obtained from the frontal cortex and hippocampal formation during different vigilance states in the developing rat have been computed and compared. The most significant ontogenetic changes were observed in the hippocampal power spectra obtained during the vigilance state of REM sleep. These spectral analyses have revealed in the hippocampus: (1) a significant increase in the frequency at which the peak power occurs in the theta-frequency (4-11 Hz) band from 14 to 45 days of age; (2) a decrease in the quality factor of the peak from 14 to 45 days of age; (3) a decrease in the relative power co-ordinate for the center of spectral mass associated with the 0-4-Hz frequency band coupled with an increase in the frequency coordinate of the 4-11-Hz frequency band from 14 to 45 days of age, and; (4) a significant decrease in the average percent relative power associated with the 0-4-Hz frequency band from 14 to 22 days of age. For the EEG obtained from the frontal cortex, the major findings of note were: (1) a dominant contribution of relative power in the 0-4-Hz frequency band which was observed at every age and during every vigilance state tested, and; (2) a significant increase in the average percent relative power associated with this band at 18, 22, and 45 days of age. The results of this study provide a quantitative description of the electroencephalographic (EEG) ontogeny of the hippocampal formation and the frontal cortex in the rat. These ontogenetic changes in EEG activity relate closely to development of the internal circuitry and synaptic maturation in the hippocampal formation and frontal cortex.

  12. Newly Developed Rat Model of Chronic Kidney Disease-Mineral Bone Disorder.

    Watanabe, Kentaro; Fujii, Hideki; Goto, Shunsuke; Nakai, Kentaro; Kono, Keiji; Watanabe, Shuhei; Shinohara, Masami; Nishi, Shinichi


    Chronic kidney disease-mineral bone disorder (CKD-MBD) is associated with all-cause and cardiovascular morbidity and mortality in patients with CKD. Thus, elucidating its pathophysiological mechanisms is essential for improving the prognosis. We evaluated characteristics of CKD-MBD in a newly developed CKD rat model. We used male Sprague-Dawley (SD) rats and spontaneously diabetic Torii (SDT) rats, which are used as models for nonobese type 2 diabetes. CKD was induced by 5/6 nephrectomy (Nx). At 10 weeks, the rats were classified into six groups and administered with a vehicle or a low- or high-dose paricalcitol thrice a week. At 20 weeks, the rats were sacrificed; blood and urinary biochemical analyses and histological analysis of the aorta were performed. At 20 weeks, hemoglobin A1c (HbA1c) levels, blood pressure, and renal function were not significantly different among the six groups. Serum calcium and phosphate levels tended to be higher in SDT-Nx rats than in SD-Nx rats. The urinary excretion of calcium and phosphate was significantly greater in SDT-Nx rats than in SD-Nx rats. After administering paricalcitol, serum parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) levels were significantly higher in SDT-Nx rats than in SD-Nx rats. The degree of aortic calcification was significantly more severe and the aortic calcium content was significantly greater in SDT-Nx rats than in SD-Nx rats. We suggest that our new CKD rat model using SDT rats represents a useful CKD-MBD model, and this model was greatly influenced by paricalcitol administration. Further studies are needed to clarify the detailed mechanisms underlying this model.

  13. Development of the microcirculation of the secondary ossification center in rat humeral head

    Morini, S; Continenza, MA; Ricciardi, G; Gaudio, E; Pannarale, L


    This work investigated the origin and development of microcirculation in the rat humeral head and the expression of vascular endothelial growth factor (VEGF) as a factor supporting the vascular growth and the development of the secondary ossification centers. Sixty rats aging 1, 3-4, 6-8, 11, and 21

  14. Pallial origin of basal forebrain cholinergic neurons in the nucleus basalis of Meynert and horizontal limb of the diagonal band nucleus.

    Pombero, Ana; Bueno, Carlos; Saglietti, Laura; Rodenas, Monica; Guimera, Jordi; Bulfone, Alexandro; Martinez, Salvador


    The majority of the cortical cholinergic innervation implicated in attention and memory originates in the nucleus basalis of Meynert and in the horizontal limb of the diagonal band nucleus of the basal prosencephalon. Functional alterations in this system give rise to neuropsychiatric disorders as well as to the cognitive alterations described in Parkinson and Alzheimer's diseases. Despite the functional importance of these basal forebrain cholinergic neurons very little is known about their origin and development. Previous studies suggest that they originate in the medial ganglionic eminence of the telencephalic subpallium; however, our results identified Tbr1-expressing, reelin-positive neurons migrating from the ventral pallium to the subpallium that differentiate into cholinergic neurons in the basal forebrain nuclei projecting to the cortex. Experiments with Tbr1 knockout mice, which lack ventropallial structures, confirmed the pallial origin of cholinergic neurons in Meynert and horizontal diagonal band nuclei. Also, we demonstrate that Fgf8 signaling in the telencephalic midline attracts these neurons from the pallium to follow a tangential migratory route towards the basal forebrain.

  15. Impact of basal forebrain cholinergic inputs on basolateral amygdala neurons.

    Unal, Cagri T; Pare, Denis; Zaborszky, Laszlo


    In addition to innervating the cerebral cortex, basal forebrain cholinergic (BFc) neurons send a dense projection to the basolateral nucleus of the amygdala (BLA). In this study, we investigated the effect of near physiological acetylcholine release on BLA neurons using optogenetic tools and in vitro patch-clamp recordings. Adult transgenic mice expressing cre-recombinase under the choline acetyltransferase promoter were used to selectively transduce BFc neurons with channelrhodopsin-2 and a reporter through the injection of an adeno-associated virus. Light-induced stimulation of BFc axons produced different effects depending on the BLA cell type. In late-firing interneurons, BFc inputs elicited fast nicotinic EPSPs. In contrast, no response could be detected in fast-spiking interneurons. In principal BLA neurons, two different effects were elicited depending on their activity level. When principal BLA neurons were quiescent or made to fire at low rates by depolarizing current injection, light-induced activation of BFc axons elicited muscarinic IPSPs. In contrast, with stronger depolarizing currents, eliciting firing above ∼ 6-8 Hz, these muscarinic IPSPs lost their efficacy because stimulation of BFc inputs prolonged current-evoked afterdepolarizations. All the effects observed in principal neurons were dependent on muscarinic receptors type 1, engaging different intracellular mechanisms in a state-dependent manner. Overall, our results suggest that acetylcholine enhances the signal-to-noise ratio in principal BLA neurons. Moreover, the cholinergic engagement of afterdepolarizations may contribute to the formation of stimulus associations during fear-conditioning tasks where the timing of conditioned and unconditioned stimuli is not optimal for the induction of synaptic plasticity.

  16. Cholinergic Neurons Excite Cortically Projecting Basal Forebrain GABAergic Neurons

    Yang, Chun; McKenna, James T.; Zant, Janneke C.; Winston, Stuart; Basheer, Radhika


    The basal forebrain (BF) plays an important role in the control of cortical activation and attention. Understanding the modulation of BF neuronal activity is a prerequisite to treat disorders of cortical activation involving BF dysfunction, such as Alzheimer's disease. Here we reveal the interaction between cholinergic neurons and cortically projecting BF GABAergic neurons using immunohistochemistry and whole-cell recordings in vitro. In GAD67-GFP knock-in mice, BF cholinergic (choline acetyltransferase-positive) neurons were intermingled with GABAergic (GFP+) neurons. Immunohistochemistry for the vesicular acetylcholine transporter showed that cholinergic fibers apposed putative cortically projecting GABAergic neurons containing parvalbumin (PV). In coronal BF slices from GAD67-GFP knock-in or PV-tdTomato mice, pharmacological activation of cholinergic receptors with bath application of carbachol increased the firing rate of large (>20 μm diameter) BF GFP+ and PV (tdTomato+) neurons, which exhibited the intrinsic membrane properties of cortically projecting neurons. The excitatory effect of carbachol was blocked by antagonists of M1 and M3 muscarinic receptors in two subpopulations of BF GABAergic neurons [large hyperpolarization-activated cation current (Ih) and small Ih, respectively]. Ion substitution experiments and reversal potential measurements suggested that the carbachol-induced inward current was mediated mainly by sodium-permeable cation channels. Carbachol also increased the frequency of spontaneous excitatory and inhibitory synaptic currents. Furthermore, optogenetic stimulation of cholinergic neurons/fibers caused a mecamylamine- and atropine-sensitive inward current in putative GABAergic neurons. Thus, cortically projecting, BF GABAergic/PV neurons are excited by neighboring BF and/or brainstem cholinergic neurons. Loss of cholinergic neurons in Alzheimer's disease may impair cortical activation, in part, through disfacilitation of BF cortically

  17. Brain leukocyte infiltration initiated by peripheral inflammation or experimental autoimmune encephalomyelitis occurs through pathways connected to the CSF-filled compartments of the forebrain and midbrain

    Schmitt Charlotte


    Full Text Available Abstract Background Cerebrospinal fluid (CSF has been considered as a preferential pathway of circulation for immune cells during neuroimmune surveillance. In order to evaluate the involvement of CSF-filled spaces in the pathogenesis of experimental autoimmune encephalomyelitis (EAE, a model of multiple sclerosis, we performed a time-course analysis of immune cell association with the CSF-containing ventricles, velae, and cisterns in two active models of this disease. Methods Guinea-pig spinal cord homogenate-induced EAE in rat and myelin oligodendrocyte glycoprotein-induced EAE in mouse were used. Leukocyte distribution and phenotypes were investigated by immunohistochemistry in serial sections of brain areas of interest, as well as in CSF withdrawn from rat. Immune cells associated with the choroid plexuses were quantified. Results Freund’s adjuvant-induced peripheral inflammation in the absence of brain antigen led to a subtle but definite increase in the number of myeloid cells in the extraventricular CSF spaces. In both rats and mice, EAE was characterized by a sustained and initial infiltration of lymphocytes and monocytes within forebrain/midbrain fluid-filled compartments such as the velum interpositum and ambient cisterns, and certain basal cisterns. Leukocytes further infiltrated periventricular and pericisternal parenchymal areas, along perivascular spaces or following a downward CSF-to-tissue gradient. Cells quantified in CSF sampled from rats included lymphocytes and neutrophils. The distinctive pattern of cell distribution suggests that both the choroid plexus and the vessels lying in the velae and cisterns are gates for early leukocyte entry in the central nervous system. B-cell infiltration observed in the mouse model was restricted to CSF-filled extraventricular compartments. Conclusion These results identified distinctive velae and cisterns of the forebrain and midbrain as preferential sites of immune cell homing following

  18. Divergent projections of catecholaminergic neurons in the nucleus of the solitary tract to limbic forebrain and medullary autonomic brain regions.

    Reyes, Beverly A S; Van Bockstaele, Elisabeth J


    The nucleus of the solitary tract (NTS) is a critical structure involved in coordinating autonomic and visceral activities. Previous independent studies have demonstrated efferent projections from the NTS to the nucleus paragigantocellularis (PGi) and the central nucleus of the amygdala (CNA) in rat brain. To further characterize the neural circuitry originating from the NTS with postsynaptic targets in the amygdala and medullary autonomic targets, distinct green or red fluorescent latex microspheres were injected into the PGi and the CNA, respectively, of the same rat. Thirty-micron thick tissue sections through the lower brainstem and forebrain were collected. Every fourth section through the NTS region was processed for immunocytochemical detection of tyrosine hydroxylase (TH), a marker of catecholaminergic neurons. Retrogradely labeled neurons from the PGi or CNA were distributed throughout the rostro-caudal segments of the NTS. However, the majority of neurons containing both retrograde tracers were distributed within the caudal third of the NTS. Cell counts revealed that approximately 27% of neurons projecting to the CNA in the NTS sent collateralized projections to the PGi while approximately 16% of neurons projecting to the PGi sent collateralized projections to the CNA. Interestingly, more than half of the PGi and CNA-projecting neurons in the NTS expressed TH immunoreactivity. These data indicate that catecholaminergic neurons in the NTS are poised to simultaneously coordinate activities in limbic and medullary autonomic brain regions.

  19. Eye development in the Cape dune mole rat.

    Nikitina, Natalya V; Kidson, Susan H


    Studies on mammalian species with naturally reduced eyes can provide valuable insights into the evolutionary developmental mechanisms underlying the reduction of the eye structures. Because few naturally microphthalmic animals have been studied and eye reduction must have evolved independently in many of the modern groups, novel evolutionary developmental models for eye research have to be sought. Here, we present a first report on embryonic eye development in the Cape dune mole rat, Bathyergus suillus. The eyes of these animals contain all the internal structures characteristic of the normal eye but exhibit abnormalities in the anterior chamber structures. The lens is small but develops normally and exhibits a normal expression of α- and γ-crystallins. One of the interesting features of these animals is an extremely enlarged and highly pigmented ciliary body. In order to understand the molecular basis of this unusual feature, the expression pattern of an early marker of the ciliary zone, Ptmb4, was investigated in this animal. Surprisingly, in situ hybridization results revealed that Ptmb4 expression was absent from the ciliary body zone of the developing Bathyergus eye.

  20. Comparison and optimization of hiPSC forebrain cortical differentiation protocols.

    Muratore, Christina R; Srikanth, Priya; Callahan, Dana G; Young-Pearse, Tracy L


    Several protocols have been developed for human induced pluripotent stem cell neuronal differentiation. We compare several methods for forebrain cortical neuronal differentiation by assessing cell morphology, immunostaining and gene expression. We evaluate embryoid aggregate vs. monolayer with dual SMAD inhibition differentiation protocols, manual vs. AggreWell aggregate formation, plating substrates, neural progenitor cell (NPC) isolation methods, NPC maintenance and expansion, and astrocyte co-culture. The embryoid aggregate protocol, using a Matrigel substrate, consistently generates a high yield and purity of neurons. NPC isolation by manual selection, enzymatic rosette selection, or FACS all are efficient, but exhibit some differences in resulting cell populations. Expansion of NPCs as neural aggregates yields higher cell purity than expansion in a monolayer. Finally, co-culture of iPSC-derived neurons with astrocytes increases neuronal maturity by day 40. This study directly compares commonly employed methods for neuronal differentiation of iPSCs, and can be used as a resource for choosing between various differentiation protocols.

  1. Comparison and optimization of hiPSC forebrain cortical differentiation protocols.

    Christina R Muratore

    Full Text Available Several protocols have been developed for human induced pluripotent stem cell neuronal differentiation. We compare several methods for forebrain cortical neuronal differentiation by assessing cell morphology, immunostaining and gene expression. We evaluate embryoid aggregate vs. monolayer with dual SMAD inhibition differentiation protocols, manual vs. AggreWell aggregate formation, plating substrates, neural progenitor cell (NPC isolation methods, NPC maintenance and expansion, and astrocyte co-culture. The embryoid aggregate protocol, using a Matrigel substrate, consistently generates a high yield and purity of neurons. NPC isolation by manual selection, enzymatic rosette selection, or FACS all are efficient, but exhibit some differences in resulting cell populations. Expansion of NPCs as neural aggregates yields higher cell purity than expansion in a monolayer. Finally, co-culture of iPSC-derived neurons with astrocytes increases neuronal maturity by day 40. This study directly compares commonly employed methods for neuronal differentiation of iPSCs, and can be used as a resource for choosing between various differentiation protocols.

  2. NKCC1 controls GABAergic signaling and neuroblast migration in the postnatal forebrain

    Murray Kerren


    Full Text Available Abstract From an early postnatal period and throughout life there is a continuous production of olfactory bulb (OB interneurons originating from neuronal precursors in the subventricular zone. To reach the OB circuits, immature neuroblasts migrate along the rostral migratory stream (RMS. In the present study, we employed cultured postnatal mouse forebrain slices and used lentiviral vectors to label neuronal precursors with GFP and to manipulate the expression levels of the Na-K-2Cl cotransporter NKCC1. We investigated the role of this Cl- transporter in different stages of postnatal neurogenesis, including neuroblast migration and integration in the OB networks once they have reached the granule cell layer (GCL. We report that NKCC1 activity is necessary for maintaining normal migratory speed. Both pharmacological and genetic manipulations revealed that NKCC1 maintains high [Cl-]i and regulates the resting membrane potential of migratory neuroblasts whilst its functional expression is strongly reduced at the time cells reach the GCL. As in other developing systems, NKCC1 shapes GABAA-dependent signaling in the RMS neuroblasts. Also, we show that NKCC1 controls the migration of neuroblasts in the RMS. The present study indeed indicates that the latter effect results from a novel action of NKCC1 on the resting membrane potential, which is independent of GABAA-dependent signaling. All in all, our findings show that early stages of the postnatal recruitment of OB interneurons rely on precise, orchestrated mechanisms that depend on multiple actions of NKCC1.

  3. Increased innervation of forebrain targets by midbrain dopaminergic neurons in the absence of FGF-2.

    Rumpel, R; Baron, O; Ratzka, A; Schröder, M-L; Hohmann, M; Effenberg, A; Claus, P; Grothe, C


    Fibroblast growth factors (FGFs) regulate development and maintenance, and reduce vulnerability of neurons. FGF-2 is essential for survival of midbrain dopaminergic (DA) neurons and is responsible for their dysplasia and disease-related degeneration. We previously reported that FGF-2 is involved in adequate forebrain (FB) target innervation by these neurons in an organotypic co-culture model. It remains unclear, how this ex-vivo phenotype relates to the in vivo situation, and which FGF-related signaling pathway is involved in this process. Here, we demonstrate that lack of FGF-2 results in an increased volume of the striatal target area in mice. We further add evidence that the low molecular weight (LMW) FGF-2 isoform is responsible for this phenotype, as this isoform is predominantly expressed in the embryonic ventral midbrain (VM) as well as in postnatal striatum (STR) and known to act via canonical transmembrane FGF receptor (FGFR) activation. Additionally, we confirm that the phenotype with an enlarged FB-target area by DA neurons can be mimicked in an ex-vivo explant model by inhibiting the canonical FGFR signaling, which resulted in decreased extracellular signal-regulated kinase (ERK) activation, while AKT activation remained unchanged.

  4. Specification of Region-Specific Neurons Including Forebrain Glutamatergic Neurons from Human Induced Pluripotent Stem Cells

    Martins-Taylor, Kristen; Wang, Xiaofang; Zhang, Zheng; Park, Jung Woo; Zhan, Shuning; Kronenberg, Mark S.; Lichtler, Alexander; Liu, Hui-Xia; Chen, Fang-Ping; Yue, Lixia; Li, Xue-Jun; Xu, Ren-He


    Background Directed differentiation of human induced pluripotent stem cells (hiPSC) into functional, region-specific neural cells is a key step to realizing their therapeutic promise to treat various neural disorders, which awaits detailed elucidation. Methodology/Principal Findings We analyzed neural differentiation from various hiPSC lines generated by others and ourselves. Although heterogeneity in efficiency of neuroepithelial (NE) cell differentiation was observed among different hiPSC lines, the NE differentiation process resembles that from human embryonic stem cells (hESC) in morphology, timing, transcriptional profile, and requirement for FGF signaling. NE cells differentiated from hiPSC, like those from hESC, can also form rostral phenotypes by default, and form the midbrain or spinal progenitors upon caudalization by morphogens. The rostrocaudal neural progenitors can further mature to develop forebrain glutamatergic projection neurons, midbrain dopaminergic neurons, and spinal motor neurons, respectively. Typical ion channels and action potentials were recorded in the hiPSC-derived neurons. Conclusions/Significance Our results demonstrate that hiPSC, regardless of how they were derived, can differentiate into a spectrum of rostrocaudal neurons with functionality, which supports the considerable value of hiPSC for study and treatment of patient-specific neural disorders. PMID:20686615

  5. Longitudinal measures of cholinergic forebrain atrophy in the transition from healthy aging to Alzheimer's disease.

    Grothe, Michel; Heinsen, Helmut; Teipel, Stefan


    Recent evidence from cross-sectional in vivo imaging studies suggests that atrophy of the cholinergic basal forebrain (BF) in Alzheimer's disease (AD) can be distinguished from normal age-related degeneration even at predementia stages of the disease. Longitudinal study designs are needed to specify the dynamics of BF degeneration in the transition from normal aging to AD. We applied recently developed techniques for in vivo volumetry of the BF to serial magnetic resonance imaging scans of 82 initially healthy elderly individuals (60-93 years) and 50 patients with very mild AD (Clinical Dementia Rating score = 0.5) that were clinically followed over an average of 3 ± 1.5 years. BF atrophy rates were found to be significantly higher than rates of global brain shrinkage even in cognitively stable healthy elderly individuals. Compared with healthy control subjects, very mild AD patients showed reduced BF volumes at baseline and increased volume loss over time. Atrophy of the BF was more pronounced in progressive patients compared with those that remained stable. The cholinergic BF undergoes disproportionate degeneration in the aging process, which is further increased by the presence of AD.

  6. Specification of region-specific neurons including forebrain glutamatergic neurons from human induced pluripotent stem cells.

    Hui Zeng

    Full Text Available BACKGROUND: Directed differentiation of human induced pluripotent stem cells (hiPSC into functional, region-specific neural cells is a key step to realizing their therapeutic promise to treat various neural disorders, which awaits detailed elucidation. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed neural differentiation from various hiPSC lines generated by others and ourselves. Although heterogeneity in efficiency of neuroepithelial (NE cell differentiation was observed among different hiPSC lines, the NE differentiation process resembles that from human embryonic stem cells (hESC in morphology, timing, transcriptional profile, and requirement for FGF signaling. NE cells differentiated from hiPSC, like those from hESC, can also form rostral phenotypes by default, and form the midbrain or spinal progenitors upon caudalization by morphogens. The rostrocaudal neural progenitors can further mature to develop forebrain glutamatergic projection neurons, midbrain dopaminergic neurons, and spinal motor neurons, respectively. Typical ion channels and action potentials were recorded in the hiPSC-derived neurons. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that hiPSC, regardless of how they were derived, can differentiate into a spectrum of rostrocaudal neurons with functionality, which supports the considerable value of hiPSC for study and treatment of patient-specific neural disorders.

  7. Brain Aging and AD-Like Pathology in Streptozotocin-Induced Diabetic Rats

    Jian-Qin Wang


    Full Text Available Objective. Numerous epidemiological studies have linked diabetes mellitus (DM with an increased risk of developing Alzheimer’s disease (AD. However, whether or not diabetic encephalopathy shows AD-like pathology remains unclear. Research Design and Methods. Forebrain and hippocampal volumes were measured using stereology in serial coronal sections of the brain in streptozotocin- (STZ- induced rats. Neurodegeneration in the frontal cortex, hypothalamus, and hippocampus was evaluated using Fluoro-Jade C (FJC. Aβ aggregation in the frontal cortex and hippocampus was tested using immunohistochemistry and ELISA. Dendritic spine density in the frontal cortex and hippocampus was measured using Golgi staining, and western blot was conducted to detect the levels of synaptophysin. Cognitive ability was evaluated through the Morris water maze and inhibitory avoidant box. Results. Rats are characterized by insulin deficiency accompanied with polydipsia, polyphagia, polyuria, and weight loss after STZ injection. The number of FJC-positive cells significantly increased in discrete brain regions of the diabetic rats compared with the age-matched control rats. Hippocampal atrophy, Aβ aggregation, and synapse loss were observed in the diabetic rats compared with the control rats. The learning and memory of the diabetic rats decreased compared with those of the age-matched control rats. Conclusions. Our results suggested that aberrant metabolism induced brain aging as characterized by AD-like pathologies.

  8. In vitro electrophysiology of developing genioglossal motoneurons in the rat.

    Núñez-Abades, P A; Spielmann, J M; Barrionuevo, G; Cameron, W E


    1. Experiments were performed to determine the change in membrane properties of genioglossal (GG) motoneurons during development. Intracellular recordings were made in 127 GG motoneurons from rats postnatal ages 1-30 days. 2. The input resistance (R(in)) and the membrane time constant (t(aum)) decreased between 5-6 and 13-15 days from 84.8 +/- 25.4 (SD) to 47.0 +/- 18.9 M omega (P average duration of the medium afterhyperpolarization (mAHPdur) decreased (P AHP (mAHPamp). From this latter relationship, a reversal potential for the mAHPamp was extrapolated to be -87 mV. No evidence for the existence of a slow AHP was found in these developing motoneurons. 5. All cells analyzed (n = 74) displayed adaptation during the first three spikes. The subsequent firing pattern was classified into two groups, adapting and nonadapting. Cells at birth were all adapting, whereas all cells but two from animals 13 days and older were nonadapting. At the intermediate age (5-6 days), the minority (27%) was adapting and the majority (73%) was nonadapting. 6. The mean slope of primary range for the first interspike interval (1st ISI) was approximately 90 Hz/nA. This value was similar for both adapting and nonadapting cells and did not change postnatally.(ABSTRACT TRUNCATED AT 400 WORDS)

  9. [Effect of premature birth on retinal vascular development in the neonatal rat].

    Yang, Xiang-min; Li, Rong; Wang, Yu-sheng; Chu, Zhao-jie; Gao, Xiang


    To study the effects of premature birth on the development of rat retinal vasculature. Experimental study. Sixty pregnant Sprague-Dawley rats were divided into four groups: bacterial lipopolysaccharide-induced preterm group (LPS group), RU-486 induced preterm group (RP group), cesarean section induced preterm group (CP group), and the normal delivery rats as the control group. The weight of rats from each group was recorded until postnatal day 21. On postnatal day 4, 7, 10 and 14 (P4, P7, P10 and P14), the retina of right eye was dissected and whole-mounted. Each premature group was divided into two subgroups based on the number of rats in each litter, the small subgroup (6-8 rats per litter, group 1) and the large subgroup (14-18 rats per litter, group 2). The development of retinal vascularization process was observed on P4, P7 and P10 (n = 6).Independent t test, one-way ANOVA and LSD-t test were used to analyzed the results. The weight of premature rats in LPS, CP and RP groups was significantly lower than that in the normal group within postnatal 21 days (LSD-t test: all P premature rats have lower weight and much slower rate of early retinal vascularization, as compared with the normal rats. Furthermore, in the premature rats, the proportion of retinal vascularization in larger litters is less than that in smaller litters. These results indicate that premature birth and larger litter size have effects on the development of rat retinal vasculature.

  10. Effects of Lead on Temporal Response Properties of Retinal Ganglion Cells in Developing Rats

    阮迪云; 汤立新; 赵晨; 郭宇静


    Neonatal rats have taken in lead, during the period from their parturition to their weaning, from the milk of dams fed with water containing 0.2% lead acetate solutions. The alterations in the temporal response properties of retinal ganglion cells in adult rats (90 days) following the lead exposure at their developing stage have been studied. The results of this investigation demonstrate that the lead exposure in neonatal rats causes decreases in the optimal temporal frequency, bandwidth at half amplitude, temporal resolution and response phase of the retinal ganglion cells in adult rats. Compared with the sustained cells, the transient cells have a much greater alteration in temporal response properties.

  11. Epidermal growth factor and lung development in the offspring of the diabetic rat

    Thulesen, J; Poulsen, Steen Seier; Nexø, Ebba


    Fetuses of diabetic mothers who were exposed to excessive glucose show delayed maturation. Under these conditions, altered growth factor expression or signaling may have important regulatory influences. We examined the role of epidermal growth factor (EGF) in lung development and maternal diabetes...... in the rat. In order to evaluate the possible role of glucose for the expression of EGF and the growth of lung tissue, we performed in vitro studies with organotypic cultures of fetal alveolar cells obtained from control rats. Compared to pups of normal rats, the newborn rats of untreated diabetic rats had...... and was associated with a reduced intensity of surfactant protein A-IR. The only difference observed between pups of treated diabetic rats and controls was a decrease in the lung weight:body weight ratio. In organotypic cultures, the presence of 13 mmol/L glucose in the cell media increased immunoreactive staining...

  12. Glia activation and cytokine increase in rat hippocampus by kainic acid-induced status epilepticus during postnatal development.

    Rizzi, Massimo; Perego, Carlo; Aliprandi, Marisa; Richichi, Cristina; Ravizza, Teresa; Colella, Daniele; Velískŏvá, Jana; Moshé, Solomon L; De Simoni, M Grazia; Vezzani, Annamaria


    In adult rats, status epilepticus (SE) induces cytokine production by glia especially when seizures are associated with neuronal injury. This suggests that cytokines may play a role in seizure-induced neuronal damage. As SE-induced injury is age-specific, we used rats of different ages (with distinct susceptibilities to seizure-induced neuronal injury) to elucidate the role of cytokines in this process. Thus, we investigated the activation of microglia and astrocytes, induction of cytokines, and hippocampal neuronal injury 4 and 24 h following kainic acid-induced SE in postnatal day (PN) 9, 15, and 21 rats. At PN9, there was little activation of microglia and astrocytes at any time point studied. Interleukin-1beta (IL), tumor necrosis factor-alpha (TNF), and IL-6 or the naturally occurring IL-1 receptor antagonist (Ra) mRNA expression did not increase. No evidence of cell injury has been detected. At PN15, immunostaining of microglia and astrocytes was enhanced, but only IL-1beta mRNA expression was increased. These changes were observed 4 h after SE. Scattered injured neurons in CA3 and subiculum, but not in any other region, were present 24 h following SE. At PN21, immunostaining of microglia and astrocytes and the mRNA expression of all cytokines studied was significantly increased already 4 h after SE. At 24 h, many injured neurons were present in CA1 and CA3 regions and in 40% of rats in other forebrain areas. These data show that (i) the pattern of glia activation and cytokine gene transcription induced by SE is age-dependent and (ii) neuronal injury in the hippocampus occurs only when cytokines are induced and their synthesis precedes the appearance of neuronal damage. Thus, cytokine expression in immature brain is associated specifically with cell injury rather than with seizures per se, suggesting that proinflammatory cytokines may contribute to the occurence of SE-induced hippocampal damage.

  13. Effects of prenatal exposure to xylene on postnatal development and behavior in rats

    Hass, Ulla; Lund, S. P.; Simonsen, L.;


    The effects of prenatal exposure to the organic solvent xylene (dimethylbenzene, GAS-no 1330-20-7) on postnatal development and behavior in rats were studied. Pregnant rats (Mol:WIST) were exposed to 500 ppm technical xylene 6 h per day on gestation days 7-20. The dose level was selected so as no...

  14. Fenugreek Prevents the Development of STZ-Induced Diabetic Nephropathy in a Rat Model of Diabetes

    Yingli Jin


    evidently reduced by fenugreek treatment. Furthermore, the upregulation of TGF-β1 and CTGF at a transcriptional and translational level in DN rats was distinctly inhibited by fenugreek. Consequently, fenugreek prevents DN development in a STZ-induced diabetic rat model.

  15. Rats

    Alexey Kondrashov


    Full Text Available We aimed to perform a chemical analysis of both Alibernet red wine and an alcohol-free Alibernet red wine extract (AWE and to investigate the effects of AWE on nitric oxide and reactive oxygen species production as well as blood pressure development in normotensive Wistar Kyoto (WKY and spontaneously hypertensive rats (SHRs. Total antioxidant capacity together with total phenolic and selected mineral content was measured in wine and AWE. Young 6-week-old male WKY and SHR were treated with AWE (24,2 mg/kg/day for 3 weeks. Total NOS and SOD activities, eNOS and SOD1 protein expressions, and superoxide production were determined in the tissues. Both antioxidant capacity and phenolic content were significantly higher in AWE compared to wine. The AWE increased NOS activity in the left ventricle, aorta, and kidney of SHR, while it did not change NOS activity in WKY rats. Similarly, increased SOD activity in the plasma and left ventricle was observed in SHR only. There were no changes in eNOS and SOD1 expressions. In conclusion, phenolics and minerals included in AWE may contribute directly to increased NOS and SOD activities of SHR. Nevertheless, 3 weeks of AWE treatment failed to affect blood pressure of SHR.

  16. 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

    Celia eHerrera-Rincon


    Full Text Available 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 decrease neither of afferent activity nor to 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.

  17. Postnatal neurobehavioral development in rats exposed in utero to caffeine.

    West, G L; Sobotka, T J; Brodie, R E; Beier, J M; O'Donnell, M W


    Potential behavioral and teratogenic effects of caffeine were studied in Charles River CD albino rats. Caffeine in distilled water was given by gavage to pregnant rats (dams) at doses of 5, 25, 50 or 75 mg/kg on Days 3-19 of gestation. Concurrent controls received distilled water gavage (10 ml/kg) on the same days. Dams were allowed to deliver normally. Physical and behavioral observations were made on dams during gestation and lactation and on F1 offspring through 9 weeks of age. Caffeine decreased body weights and food intake and increased water intake in gestating dams but these effects dissipated during lactation. Spontaneous locomotor activity (PAC) and open field (OF) were increased immediately after caffeine gavage but not before. Parturition was slightly delayed. With analyses of data based on individual pups the following effects were noted. Pre- and post-weaning offspring body weights were decreased in females at 50 and 75 mg/kg and in males at 75 mg/kg. Incisor eruption was delayed in females at 5, 50 and 75 mg/kg and in males at all doses. Auditory startle developed earlier in the 5 mg/kg dose group but was delayed at 75 mg/kg for males only. Eye opening was delayed in both sexes at 25, 50 and 75 mg/kg. In females, vaginal opening was delayed at 5, 25 and 75 mg/kg and 9-week ovary weights were increased at 75 mg/kg. In postweaning males, food intake was decreased and water intake was increased with increasing dose. In males, PAC was decreased at 75 mg/kg only on Day 12. At 7 weeks of age, step-down passive avoidance was decreased at 5 and 25 mg/kg but increased at 50 and 75 mg/kg, and at 8 weeks of age, shuttlebox active avoidance was decreased with increasing dose. Maternal and offspring behaviors were only weakly correlated. Correction for litter effect in developmental data yielded fewer significant results and only at 50 and 75 mg/kg. The issue of whether it is always appropriate to correct for "litter effect" is discussed.

  18. Development of hepatorenal syndrome in bile duct ligated rats

    Regina M Pereira; Ana Cristina Sim(o)es e Silva; Robson AS dos Santos; Eduardo A Oliveira; Virg(i)nia HR Leite; Filipi LC Dias; Alysson S Rezende; Lincoln P Costa; Luciola S Barcelos; Mauro M Teixeira


    AIM: To evaluate in bile duct ligated rats whether there were progressive alterations of renal function without changes in histopathology.METHODS: Male Wistar rats were submitted to sham-surgery or bile duct ligation (BDL) and divided according to the post-procedure time (2, 4 and 6-wk).To determine renal function parameters, rats were placed in metabolic cages and, at the end of the experiment, blood and urine samples were obtained.Histology and hydroxyproline content were analyzed in liver and renal tissue.RESULTS: Rats with 2 wk of BDL increased free water clearance (P = 0.02), reduced urinary osmolality (P =0.03) and serum creatinine (P = 0.01) in comparison to the sham group. In contrast, rats at 6 wk of BDL showed features of HRS, including significant increase in serum creatinine and reductions in creatinine clearance,water excretion and urinary sodium concentration. Rats with 4 wk of BDL exhibited an intermediate stage of renal dysfunction. Progressive hepatic fibrosis according to post-procedure time was confirmed by histology.The increased levels of liver hydroxyproline contrasted with the absence of structural changes in the kidney, as assessed by histology and unchanged hydroxyproline content in renal tissue.CONCLUSION: Our data show that BDL produced progressive renal dysfunction without structural changes in the kidney, characterizing HRS. The present model will be useful to understand the pathophysiology of HRS.

  19. Robot-Assisted Thoracic Surgery (RATS): Perioperative Nursing Professional Development Program.

    Sarmanian, Julie D


    Robot-assisted surgery continues to grow in popularity worldwide. Competency and training of personnel for robot-assisted thoracic surgery (RATS) is less established compared with other robot-assisted specialties. Major differences between minimally invasive approaches to thoracic surgery (eg, video-assisted thoracoscopic surgery) and RATS are presented to address a paucity of literature on the subject. Although perioperative nursing considerations are universal to all robot-assisted procedures, there are nursing consideration specific to RATS. This article provides a RATS perioperative nursing development program for RN circulators and scrub personnel. Development of perioperative nursing knowledge and skills through implementation of targeted training programs enables nurses to provide a safe surgical experience for patients undergoing RATS.

  20. Development of the gubernaculum during testicular descent in the rat.

    Nation, T R; Buraundi, S; Farmer, P J; Balic, A; Newgreen, D; Southwell, B R; Hutson, J M


    Gubernacular elongation during inguinoscrotal testicular descent and cremaster muscle development remains poorly described in mammals. The role of the genitofemoral nerve (GFN) remains elusive. We performed detailed histological analysis of testicular descent in normal rats to provide a comprehensive anatomical description for molecular studies. Fetuses and neonatal male offspring (5-10 per group) from time-mated Sprague-Dawley dams (embryonic days 15, 16, and 19; postnatal days 0, 2, and 8) were prepared for histology. Immunohistochemistry was performed for nerves (Class III tubulin, Tuj1) and muscle (desmin). At embryonic days 15 and 16, the gubernaculum and breast bud are adjacent and both supplied by the GFN. By embryonic day 19, the breast bud has regressed and the gubernacular swelling reaction is completed. Postnatally, the gubernacular core regresses, except for a cranial proliferative zone. The cremaster is continuous with internal oblique and transversus abdominis. By postnatal day 2 (P2), the gubernaculum has everted, locating the proliferative zone caudally and the residual mesenchymal core externally. Eversion creates the processus vaginalis, with the everted gubernaculum loose in subcutaneous tissue but still remote from the scrotum. By P8, the gubernaculum has nearly reached the scrotum with fibrous connections attaching the gubernaculum to the scrotal skin. A direct link between GFN, gubernaculum, and breast bud suggests that the latter may be involved in gubernacular development. Second, the cremaster muscle is continuous with abdominal wall muscles, but most of its growth occurs in the distal gubernacular tip. Finally, gubernacular eversion at birth brings the cranial proliferative zone to the external distal tip, enabling gubernacular elongation similar to a limb bud.

  1. Ikaros family transcription factors expression in rat thymus: detection of impaired development.

    Paradzik, M; Novak, S; Mokrovic, G; Bordukalo Niksic, T; Heckel, D; Stipic, J; Pavicic Baldani, D; Cicin-Sain, L; Antica, M


    The expression of Ikaros family transcription factors and consequently their signalling pathway is limiting for hematopoietic and lymphocyte development in mice and human. Due to their importance, these transcription factors are highly homologous between species. As an initial approach to examining the possible involvement of Ikaros transcription factors in pathogenesis of rat lymphoid development, we analyzed the expression of all known Ikaros family members, Ikaros, Aiolos, Helios, Eos and Pegasus in the rat thymus. We established a semi-quantitative RT-PCR to detect mRNA of each transcription factor. For the first time we give evidence of the expression of Ikaros family transcription factors in the rat thymus. Further, we evaluated whether their mRNA expression was succumbed to changes when the rats were exposed to ethanol, as a known debilitating agent during development. Therefore we analyzed the thymus of adult rats whose mothers were forced to drink ethanol during gestation, to detect possible changes in thymus mRNA expression levels of Ikaros, Aiolos, Helios, Eos and Pegasus. We found that rats prenatally exposed to ethanol show a slightly higher expression of Ikaros family transcription factors in the adult thymus when compared to control rats, but these differences were not statistically significant. We further studied the distribution of the major lymphocyte subpopulations in the rat thymus according to CD3, CD4 and CD8 expression by four color flow cytometry. We found a higher incidence of CD3 positive cells in the double positive, CD4+CD8+ thymic subpopulation of rats prenatally exposed to ethanol when compared to non-exposed animals. Our findings indicate that ethanol exposure of pregnant rats might influence the development of CD3 positive cells in the thymus of the offspring but this result should be further tackled at the level of transcription factor expression.

  2. Aging-induced Seizure-related Changes to the Hippocampal Mossy Fiber Pathway in Forebrain Specific BDNF Overexpressing Mice.

    Weidner, Kate L; Goodman, Jeffrey H; Chadman, Kathryn K; McCloskey, Daniel P


    Aging confers an increased risk for developing seizure activity, especially within brain regions that mediate learning and synaptic plasticity. Brain derived neurotrophic factor (BDNF) is a member of the neurotrophin family that has an important role in regulating growth and development of the nervous system. BDNF is upregulated after pharmacological seizure induction and this upregulation contributes to enhanced excitability of the hippocampal mossy fiber-CA3 pathway, which is accompanied by neuropeptide Y (NPY) upregulation. Mice overexpressing a BDNF transgene in forebrain neurons provide an avenue for understanding the role of neurotrophic support in the aged hippocampus. In this study BDNF transgenic (TG) mice were utilized to determine whether increased BDNF expression through genetic manipulation resulted in age-related changes in hippocampal excitability and NPY expression. Spontaneous behavioral seizures were observed in TG mice, but not WT mice, past 5 months of age and the severity of behavioral seizures increased with age. Electrophysiological investigation of hippocampal CA3 activity indicated that slices from aged TG mice (86%), but not age-matched WT mice, or young TG mice, showed epileptiform activity in response to either repeated paired pulse or high frequency (tetanic) stimulation. Electrophysiological results were supported by the observation of robust ectopic NPY immunoreactivity in hippocampal mossy fibers of most aged TG mice (57%), which was absent in age-matched WT mice and young TG mice. The results from this study indicate that forebrain restricted BDNF overexpression produces age-related changes in hyperexcitability and NPY immunoreactivity in mossy fiber-CA3 pathway. Together, these data suggest that the capability for BDNF to promote epileptogenesis is maintained, and may be enhanced, in the aging hippocampus.

  3. Effects of heavy ions on rabbit tissues: damage to the forebrain

    Cox, A.B.; Keng, P.C.; Lee, A.C.; Lett, J.T. (Colorado State Univ., Fort Collins (USA). Dept. of Radiology and Radiation Biology)


    As part of a study of progressive radiation effects in normal tissues, the forebrains of New Zealand white rabbits (Oryctolagus cuniculus) (about 6 weeks old) were irradiated locally with single acute doses of /sup 60/Co ..gamma..-photons (LETsub(infinity)=0.3 keV/, Ne ions (LETsub(infinity)=35+-3 keV/ or Ar ions (LETsub(infinity)=90+-5 keV/ Other rabbits received fractionated doses of /sup 60/Co ..gamma..-photons according to a standard radiotherapeutic protocol. Irradiated rabbits and appropriately aged controls were sacrificed at selected intervals, and whole sagittal sections of their brains were examined for pathological changes. Forebrain damage was scored with subjective indices based on histological differences between the anterior (irradiated) and posterior (unirradiated) regions of the brain. Those indices ranged from zero (no apparent damage) to five (severe infarctions, etc.). At intermediate levels of forebrain damage, the relative biological effectiveness (r.b.e.) of each heavy ion was similar to that found for alopecia and cataractogenesis, and the early expression of the damage was also accelerated as the LETsub(infinity) increased. Late deterioration of the forebrain appeared also to be accelerated by increasing LETsub(infinity), although its accurate quantification was not possible because other priorities in the overall experimental design limited systematic sacrifice of the animals.

  4. Development of Wistar rat model of insulin resistance

    Jing Ai; Ning Wang; Mei Yang; Zhi-Min Du; Yong-Chun Zhang; Bao-Feng Yang


    AIM: To establish a simplified and reliable animal model of insulin resistance with low cost in Wistar rats. METHODS: Wistar rats were treated with a high fat emulsion by ig for 10 d. Changes of the diets, drinking and body weight were monitored every day and insulin resistance was evaluated by hyperinsulinemic-euglycemicclamp techniques and short insulin tolerance test using capillary blood glucose. Morphologic changes of liver, fat, skeletal muscles, and pancreatic islets were assessed under light microscope. mRNA expressions of GLUT2 and α-glucosidase in small intestine epithelium, GLUT4 in skeletal muscles and Kir6.2 in beta cell of islets were determined by in situ hybridization.RESULTS: KITT was smaller in treated animals (4.5±0.9)than in untreated control Wistar rats (6.8±1.5), and so was glucose injection rate. Both adipocyte hypertrophy and large pancreatic islets were seen in high fat fed rats,but no changes of skeletal muscles and livers wereobserved. mRNA levels of GLUT2, α-glucosidase in small intestinal epithelium and Kir6.2 mRNA in beta cells of islets increased, whereas that of GLUT4 in skeletal muscles decreased in high fat fed group compared with normal control group.CONCLUSION: An insulin resistance animal model in Wistar rats is established by ig special fat emulsion.

  5. Development of cardioplegic solution without potassium: experimental study in rat.

    Reichert, Karla; Carmo, Helison Rafael Pereira do; Lima, Fany; Torina, Anali Galluce; Vilarinho, Karlos Alexandre de Souza; Oliveira, Pedro Paulo Martins de; Silveira Filho, Lindemberg Mota; Severino, Elaine Soraya Barbosa de Oliveira; Petrucci, Orlando


    Myocardial preservation during open heart surgeries and harvesting for transplant are of great importance. The heart at the end of procedure has to resume its functions as soon as possible. All cardioplegic solutions are based on potassium for induction of cardioplegic arrest. To assess a cardioplegic solution with no potassium addition to the formula with two other commercially available cardioplegic solutions. The comparative assessment was based on cytotoxicity, adenosine triphosphate myocardial preservation, and caspase 3 activity. The tested solution (LIRM) uses low doses of sodium channel blocker (lidocaine), potassium channel opener (cromakalin), and actin/myosin cross bridge inhibitor (2,3-butanedione monoxime). Wistar rats underwent thoracotomy under mechanical ventilation and three different solutions were used for "in situ" perfusion for cardioplegic arrest induction: Custodiol (HTK), Braile (G/A), and LIRM solutions. After cardiac arrest, the hearts were excised and kept in cold storage for 4 hours. After this period, the hearts were assessed with optical light microscopy, myocardial ATP content and caspase 3 activity. All three solutions were evaluated for direct cytotoxicity with L929 and WEHI-164 cells. The ATP content was higher in the Custodiol group compared to two other solutions (P<0.05). The caspase activity was lower in the HTK group compared to LIRM and G/A solutions (P<0.01). The LIRM solution showed lower caspase activity compared to Braile solution (P<0.01). All solutions showed no cytotoxicity effect after 24 hours of cells exposure to cardioplegic solutions. Cardioplegia solutions without potassium are promised and aminoacid addition might be an interesting strategy. More evaluation is necessary for an optimal cardioplegic solution development.

  6. Development of cardioplegic solution without potassium: experimental study in rat

    Karla Reichert


    Full Text Available INTRODUCTION: Myocardial preservation during open heart surgeries and harvesting for transplant are of great importance. The heart at the end of procedure has to resume its functions as soon as possible. All cardioplegic solutions are based on potassium for induction of cardioplegic arrest. OBJECTIVE: To assess a cardioplegic solution with no potassium addition to the formula with two other commercially available cardioplegic solutions. The comparative assessment was based on cytotoxicity, adenosine triphosphate myocardial preservation, and caspase 3 activity. The tested solution (LIRM uses low doses of sodium channel blocker (lidocaine, potassium channel opener (cromakalin, and actin/myosin cross bridge inhibitor (2,3-butanedione monoxime. METHODS: Wistar rats underwent thoracotomy under mechanical ventilation and three different solutions were used for "in situ" perfusion for cardioplegic arrest induction: Custodiol (HTK, Braile (G/A, and LIRM solutions. After cardiac arrest, the hearts were excised and kept in cold storage for 4 hours. After this period, the hearts were assessed with optical light microscopy, myocardial ATP content and caspase 3 activity. All three solutions were evaluated for direct cytotoxicity with L929 and WEHI-164 cells. RESULTS: The ATP content was higher in the Custodiol group compared to two other solutions (P<0.05. The caspase activity was lower in the HTK group compared to LIRM and G/A solutions (P<0.01. The LIRM solution showed lower caspase activity compared to Braile solution (P<0.01. All solutions showed no cytotoxicity effect after 24 hours of cells exposure to cardioplegic solutions. CONCLUSION: Cardioplegia solutions without potassium are promised and aminoacid addition might be an interesting strategy. More evaluation is necessary for an optimal cardioplegic solution development.

  7. Evidence for the involvement of two areas of the zebra finch forebrain in sexual imprinting.

    Rollenhagen, A; Bischof, H J


    Sexual imprinting in male zebra finches is a two-step process, including an acquisition period early in life and a stabilization process normally occuring during the first courtship attempts of the male. During the acquisition period, a young male learns about its social environment. During stabilization, which can be delayed experimentally until day 100, it develops a preference for the appropriate object for courtship behavior on the basis of its previous and acute experience. Thereafter, this preference cannot be altered again. Exploring the physiological basis for imprinting, we have previously shown that the neurons of two forebrain areas (ANC and HAD) increase their spine density in the course of the stabilization process, while in two other areas (MNH and LNH) a decrease of spine density can be observed. With the present experiments, we tested the idea that the spine density decrease in MNH and LNH is the anatomical manifestation of the imprinting process. Previous behavioral experiments have shown that exposure to a nestbox after 100 days of age stabilizes the sexual preference of a zebra finch male as well as does exposure to a female. The present study shows that nestbox exposure also reduces the spine density in MNH and LNH, but has no effect on ANC and HAD. It has also been shown previously that treating males with an antiandrogen between days 40 and 100 affects the final preference of a male. The present experiment indicates that the same treatment affects spine growth during development in MNH and LNH and prevents the increase of spine density within HAD and ANC normally induced by exposure to a female. The results are interpreted as strong evidence for the involvement of MNH and LNH in sexual imprinting. Copyright 2000 Academic Press.

  8. TDP-43 pathology in the basal forebrain and hypothalamus of patients with amyotrophic lateral sclerosis.

    Cykowski, Matthew D; Takei, Hidehiro; Schulz, Paul E; Appel, Stanley H; Powell, Suzanne Z


    Amyotrophic lateral sclerosis is a neurodegenerative disease characterized clinically by motor symptoms including limb weakness, dysarthria, dysphagia, and respiratory compromise, and pathologically by inclusions of transactive response DNA-binding protein 43 kDa (TDP-43). Patients with amyotrophic lateral sclerosis also may demonstrate non-motor symptoms and signs of autonomic and energy dysfunction as hypermetabolism and weight loss that suggest the possibility of pathology in the forebrain, including hypothalamus. However, this region has received little investigation in amyotrophic lateral sclerosis. In this study, the frequency, topography, and clinical associations of TDP-43 inclusion pathology in the basal forebrain and hypothalamus were examined in 33 patients with amyotrophic lateral sclerosis: 25 men and 8 women; mean age at death of 62.7 years, median disease duration of 3.1 years (range of 1.3 to 9.8 years). TDP-43 pathology was present in 11 patients (33.3%), including components in both basal forebrain (n=10) and hypothalamus (n=7). This pathology was associated with non-motor system TDP-43 pathology (Χ2=17.5, p=0.00003) and bulbar symptoms at onset (Χ2=4.04, p=0.044), but not age or disease duration. Furthermore, TDP-43 pathology in the lateral hypothalamic area was associated with reduced body mass index (W=11, p=0.023). This is the first systematic demonstration of pathologic involvement of the basal forebrain and hypothalamus in amyotrophic lateral sclerosis. Furthermore, the findings suggest that involvement of the basal forebrain and hypothalamus has significant phenotypic associations in amyotrophic lateral sclerosis, including site of symptom onset, as well as deficits in energy metabolism with loss of body mass index.

  9. Dynamic expression and localization of c-MET isoforms in the developing rat pancreas.

    Wu, Yulong; Cheng, Mei; Shi, Zhen; Feng, Zhenqing; Guan, Xiaohong


    Pancreata from Sprague Dawley rats of different developmental stages were studied to determine the expression and cellular localization of different c-MET isoforms in the developing rat pancreas. Pancreatic mRNA and protein expression levels of c-MET at different developmental stages from embryo to adult were detected by reverse transcription-polymerase chain reaction and by western blotting. To identify the cellular localization of c-MET protein in the developing rat pancreas, double immunofluorescent staining was performed using antibodies for cell type-specific markers and for c-MET. The expression of two isoforms of c-MET (190 kDa and 170 kDa) coincided with the development of the pancreas. The 190 kDa isoform of c-MET is expressed during embryonic stages, and its expression is replaced by the expression of the 170 kDa isoform as the pancreas develops. Only the 170 kDa isoform is expressed in the adult rat pancreas. Throughout all stages of pancreatic development, c-MET is expressed by vimentin-positive cells. In contrast, c-MET staining was stronger in rat pancreata from newborn to adult stages and overlapped with insulin-positive beta-cells. The dynamic expression and localization of different c-MET isoforms in the rat pancreas during different developmental stages indicates that distinct c-MET isoform might be involved in different aspects of pancreatic development.

  10. Impairment of synaptic development in the hippocampus of diabetic Goto-Kakizaki rats.

    Matsunaga, Yuki; Negishi, Takayuki; Hatakeyama, Akinori; Kawagoe, Yuta; Sawano, Erika; Tashiro, Tomoko


    Insulin receptor signaling has been shown to regulate essential aspects of CNS function such as synaptic plasticity and neuronal survival. To elucidate its roles during CNS development in vivo, we examined the synaptic and cognitive development of the spontaneously diabetic Goto-Kakizaki (GK) rats in the present study. GK rats are non-obese models of type 2 diabetes established by selective inbreeding of Wistar rats based on impaired glucose tolerance. Though they start exhibiting only moderate hyperglycemia without changes in plasma insulin levels from 3 weeks postnatally, behavioral alterations in the open-field as well as significant impairments in memory retention compared with Wistar rats were observed at 10 weeks and were worsened at 20 weeks. Alterations in insulin receptor signaling and signs of insulin resistance were detected in the GK rat hippocampus at 3 weeks, as early as in other insulin-responsive peripheral tissues. Significant reduction of an excitatory postsynaptic scaffold protein, PSD95, was found at 5w and later in the hippocampus of GK rats due to the absence of a two-fold developmental increase of this protein observed in Wistar control rats between 3 and 20w. In the GK rat hippocampus, NR2A which is a NMDA receptor subunit selectively anchored to PSD95 was also reduced. In contrast, both NR2B and its anchoring protein, SAP102, showed similar developmental profiles in Wistar and GK rats with expression peaks at 2 and 3w. The results suggest that early alterations in insulin receptor signaling in the GK rat hippocampus may affect cognitive performance by suppressing synaptic maturation.

  11. Development and characterization of a novel rat model of estrogen-induced mammary cancer.

    Dennison, Kirsten L; Samanas, Nyssa Becker; Harenda, Quincy Eckert; Hickman, Maureen Peters; Seiler, Nicole L; Ding, Lina; Shull, James D


    The ACI rat model of 17β-estradiol (E2)-induced mammary cancer is highly relevant for use in establishing the endocrine, genetic, and environmental bases of breast cancer etiology and identifying novel agents and strategies for preventing breast cancer. E2 treatment rapidly induces mammary cancer in female ACI rats and simultaneously induces pituitary lactotroph hyperplasia and adenoma. The pituitary tumors can result in undesired morbidity, which compromises long-term studies focused on mammary cancer etiology and prevention. We have defined the genetic bases of susceptibility to E2-induced mammary cancers and pituitary tumors and have utilized the knowledge gained in these studies to develop a novel inbred rat strain, designated ACWi, that retains the high degree of susceptibility to E2-induced mammary cancer exhibited by ACI rats, but lacks the treatment-related morbidity associated with pituitary lactotroph hyperplasia/adenoma. When treated with E2, female ACWi rats developed palpable mammary cancer at a median latency of 116 days, an incidence of 100% by 161 days and exhibited an average of 15.6 mammary tumors per rat following 196 days of treatment. These parameters did not differ from those observed for contemporaneously treated ACI rats. None of the E2-treated ACWi rats were killed before the intended experimental end point due to any treatment-related morbidity other than mammary cancer burden, whereas 20% of contemporaneously treated ACI rats exhibited treatment-related morbidity that necessitated premature killing. The ACWi rat strain is well suited for use by those in the research community, focusing on breast cancer etiology and prevention.

  12. Follicle Development of Xenotransplanted Sheep Ovarian Tissue into Male and Female Immunodeficient Rats

    Leila Sadat Tahaei


    Full Text Available Background: This study aimed to assess follicle survival after xenotransplantation of sheep ovarian tissue into male and female immunodeficient rats. We evaluated the effects of gonadotropin treatment on follicular development in the transplanted tissue. Materials and Methods: In this experimental study, sheep ovarian cortical strips were transplanted into the neck back muscles of 8 male and 8 female immunodeficient, castrated rats. Fourteen days after surgery, each rat was treated with human menopausal gonadotropin (hMG for 9 weeks. One day after the last injection, ovarian tissues were removed and fixed for histology assessment. Histology analyses were performed before and after grafting. Estradiol (E2 levels were measured before and after gonadectomy, and at the end of the experiment. The control group consisted of 7 male and 7 female noncastrated/ non-grafted rats and the sham group comprised 7 male and 7 female castrated/ non-grafted rats for comparison of serum E2 concentrations. Results: The percentage of primordial follicles decreased after transplantation in male (25.97% and female (24.14% rats compared to the control group (ovarian tissue nongrafted; 37.51%. Preantral follicles increased in the male (19.5% and female (19.49% transplanted rats compared to the control group (11.4%. Differences in antral follicles between male (0.06 ± 0.0% and female (0.06 ± 0.0% rats were not noticeable compared to control (1.25 ± 0.0% rats. We observed a significantly higher percent of mean E2 secretion in grafted males compared to grafted females (P˂0.05. Conclusion: Despite significant differences in E2 secretion between xenografted male and female rats, we observed no statistical differences in terms of follicular development.

  13. The uptake and distribution of 14-C-mescaline in different organs of developing rat.

    Shah, N S; Shah, K R; Lawrence, R S; Neely, A E


    Rats of 1,4,8,12,20, and 60 days postnatal age were injected ip with 14-C-mescaline (50 nCi/g). The levels of mescaline and its deaminated metabolite, 3,4,5-trimethoxyphenylacetic acid, were examined in the brain, liver, heart, spleen, lung, and kidney at 30, 60, 90, and 120 min. Mescaline was rapidly taken up by all the organs examined. In general, the organs of younger rats accumulated much larger amounts than those of adult animals. Brain concentrated the lowest amounts in comparison with other tissues. In the brain, the uptake was the highest in 1-day-old rats and decreased with age. The disappearance of mescaline in various organs was comparatively slower in younger animals than in 20-day or older rats. Rats immediately after birth and uptake was the highest in 1-day-old rats and decreased with age. The disappearance of mescaline in various organs was comparatively slower in younger animals than in 20-day or older rats. Rats immediately after birth and up to 20 days of age metabolized mescaline less efficiently than adults. From the data, it appears that the blood-brain barrier for mescaline develops gradually with age but is not completely impermeable in adults.

  14. Moderate hyperglycemia augments ischemic brain damage: a neuropathologic study in the rat.

    Pulsinelli, W A; Waldman, S; Rawlinson, D; Plum, F


    We compared the effects of glucose injection with those of saline or mannitol on ischemic brain damage and brain water content in a four-vessel occlusion (4-VO) rat model, which simultaneously causes severe forebrain ischemia and moderate hindbrain ischemia. Glucose given before onset of ischemia was followed by severe brain injury, with necrosis of the majority of neocortical neurons and glia, substantial neuronal damage throughout the remainder of forebrain, and severe brain edema. By comparison, saline injection before forebrain ischemia resulted in only scattered ischemic damage confined to neurons and no change in the brain water content. Mannitol injection before 4-VO or D-glucose injection during or after 4-VO produced no greater forebrain damage than did the saline injection. Morphologic damage in the cerebellum, however, was increased by D-glucose injection given either before or during 4-VO. The results demonstrate that hyperglycemia before severe brain ischemia or during moderate ischemia markedly augments morphologic brain damage.

  15. Expression and location of α-fetoprotein during rat colon development

    Xiao-Yan Liu; Dan Dong; Peng Sun; Jun Du; Luo Gu; Ying-Bin Ge


    AIM: To investigate the expression of a-fetoprotein (AFP), a cancer-associated fetal glycoprotein, and its involvement during rat colon development.METHODS: Colons from Sprague-Dawley rat fetuses, young and adult (8 wk old) animals were used in this study. Expression levels of AFP in colons of different development stage were detected by reversetranscriptase PCR (RT-PCR) and Western blotting. To identify the cell location of AFP in the developing rat colons, double-immunofluorescent staining was performed using antibodies to specific cell markers and AFP, respectively. RESULTS: The highest levels of AFP mRNA were detected in colons of rats at embryonic day 18.5 (e18.5). Compared to e18.5 d, the AFP expression was significantly decreased during rat development [85% for e20.5, P < 0.05, 58% for postnatal day 0.5 (P0.5), P < 0.05, 37% for P7, P < 0.05, 24% for P14, P < 0.05, and 11% for P21, P < 0.05] and undetected in adult rats. Only the 72-kDa isoform of AFP was detected by Western blotting, the expression pattern was similar to AFP mRNA and conformed to the results of mRNA expression. The AFP positive staining was identical to different distribution patterns in fetuses, young and adult animals and positive staining for both AFP and vimentin was overlapped in mesenchymal cells at each stage tested. CONCLUSION: This study has for the first time This study has for the first time demonstrated that AFP is localized in the mesenchyme of rat colon from the embryo to the weaning stage by immunofluorescence and presents 72-kDa isoform in the developing rat colons by Western blotting. The dynamic expression of AFP in the various developmental stages of the colon indicates that AFP might be involved in many aspects of colon development.

  16. Prenatal Development of Interlimb Motor Learning in the Rat Fetus

    Robinson, Scott R.; Kleven, Gale A.; Brumley, Michele R.


    The role of sensory feedback in the early ontogeny of motor coordination remains a topic of speculation and debate. On E20 of gestation (the 20th day after conception, 2 days before birth), rat fetuses can alter interlimb coordination after a period of training with an interlimb yoke, which constrains limb movement and promotes synchronized,…

  17. Post-thymic T-cell development in the rat

    Kampinga, J; Groen, H; Klatter, FA; Pater, JM; VanPetersen, AS; Roser, B; Nieuwenhuis, P; Aspinall, R


    The presence or absence of CD4, CD8, Thy-1, RT6 and CD45RC revealed a number of T-cell subpopulations in the rat. Vascular thymus transplantation was used in RT7 congenics to establish the lineage relationship between these subpopulations by following phenotypic changes after thymus emigration. We f

  18. Reduced Cholinergic Basal Forebrain Integrity Links Neonatal Complications and Adult Cognitive Deficits After Premature Birth.

    Grothe, Michel J; Scheef, Lukas; Bäuml, Josef; Meng, Chun; Daamen, Marcel; Baumann, Nicole; Zimmer, Claus; Teipel, Stefan; Bartmann, Peter; Boecker, Henning; Wolke, Dieter; Wohlschläger, Afra; Sorg, Christian


    Prematurely born individuals have an increased risk for long-term neurocognitive impairments. In animal models, development of the cholinergic basal forebrain (cBF) is selectively vulnerable to adverse effects of perinatal stressors, and impaired cBF integrity results in lasting cognitive deficits. We hypothesized that cBF integrity is impaired in prematurely born individuals and mediates adult cognitive impairments associated with prematurity. We used magnetic resonance imaging-based volumetric assessments of a cytoarchitectonically defined cBF region of interest to determine differences in cBF integrity between 99 adults who were born very preterm and/or with very low birth weight and 106 term-born control subjects from the same birth cohort. Magnetic resonance imaging-derived cBF volumes were studied in relation to neonatal clinical complications after delivery and intelligence measures (IQ) in adulthood. In adults who were born very preterm and/or with very low birth weight, cBF volumes were significantly reduced compared with term-born adults (-4.5% [F1,202 = 11.82, p = .001]). Lower cBF volume in adults who were born very preterm and/or with very low birth weight was specifically associated with both neonatal complications (rpart,92 = -.35, p premature birth and links neonatal complications with long-term cognitive outcome. Data suggest that cholinergic system abnormalities may play a relevant role for long-term neurocognitive impairments associated with premature delivery. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  19. Mechanisms underlying the basal forebrain enhancement of top-down and bottom-up attention.

    Avery, Michael C; Dutt, Nikil; Krichmar, Jeffrey L


    Both attentional signals from frontal cortex and neuromodulatory signals from basal forebrain (BF) have been shown to influence information processing in the primary visual cortex (V1). These two systems exert complementary effects on their targets, including increasing firing rates and decreasing interneuronal correlations. Interestingly, experimental research suggests that the cholinergic system is important for increasing V1's sensitivity to both sensory and attentional information. To see how the BF and top-down attention act together to modulate sensory input, we developed a spiking neural network model of V1 and thalamus that incorporated cholinergic neuromodulation and top-down attention. In our model, activation of the BF had a broad effect that decreases the efficacy of top-down projections and increased the reliance of bottom-up sensory input. In contrast, we demonstrated how local release of acetylcholine in the visual cortex, which was triggered through top-down gluatmatergic projections, could enhance top-down attention with high spatial specificity. Our model matched experimental data showing that the BF and top-down attention decrease interneuronal correlations and increase between-trial reliability. We found that decreases in correlations were primarily between excitatory-inhibitory pairs rather than excitatory-excitatory pairs and suggest that excitatory-inhibitory decorrelation is necessary for maintaining low levels of excitatory-excitatory correlations. Increased inhibitory drive via release of acetylcholine in V1 may then act as a buffer, absorbing increases in excitatory-excitatory correlations that occur with attention and BF stimulation. These findings will lead to a better understanding of the mechanisms underyling the BF's interactions with attention signals and influences on correlations.

  20. Temperature manipulation of neuronal dynamics in a forebrain motor control nucleus

    Mindlin, Gabriel B.


    Different neuronal types within brain motor areas contribute to the generation of complex motor behaviors. A widely studied songbird forebrain nucleus (HVC) has been recognized as fundamental in shaping the precise timing characteristics of birdsong. This is based, among other evidence, on the stretching and the “breaking” of song structure when HVC is cooled. However, little is known about the temperature effects that take place in its neurons. To address this, we investigated the dynamics of HVC both experimentally and computationally. We developed a technique where simultaneous electrophysiological recordings were performed during temperature manipulation of HVC. We recorded spontaneous activity and found three effects: widening of the spike shape, decrease of the firing rate and change in the interspike interval distribution. All these effects could be explained with a detailed conductance based model of all the neurons present in HVC. Temperature dependence of the ionic channel time constants explained the first effect, while the second was based in the changes of the maximal conductance using single synaptic excitatory inputs. The last phenomenon, only emerged after introducing a more realistic synaptic input to the inhibitory interneurons. Two timescales were present in the interspike distributions. The behavior of one timescale was reproduced with different input balances received form the excitatory neurons, whereas the other, which disappears with cooling, could not be found assuming poissonian synaptic inputs. Furthermore, the computational model shows that the bursting of the excitatory neurons arises naturally at normal brain temperature and that they have an intrinsic delay at low temperatures. The same effect occurs at single synapses, which may explain song stretching. These findings shed light on the temperature dependence of neuronal dynamics and present a comprehensive framework to study neuronal connectivity. This study, which is based on

  1. The medial forebrain bundle as a target for deep brain stimulation for obsessive-compulsive disorder.

    Coenen, Volker A; Schlaepfer, Thomas E; Goll, Peter; Reinacher, Peter C; Voderholzer, Ulrich; Tebartz van Elst, Ludger; Urbach, Horst; Freyer, Tobias


    Deep brain stimulation (DBS) is a promising putative modality for the treatment of refractory psychiatric disorders such as major depression and obsessive-compulsive disorder (OCD). Several targets have been posited; however, a clear consensus on differential efficacy and possible modes of action remain unclear. DBS to the supero-lateral branch of the medial forebrain bundle (slMFB) has recently been introduced for major depression (MD). Due to our experience with slMFB stimulation for MD, and because OCD might be related to similar dysfunctions of the reward system, treatment with slMFB DBS seams meaningful. Here we describe our first 2 cases together with a hypothetical mode of action. We describe diffusion tensor imaging (DTI) fiber tractographically (FT)-assisted implantation of the bilateral DBS systems in 2 male patients. In a selected literature overview, we discuss the possible mode of action. Both patients were successfully implanted and stimulated. The follow-up time was 12 months. One patient showed a significant response (Yale-Brown Obsessive-Compulsive Scale [YBOCS] reduction by 35%); the other patient reached remission criteria 3 months after surgery (YBOCS<14) and showed mild OCD just above the remission criterion at 12 months follow-up. While the hypermetabolism theory for OCD involves the cortico-striato-thalamo-cortical (CSTC) network, we think that there is clinical evidence that the reward system plays a crucial role. Our findings suggest an important role of this network in mechanisms of disease development and recovery. In this uncontrolled case series, continuous bilateral DBS to the slMFB led to clinically significant improvements of ratings of OCD severity. Ongoing research focuses on the role of the reward system in OCD, and its yet-underestimated role in this underlying neurobiology of the disease.

  2. Effect of Sinai San decoction on the development of non-alcoholic steatohepatitis in rats

    Qi Zhang; Yan Zhao; Deng-Ben Zhang; Li-Jun Sun


    AIM: To explore the effect of Sinai san decoction on the development of non-alcoholic steatohepatitis induced by CCL4 combined with a fat-rich diet in rats.METHODS: Twenty-seven Sprague-Dawley rats were divided into three groups randomly: control group (n = 9),model group (n = 9) and treatment group (n = 9). The rats of model group and treatment group were given small dosage of CCL4 combined with a fat-rich diet, andthose of control group were given normal diet. After four weeks of fat-rich diet feeding, the rats of treatment group were given Sinai san decoction. The serum levels of aminotransferase and lipid were measured, and the pathology of livers was observed by HE staining after the rats were sacrificed at eight weeks.RESULTS: The rats' livers presented the pathology of steatosis and inflammation with higher serum levels of ALT and AST in the model group. In the treatment group the serum ALT and AST levels decreased significantly and were close to the control group. The hepatic inflammation scores also decreased markedly, but were still higher than those of control group. And the degree of hepatocyte steatosis was similar to that of model group.CONCLUSION: Sinai san decoction may ameliorate the hepatic inflammation of rats with steatohepatitis induced by small dosage of CCL4 combined with a fat-rich diet,but does not prevent the development of hepatocyte steatosis.

  3. Serum N-glycome biomarker for monitoring development of DENA-induced hepatocellular carcinoma in rat

    Fang Meng


    Full Text Available Abstract Background There is a demand for serum markers for the routine assessment of the progression of liver cancer. We previously found that serum N-linked sugar chains are altered in hepatocellular carcinoma (HCC. Here, we studied glycomic alterations during development of HCC in a rat model. Results Rat HCC was induced by the hepatocarcinogen, diethylnitrosamine (DENA. N-glycans were profiled using the DSA-FACE technique developed in our laboratory. In comparison with control rats, DENA rats showed a gradual but significant increase in two glycans (R5a and R5b in serum total N-glycans during progression of liver cirrhosis and cancer, and a decrease in a biantennary glycan (P5. The log of the ratio of R5a to P1 (NGA2F and R5b to P1 [log(R5a/P1 and log(R5b/P1] were significantly (p Conclusions: We found an increase in core-α-1,6-fucosylated glycoproteins in serum and liver of rats with HCC, which demonstrates that fucosylation is altered during progression of HCC. Our GlycoTest model can be used to monitor progression of HCC and to follow up treatment of liver tumors in the DENA rat. This GlycoTest model is particularly important because a rapid non-invasive diagnostic procedure for tumour progression in this rat model would greatly facilitate the search for anticancer drugs.

  4. Neonatal sensory deprivation promotes development of absence seizures in adult rats with genetic predisposition to epilepsy.

    Sitnikova, Evgenia


    Absence epilepsy has age-related onset. In a WAG/Rij rat genetic model, absence seizures appear after puberty and they are increased with age. It is known that (1) epileptic activity in WAG/Rij rats is initiated at the perioral area in the somatosensory cortex; (2) sensory deprivation, i.e., whisker trimming during the critical period of development, could enhance excitatory activity in the somatosensory cortex. It is hypothesized that the cortex may become more excitable after neonatal vibrissae removal, and this may precipitate absence seizures in adult rats. We found that whisker trimming during the first postnatal weeks caused more rapid development of EEG seizure activity in adult WAG/Rij rats. Epileptic discharges in the trimmed rats were more numerous (vs control), showed longer duration and often appeared in desynchronized and drowsy EEG. The number of absence-like spindle-shaped EEG events (spike-wave spindles) in the whisker-trimmed rats was higher than in control, especially during the intermediate sleep state. An age-dependent increase of intermediate sleep state was found in the trimmed rats, but not in the intact animals. We discuss epigenetic factors that can modulate absence epilepsy in genetically prone subjects.

  5. Embryo development alteration in rats treated with lapachol

    Juliana Maganha


    Full Text Available Lapachol, a naphthoquinone extracted from plants of the genus Tabebuia (family Bignoneaceae, showed multiple therapeutic activities. Pregnant Wistar rats were treated with Lapachol from the 1st to the 4th (pre-implantation period and from 5th to 7th (implantation period post insemination day (PID. Mothers were sacrificed on the 5th or on the15th PID. Number of corpora lutea, preimplantation embryo, blastocysts, live and dead fetuses and resorptions were counted. There were no signs of maternal toxicity. The number and the morphology of embryos, during oviduct development (pre-implantation period, did not seem to be affected by this drug, but during the implantation period, lapachol was toxic causing the death of embryos and intrauterine growth retardation.O Lapachol é uma naftoquinona, extraída de plantas do gênero Tabebuia (família Bignoneaceae, que apresenta múltiplas atividades terapêuticas. Estudos prévios sobre o efeito do lapachol no início do desenvolvimento embrionário de ratas são controversos. No presente trabalho ratas Wistar prenhes foram tratadas com lapachol do 1º ao 4º dias pós-inseminação (período de pré-implantação e do 5º ao 7º dias (período de implantação do blastocisto. As mães foram sacrificadas no 5º o e no 15º dia pós-inseminação. Contaram-se corpos lúteos, embriões em fase de pré-implantação, blastocistos, fetos vivos e mortos e reabsorções.Fetos e placentas foram pesados. Não ocorreram indícios de toxicidade materna.O número e a morfologia dos embriões durante o desenvolvimento tubário não foi afetado pela droga, mas durante o período de implantação o lapachol foi tóxico, causando morte de embriões e retardo de crescimento intra-uterino.

  6. Expressions of Estrogen Receptorαand β in the Development and Maturation of Rat Heart


    1 IntroductionPhysiological effects of estrogen on myocardium are mediated by two intracellular estrogen receptors (ER), alpha (ERα) and beta (ERβ). Their role in cardiovascular physiology is not well understood. For this reason,we investigated the expressions of ERα and ERβ in the development and maturation of rat heart.2 Materials and Methods2.1 Experimental animals The study on changes of ERs was performed in six newborn rats with both sexes and six adult female Wistar rats respedively.2.2 Semiquantitati...

  7. Increased dopamine receptor expression and anti-depressant response following deep brain stimulation of the medial forebrain bundle.

    Dandekar, Manoj P; Luse, Dustin; Hoffmann, Carson; Cotton, Patrick; Peery, Travis; Ruiz, Christian; Hussey, Caroline; Giridharan, Vijayasree V; Soares, Jair C; Quevedo, Joao; Fenoy, Albert J


    Among several potential neuroanatomical targets pursued for deep brain stimulation (DBS) for treating those with treatment-resistant depression (TRD), the superolateral-branch of the medial forebrain bundle (MFB) is emerging as a privileged location. We investigated the antidepressant-like phenotypic and chemical changes associated with reward-processing dopaminergic systems in rat brains after MFB-DBS. Male Wistar rats were divided into three groups: sham-operated, DBS-Off, and DBS-On. For DBS, a concentric bipolar electrode was stereotactically implanted into the right MFB. Exploratory activity and depression-like behavior were evaluated using the open-field and forced-swimming test (FST), respectively. MFB-DBS effects on the dopaminergic system were evaluated using immunoblotting for tyrosine hydroxylase (TH), dopamine transporter (DAT), and dopamine receptors (D1-D5), and high-performance liquid chromatography for quantifying dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in brain homogenates of prefrontal cortex (PFC), hippocampus, amygdala, and nucleus accumbens (NAc). Animals receiving MFB-DBS showed a significant increase in swimming time without alterations in locomotor activity, relative to the DBS-Off (p<0.039) and sham-operated groups (p<0.014), indicating an antidepressant-like response. MFB-DBS led to a striking increase in protein levels of dopamine D2 receptors and DAT in the PFC and hippocampus, respectively. However, we did not observe appreciable differences in the expression of other dopamine receptors, TH, or in the concentrations of dopamine, DOPAC, and HVA in PFC, hippocampus, amygdala, and NAc. This study was not performed on an animal model of TRD. MFB-DBS rescues the depression-like phenotypes and selectively activates expression of dopamine receptors in brain regions distant from the target area of stimulation. Copyright © 2017. Published by Elsevier B.V.

  8. 亚低温对大鼠短暂性全脑缺血后APE/Ref-1表达、神经元凋亡的影响%Effects of Hypothermia on apoptosis and the expression of APE/Ref-1 following transient forebrain ischemia in rat

    汪效松; 雷惠新; 张旭; 李智文; 张志坚


    To explore the neuroprotective mechanism of mild hypothermia by studying the effects of mild hypothermia on the expression of APE/Ref - 1 and neuronal apoptosis in the hippocampal CA1 subregion after transient global cerebral ischemia in rats. [Methods] A model of transient global cerebral ischemia was made by lOmin of bilateral common carotid artery occlusion and hypotension in rat. Expression of the APE/Ref - 1 protein was detected by immunohisto-chemical analysis. Apoptosis after global ischemia was observed with TUNEL. [Results] Immunohisto - chemistry showed the nuclear expression of APE/Ref - 1 in the control brains. Nuclear decreasing immunoreactivity of APE/Ref - 1 started at 1st day and became significantly at 2nd day and the TUNEL positive neurons were observed at 2nd day and became significant at 3rd day in the hippocampal CA1 subregion after transient global ischemia in normothermic group. Mild hypothermic ischemic group was less decreased in nuclear immunoreactivity of APE/Ref- 1 (P <0. 01) and less quantitv of apoptotic neurons(P<0.01) than those of normothermic group . Double staining with APE/Ref- 1 and TUNEL clearly showed that the neurons which lost APE/Ref- 1 immunoreactivity became TUNEL positive. [Conclusions] The mild hypothermia had remarkable neuroprotection action. The inhibition of APE/Ref - 1 reduction and ischemic neuronal apoptosis were assumed to be a neuroprotective mechanism of mild hypothermia.%[目的]通过大鼠短暂全脑缺血模型来探讨亚低温对大鼠脑缺血后APE/Ref-1(apurinic/apyrimidimic endonuclase/redox factor 1,无嘌呤/无嘧啶核酸内切酶/氧化还原因子-1)蛋白表达及缺血性神经元凋亡的影响,揭示亚低温的部分神经保护机制.[方法]采用“双侧颈总动脉夹闭+低血压法”建立大鼠短暂性全脑缺血模型.实验动物分假手术组、手术后常温存活1d、2d、3d组及手术后亚低温存活1d、2d、3d组.用免疫组化方法检测各组APE/Ref-1蛋白的

  9. Prenatal exposure to lambda-cyhalothrin alters brain dopaminergic signaling in developing rats.

    Dhuriya, Yogesh K; Srivastava, Pranay; Shukla, Rajendra K; Gupta, Richa; Singh, Dhirendra; Parmar, Devendra; Pant, Aditya B; Khanna, Vinay K


    The present study is focused to decipher the molecular mechanisms associated with dopaminergic alterations in corpus striatum of developing rats exposed prenatally to lambda-cyhalothrin (LCT), a new generation type II synthetic pyrethroid. There was no significant change in the mRNA and protein expression of DA-D1 receptors at any of the doses of LCT (0.5, 1 and 3mg/kg body weight) in corpus striatum of developing rats exposed prenatally to LCT on PD22 and PD45. Prenatal exposure to LCT (1 and 3mg/kg body weight) resulted to decrease the levels of mRNA and protein of DA-D2 receptors in corpus stratum of developing rats on PD22 as compared to controls. Decrease in the binding of 3H-Spiperone in corpus striatum, known to label DA-D2 receptors was also distinct in developing rats on PD22. These rats also exhibited decrease in the expression of proteins - TH, DAT and VMAT2 involved in pre-dopaminergic signaling. Further, decrease in the expression of DARPP-32 and pCREB associated with increased expression of PP1α was evident in developing rats on PD22 as compared to controls. Interestingly, a trend of recovery in the expression of these proteins was observed in developing rats exposed to LCT at moderate dose (1.0mg/kg body weight) while alteration in the expression of these proteins continued to persist in those exposed at high dose (3.0mg/kg body weight) on PD45 as compared to respective controls. No significant change in the expression of any of these proteins was observed in corpus striatum of developing rats prenatally exposed to LCT at low dose (0.5mg/kg body weight) on PD22 and PD45 as compared to respective controls. The results provide interesting evidence that alterations in dopaminergic signaling on LCT exposure are due to selective changes in DA-D2 receptors in corpus striatum of developing rats. Further, these changes could be attributed to impairment in spontaneous motor activity on LCT exposure in developing rats. Copyright © 2017 Elsevier B.V. All

  10. Homozygous and Heterozygous p53 Knockout Rats Develop Metastasizing Sarcomas with High Frequency

    van Boxtel, Ruben; Kuiper, Raoul V.; Toonen, Pim W.; van Heesch, Sebastiaan; Hermsen, Roel; de Bruin, Alain; Cuppen, Edwin


    The TP53 tumor suppressor gene is mutated in the majority of human cancers. Inactivation of p53 in a variety of animal models results in early-onset tumorigenesis, reflecting the importance of p53 as a gatekeeper tumor suppressor. We generated a mutant Tp53 allele in the rat using a target-selected mutagenesis approach. Here, we report that homozygosity for this allele results in complete loss of p53 function. Homozygous mutant rats predominantly develop sarcomas with an onset of 4 months of age with a high occurrence of pulmonary metastases. Heterozygous rats develop sarcomas starting at 8 months of age. Molecular analysis revealed that these tumors exhibit a loss-of-heterozygosity of the wild-type Tp53 allele. These unique features make this rat highly complementary to other rodent p53 knockout models and a versatile tool for investigating tumorigenesis processes as well as genotoxic studies. PMID:21854749

  11. The kinetics and distribution of different macrophage populations in the developing rat skin


    Macrophages play important roles in host defense and homeostasis. In contrast to adulthood, far less is known about macrophage populations in fetuses and neonates. Macrophages were evaluated in the developing rat skin at different anatomical sites (head, anterior dorsal, posterior dorsal, and abdomen) of F344 rats obtained on gestational days 18 and 20, on neonatal days 1-21, and at adult weeks 5-15. The numbers of macrophages in the epidermis, dermis or perifollicular...

  12. Morphology of CA3 non-pyramidal cells in the developing rat hippocampus.

    Gaïarsa, Jean-Luc; Khalilov, Ilgam; Gozlan, Henri; Ben-Ari, Yehezkel


    International audience; Although several investigations have shown that the local GABAergic circuit in the rat hippocampus is functional very early in development, this result has not been yet completed by the investigation of the full dendritic and axonal arborization of the neonatal interneurones. In the present study, intracellular injection of biocytin was used to assess the branching pattern of interneurones in the hippocampal CA3 region of rat between 2 and 6 days of age. Based on their...

  13. Zinc influences on brain development, pituitary an thyroidfunction iniodine-deficient pregnant and neonatal rats

    Xiaoxia Yang; Jianchao Bian; Xin Wang; Haiming Wang; Yongping Liu; Shuzhen Wang; Zhichun Mu; Xinluan Li


    BACKGROUND: Zinc (Zn) has been shown to greatly influence brain development. Zn supplements may reduce injury to cell membranes of the thyroid gland due to iodine deficiency. OBJECTIVE: To establish an iodine deficiency rat model using low-iodine food, which was supplemented with compound Zn and Zn gluconate, to observe the effects of Zn on brain development, as well as pituitary gland and thyroid gland function in iodine-deficient rats. DESIGN, TIME AND SETTING: Randomized grouping study of neural development was performed in the central laboratory of Shandong Institute for Prevention and Treatment of Endemic Disease from 1998 to 1999. MATERIALS: A total of 270 Wistar, female rats, one month after weaning, were used in this study, including 150 pregnant and 120 neonatal rats. Rats were randomly divided into six groups: normal control, model, iodine, compound Zn, iodine and compound Zn, and zinc gluconate. Each group contained 25 pregnant rats and 20 nenoatal rats. METHODS: The pregnant rats and 20 neonatal rats, and well as the normal group, were fed standard chow and allowed free access to tap water (containing 5 μ g/L iodine and 1 mg/L Zn). The remaining five groups were fed low-iodine chow. However, the model group received distilled water, the iodine group received potassium-iodide distilled water (containing 300 μ g/L iodine), the compound Zn group received distilled water and intragastrically administrated 10 mL/kg compound Zn solution, once per day, the iodine and compound Zn group received distilled water with 300 p g/L iodine and intragastrically administrated 10 mL/kg compound Zn solution, once per day. All treatments lasted 90 days. MAIN OUTCOME MEASURES: All pregnant rats were sacrificed on the day 21 of pregnancy. Body mass, number and rate of fetal absorption, as well as fetal death and malformation, were determined. Thyroid and pituitary gland weights were measured, as well as serum levels of thyroid hormone, gonadotropin, and sex hormones. In the

  14. Perinatal and chronic hypothyroidism impair behavioural development in male and female rats.

    Wijk, van N.; Rijntjes, E.; Heijning, van de B.J.


    Perinatal and chronic hypothyroidism impair behavioural development in male and female rats. EXP PHYSIOL 00(0) 000-000, 0000. - A lack of thyroid hormone, i.e. hypothyroidism, during early development results in multiple morphological and functional alterations in the developing brain. In the presen

  15. Investigation of diazepam efficacy on anxiety-like behavior in hemiparkinsonian rats.

    O'Connor, Katherine A; Feustel, Paul J; Ramirez-Zamora, Adolfo; Molho, Eric; Pilitsis, Julie G; Shin, Damian S


    There is growing recognition that anxiety disorders have a greater impact on quality of life in Parkinson's disease than motor symptoms. Yet, little is known about the pathophysiology underlying this non-motor symptom in Parkinson's disease which poses a considerable barrier in developing effective treatment strategies. Here, we administered diazepam to hemiparkinsonian and non-parkinsonian rats and assessed its efficacy in three anxiety behavioral tests. At present, no information about this exists in preclinical research with sparse data in the clinical literature. Moreover, diazepam is an acute anxiolytic which makes this drug a suitable research tool to unmask differences in anxiety-like behavior. Using the unilateral, medial forebrain bundle 6-hydroxydopamine rat model of Parkinson's disease, we noted that hemiparkinsonian rats had more baseline anxiety-like behavior with 60% of them exhibiting high anxiety (HA) behavior in the elevated plus maze. In contrast, 41% of sham-lesioned rats and 8% of naïve rats exhibited HA behavior. Next, we employed the elevated plus maze and noted that diazepam (1.5mg/kg) was anxiolytic in low anxiety (LA) sham-lesioned (p=0.006) and HA sham-lesioned rats (p=0.016). Interestingly, diazepam was anxiolytic for LA hemiparkinsonian rats (p=0.017), but not for HA hemiparkinsonian rats (p=0.174) despite both groups having similar motor impairment and parkinsonian phenotype. Overall, diazepam administration unmasked differences in anxiolytic efficacy between HA hemiparkinsonian rats, LA hemiparkinsonian rats and non-parkinsonian rats. Our data suggests that neuro-circuits involved in anxiety-like behavior may differ within these groups and posits that diazepam may have reduced efficacy in certain individuals with PD anxiety disorders.


    This work describes the development of a physiologically based pharmacokinetic (PBPK) model of deltamethrin, a type II pyrethroid, in the developing male Sprague-Dawley rat. Generalized Michaelis-Menten equations were used to calculate metabolic rate constants and organ weights ...

  17. Taenia taeniaeformis: inhibition of metacestode development in the rat by gossypol.

    Rikihisa, Y; Lin, Y C


    The effect of gossypol, a polyphenolic compound, on developing Taenia taeniaeformis larvae in the rat liver was examined. Five groups of rats were used. In group 1, subcutaneous injection of gossypol at 10 mg/kg was started 5 days prior to administration of tapeworm eggs. In group 2, gossypol injections were started 5 days after administration of eggs. Groups 3 and 4 were infected and noninfected rats, respectively, which received the vehicle (10% ethyl alcohol in 0.85% NaCl) only. Group 5 rats were noninfected but received gossypol. From each group, 5 rats were killed on days 7, 12, and 22 of infection, respectively. The number and size of larvae and the size of the livers were much less in rats gossypol injected 5 days before infection than those in the vehicle-treated group. Administration of gossypol 5 days after infection resulted in less inhibition. The size and the thickness of the fibrous capsule around larvae of the gossypol-treated rats were much smaller than those of the control-infected group. The actively developing larvae excrete or secrete a sulfated glycosaminoglycan which is specifically stained with alcian blue. There was much more alcian blue-positive substance around the larvae and the capsule of the control-infected liver compared to the gossypol-treated infected animal. The percentage body weight of the spleen was significantly greater in the gossypol-treated rats in both infected and noninfected groups. These results suggest that gossypol may directly inhibit tapeworm larval development or that elimination of the tapeworm may be resulted from gossypol-induced stimulation of host cell-mediated immunity.

  18. Rabbit Forebrain cholinergic system: Morphological characterization of nuclei and distribution of cholinergic terminals in the cerebral cortex and hippocampus

    C. Varga; Hartig, W.; Grosche, J.; Luiten, PGM; Seeger, J.; K. Brauer; Harkany, T.; Härtig, Wolfgang; Keijser, Jan N.


    Although the rabbit brain, in particular the basal forebrain cholinergic system, has become a common model for neuropathological changes associated with Alzheimer's disease, detailed neuroanatomical studies on the morphological organization of basal forebrain cholinergic nuclei and on their output pathways are still awaited. Therefore, we performed quantitative choline acetyltransferase (ChAT) immunocytochemistry to localize major cholinergic nuclei and to determine the number of respective c...

  19. Rapid whisker movements in sleeping newborn rats.

    Tiriac, Alexandre; Uitermarkt, Brandt D; Fanning, Alexander S; Sokoloff, Greta; Blumberg, Mark S


    Spontaneous activity in the sensory periphery drives infant brain activity and is thought to contribute to the formation of retinotopic and somatotopic maps. In infant rats during active (or REM) sleep, brainstem-generated spontaneous activity triggers hundreds of thousands of skeletal muscle twitches each day; sensory feedback from the resulting limb movements is a primary activator of forebrain activity. The rodent whisker system, with its precise isomorphic mapping of individual whiskers to discrete brain areas, has been a key contributor to our understanding of somatotopic maps and developmental plasticity. But although whisker movements are controlled by dedicated skeletal muscles, spontaneous whisker activity has not been entertained as a contributing factor to the development of this system. Here we report in 3- to 6-day-old rats that whiskers twitch rapidly and asynchronously during active sleep; furthermore, neurons in whisker thalamus exhibit bursts of activity that are tightly associated with twitches but occur infrequently during waking. Finally, we observed barrel-specific cortical activity during periods of twitching. This is the first report of self-generated, sleep-related twitches in the developing whisker system, a sensorimotor system that is unique for the precision with which it can be experimentally manipulated. The discovery of whisker twitching will allow us to attain a better understanding of the contributions of peripheral sensory activity to somatosensory integration and plasticity in the developing nervous system. Copyright © 2012 Elsevier Ltd. All rights reserved.

  20. Kinetics of Label Retaining Cells in the Developing Rat Kidneys.

    Jianwen Wang

    Full Text Available The kidney is a specialized low-regenerative organ with several different types of cellular lineages. The BrdU label-retaining cell (LRCs approach has been used as part of a strategy to identify tissue-specific stem cells in the kidney; however, because the complementary base pairing in double-stranded DNA blocks the access of the anti-BrdU antibody to BrdU subunits, the stem cell marker expression in BrdU-labeled cells are often difficult to detect. In this study, we introduced a new cell labeling and detection method in which BrdU was replaced with 5-ethynyl-2-deoxyuridine (EdU and examined the time-dependent dynamic changes of EdU-labeled cells and potential stem/progenitor markers in the development of kidney.Newborn rats were intraperitoneally injected with EdU, and their kidneys were harvested respectively at different time points at 1 day, 3 days, 1 week, 2 weeks, and 6 weeks post-injection. The kidney tissues were processed for EdU and cellular markers by immunofluorescence staining.At the early stage, LRCs labeled by EdU were 2176.0 ± 355.6 cells at day one in each renal tissue section, but dropped to 168 ± 48.4 cells by week 6. As time increased, the numbers of LRCs were differentially expressed in the renal cortex and papilla. At the postnatal day one, nearly twice as many cells in the cortex were EdU-labeled as compared to the papilla (28.6 ± 3.6% vs. 15.6 ± 3.4%, P<0.05, while there were more LRCs within the renal papilla since the postnatal week one, and at the postnatal week 6, one third as many cells in the cortex were EdU-labeled as compared to the papilla (2.5 ± 0.1% vs. 7.7 ± 2.7%, P<0.05. The long-term LRCs at 6-week time point were associated exclusively with the glomeruli in the cortex and the renal tubules in the papilla. At 6 weeks, the EdU-labeled LRCs combined with expression of CD34, RECA-1, Nestin, and Synaptopodin were discretely but widely distributed within the glomeruli; Stro-1 around the glomeruli; and

  1. Distribution of glutamine synthetase in the chick forebrain: implications for passive avoidance memory formation.

    O'Dowd, B S; Ng, K T; Robinson, S R


    The glial enzyme glutamine synthetase (GS) converts glutamate to glutamine; the latter is used by neurons for the resynthesis of glutamate and GABA. We have used a monoclonal antibody to GS to examine the regional distribution of this enzyme in the forebrains of day-old chicks. GS was detected in glia throughout the rostral and caudal regions of the forebrain and was particularly intense in the hippocampus, area parahippocampus and parts of the hyperstriatal and paleostriatal complex, regions widely considered to be involved in memory formation. Thus, our data provide an anatomical framework for the conclusion that neurons require the support of glia in order to restock their glutamate and/or GABA transmitter supplies during memory processing.

  2. Clonally Related Forebrain Interneurons Disperse Broadly across Both Functional Areas and Structural Boundaries.

    Mayer, Christian; Jaglin, Xavier H; Cobbs, Lucy V; Bandler, Rachel C; Streicher, Carmen; Cepko, Constance L; Hippenmeyer, Simon; Fishell, Gord


    The medial ganglionic eminence (MGE) gives rise to the majority of mouse forebrain interneurons. Here, we examine the lineage relationship among MGE-derived interneurons using a replication-defective retroviral library containing a highly diverse set of DNA barcodes. Recovering the barcodes from the mature progeny of infected progenitor cells enabled us to unambiguously determine their respective lineal relationship. We found that clonal dispersion occurs across large areas of the brain and is not restricted by anatomical divisions. As such, sibling interneurons can populate the cortex, hippocampus striatum, and globus pallidus. The majority of interneurons appeared to be generated from asymmetric divisions of MGE progenitor cells, followed by symmetric divisions within the subventricular zone. Altogether, our findings uncover that lineage relationships do not appear to determine interneuron allocation to particular regions. As such, it is likely that clonally related interneurons have considerable flexibility as to the particular forebrain circuits to which they can contribute.

  3. Toward a neurobiology of auditory object perception: What can we learn from the songbird forebrain?

    Kai LU; David S. VICARIO


    In the acoustic world,no sounds occur entirely in isolation; they always reach the ears in combination with other sounds.How any given sound is discriminated and perceived as an independent auditory object is a challenging question in neuroscience.Although our knowledge of neural processing in the auditory pathway has expanded over the years,no good theory exists to explain how perception of auditory objects is achieved.A growing body of evidence suggests that the selectivity of neurons in the auditory forebrain is under dynamic modulation,and this plasticity may contribute to auditory object perception.We propose that stimulus-specific adaptation in the auditory forebrain of the songbird (and perhaps in other systems) may play an important role in modulating sensitivity in a way that aids discrimination,and thus can potentially contribute to auditory object perception [Current Zoology 57 (6):671-683,2011].

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

    Zofeyah L McBrayer

    Full Text Available 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.

  5. Brain-derived neurotrophic factor (BDNF) overexpression in the forebrain results in learning and memory impairments.

    Cunha, Carla; Angelucci, Andrea; D'Antoni, Angela; Dobrossy, Mate D; Dunnett, Stephen B; Berardi, Nicoletta; Brambilla, Riccardo


    In this study we analyzed the effect on behavior of a chronic exposure to brain-derived neurotrophic factor (BDNF), by analysing a mouse line overexpressing BDNF under the alphaCaMKII promoter, which drives the transgene expression exclusively to principal neurons of the forebrain. BDNF transgenic mice and their WT littermates were examined with a battery of behavioral tests, in order to evaluate motor coordination, learning, short and long-term memory formation. Our results demonstrate that chronic BDNF overexpression in the central nervous system (CNS) causes learning deficits and short-term memory impairments, both in spatial and instrumental learning tasks. This observation suggests that a widespread increase in BDNF in forebrain networks may result in adverse effects on learning and memory formation.

  6. Molecular taxonomy of major neuronal classes in the adult mouse forebrain.

    Sugino, Ken; Hempel, Chris M; Miller, Mark N; Hattox, Alexis M; Shapiro, Peter; Wu, Caizi; Huang, Z Josh; Nelson, Sacha B


    Identifying the neuronal cell types that comprise the mammalian forebrain is a central unsolved problem in neuroscience. Global gene expression profiles offer a potentially unbiased way to assess functional relationships between neurons. Here, we carried out microarray analysis of 12 populations of neurons in the adult mouse forebrain. Five of these populations were chosen from cingulate cortex and included several subtypes of GABAergic interneurons and pyramidal neurons. The remaining seven were derived from the somatosensory cortex, hippocampus, amygdala and thalamus. Using these expression profiles, we were able to construct a taxonomic tree that reflected the expected major relationships between these populations, such as the distinction between cortical interneurons and projection neurons. The taxonomic tree indicated highly heterogeneous gene expression even within a single region. This dataset should be useful for the classification of unknown neuronal subtypes, the investigation of specifically expressed genes and the genetic manipulation of specific neuronal circuit elements.

  7. Basal forebrain cholinergic input is not essential for lesion-induced plasticity in mature auditory cortex.

    Kamke, Marc R; Brown, Mel; Irvine, Dexter R F


    The putative role of the basal forebrain cholinergic system in mediating lesion-induced plasticity in topographic cortical representations was investigated. Cholinergic immunolesions were combined with unilateral restricted cochlear lesions in adult cats, demonstrating the consequence of cholinergic depletion on lesion-induced plasticity in primary auditory cortex (AI). Immunolesions almost eliminated the cholinergic input to AI, while cochlear lesions produced broad high-frequency hearing losses. The results demonstrate that the near elimination of cholinergic input does not disrupt reorganization of the tonotopic representation of the lesioned (contralateral) cochlea in AI and does not affect the normal representation of the unlesioned (ipsilateral) cochlea. It is concluded that cholinergic basal forebrain input to AI is not essential for the occurrence of lesion-induced plasticity in AI.

  8. Enhancement of Spatial Learning-Memory in Developing Rats via Mozart Music

    Jian-Gao Yao; Yang Xia; Sheng-Jun Dai; Guang-Zhan Fang; Hua Guo; De-Zhong Yao


    This paper studies the effect of musical stimulations on the capability of the spatial learning-memory in developing rats by behavioral and electro-physiological techniques.Rats,which are exposed to Mozart's Sonata for Two Pianos in D Major,complete learning tasks of the Moriss water maze with significantly shorter latencies,and the power spectrum of alpha band of electrohippocampogram (EHG) significantly increase,compared with the control rats and rats exposed to the horror music.The results indicate that if given the stimulation of Mozart music in the developmental period of the auditory cortex,the capability of the spatial learning-memory can be significantly changed.The enhancement of alpha band of EHG may be related to the change of this function mainly.

  9. Clearance of refractory ceramic fibers (RCF) from the rat lung: development of a model.

    Yu, C P; Zhang, L; Oberdörster, G; Mast, R W; Glass, L R; Utell, M J


    Chronic exposure and postexposure experiments have been recently performed in rats to evaluate the biological responses of inhaled refractory ceramic fibers (RCF) at different concentration levels. The lung burden data in the accessory lobe of the rat lung were collected during and after different exposure and postexposure periods. The size distribution of retained fibers in the lung at different time points was also measured. We used these data to develop a mathematical model of fiber clearance from the rat lung. It was found that the clearance rate did not depend significantly upon fiber size but there was a clear dependence on lung burden. As lung burden increased, the clearance rate was found to decrease. An empirical equation was derived for the clearance rate as a function of lung burden. At low burdens, rats had a retention half-time of about 126 days for RCF compared to a typical half-time of about 60 days for insoluble nonfibrous particles.

  10. Wnt/β-catenin signaling pathway is active in pancreatic development of rat embryo

    Qi-Ming Wang; Ye Zhang; Kai-Ming Yang; Hong-Ying Zhou; Hui-Jun Yang


    AIM: To elucidate the role of Wnt/β-catenin signaling pathway in pancreatic development of rat embryo.METHODS: The mRNAs of β-catenin, APC, cyclin D1 genes were amplified by means of semiquantitative reverse transcription polymerase chain reaction (RTPCR) from embryonic pancreas in different periods and normal pancreas of rat, respectively. Protein expression of these genes in embryonic pancreas of E14.5-E18.5was examined by immunohistochemical method.RESULTS: In embryonic pancreas of E14.5, the transcript amplification of β-catenin and cyclinD1 genes was detected. In embryonic pancreas of E18.5, the transcription levels of β-catenin and cyclinD1 genes became much higher than in other periods. But in adult rat pancreas the transcription of cyclinD1 gene could not be observed. Only until E18.5, the transcript amplification of mRNA of APC gene could be detected.Surprisingly, the transcription level of APC gene became much higher in adult rat pancreas than in embryonic pancreas. By means of immunohistochemical staining,identical results were obtained to the above by RP-PCR,except for β-catenin protein in adult rat pancreas.CONCLUSION: Active Wnt/β-catenin signaling occursin rat embryonic pancreas and is probably important for pancreatic development and organ formation.

  11. Correlation of expression of preprothyrotropin-releasing hormone and receptor with rat testis development

    李臻; 张远强; 刘新平; 许若军


    Objective To investigate the expression regulation of thyrotrophin-releasing hormone (TRH) and TRH receptor (TRH-R), and their role in the development of rat testis.Methods Oligonucleotide primers were designed from the sequences of rat hypothalamus prepro TRH (ppTRH) and pituitary TRH-R cDNA for reverse transcription polymerase chain reaction (RT-PCR). Specific fragments of ppTRH and TRH-R cDNA were cloned and sequenced. Expression plasmids containing ppTRH and TRH-R genes were then constructed, and expression was found in E.coli DH5-α. ppTRH and TRH-R mRNA in the testis was quantitated in RNA samples prepared from rats at different developmental stages by real time quantitative RT-PCR.Results The quantitative analyses demonstrated that no ppTRH and TRH mRNA could be detected at the earliest stage (day 8). ppTRH and TRH mRNA signals were detected on day 15 and increased progressively on days 20, 35, 60 and 90. Conclusion Our results suggest that rat testis could specifically express TRH and TRH-R, and the transcriptions of ppTRH and TRH-R genes in the rat testis were development-dependent. The acquirement of expressed products for ppTRH and TRH-R can be used for further research on the physiological significance of TRH and TRH-R expression in rat testis.

  12. Quantitative Indexes of Leukocytes in Spontaneously Hypertensive Rats During Various Periods of Arterial Hypertension Development.

    Aliev, O I; Anishchenko, A M; Sidekhmenova, A V; Shamanaev, A Yu; Fedorova, E P; Plotnikov, M B


    SHR rats were examined in the period before arterial hypertension development (5th week), during the increase in BP (6th-10th weeks), and under conditions of constantly elevated BP (11th-12th weeks). The total number of leukocytes did not differ in SHR and normotensive WKY rats. However, the relative number of lymphocytes and monocytes was shown to differ in various periods of arterial hypertension development. Our results suggest that white blood cells (primarily lymphocytes) are involved in the development of arterial hypertension.

  13. The expression of LIM-homeobox genes, Lhx1 and Lhx5, in the forebrain is essential for neural retina differentiation.

    Inoue, Junji; Ueda, Yuuki; Bando, Tetsuya; Mito, Taro; Noji, Sumihare; Ohuchi, Hideyo


    Elucidating the mechanisms underlying eye development is essential for advancing the medical treatment of eye-related disorders. The primordium of the eye is an optic vesicle (OV), which has a dual potential for generation of the developing neural retina and retinal pigment epithelium. However, the factors that regulate the differentiation of the retinal primordium remain unclear. We have previously shown that overexpression of Lhx1 and Lhx5, members of the LIM-homeobox genes, induced the formation of a second neural retina from the presumptive pigmented retina of the OV. However, the precise timing of Lhx1 expression required for neural retina differentiation has not been clarified. Moreover, RNA interference of Lhx5 has not been previously reported. Here, using a modified electroporation method, we show that, Lhx1 expression in the forebrain around stage 8 is required for neural retina formation. In addition, we have succeeded in the knockdown of Lhx5 expression, resulting in conversion of the neural retina region to a pigment vesicle-like tissue, which indicates that Lhx5 is also required for neural retina differentiation, which correlates temporally with the activity of Lhx1. These results suggest that Lhx1 and Lhx5 in the forebrain regulate neural retina differentiation by suppressing the development of the retinal pigment epithelium, before the formation of the OV.

  14. Activation of the Basal Forebrain by the Orexin/Hypocretin Neurons: Orexin International Symposium

    Arrigoni, Elda; Mochizuki, Takatoshi; Scammell, Thomas E.


    The orexin neurons play an essential role in driving arousal and in maintaining normal wakefulness. Lack of orexin neurotransmission produces a chronic state of hypoarousal characterized by excessive sleepiness, frequent transitions between wake and sleep, and episodes of cataplexy. A growing body of research now suggests that the basal forebrain (BF) may be a key site through which the orexin-producing neurons promote arousal. Here we review anatomical, pharmacological and electrophysiologic...

  15. Effect of stress hormone antagonists on ovarian follicular development in pre-pubertal rat

    Kalid Hamood Abdullah


    Full Text Available Effect of stress on pre-pubertal ovarian follicular development was studied. Fifteen day old female rats were administered under stress (exposed to maternal separation; 6 hours/day from post-natal day 15 to 21 for 7 days, and appropriate controls were maintained. The time of exposure was randomly changed every day during light phase (7AM to 7 PM of the day to avoid habituation. There was a significant decrease in serum estrogen levels on post-natal day 21 in stress group rats compared to controls indicating stress response in these rats. However, mean number of healthy follicles in all categories of follicles were significantly lower in stressed rats compared to controls. Concomitant with these changes, mean number of atreitic follicles showed an increase over control values in stressed rats. In contrast administration of Naltrexone (5μg NTX/rat/day, Mifepristone (1 μg MP/rat/day, FSH (10 IU FSH/rat/day with stressed the significant increases in the relative weight of ovary, uterus, fallopian tube, body weight and the mean number of healthy follicles in the ovary compared to the controls. In the ovary treatment of stressed did not affect primordial follicles. Primordial follicles were reduced in number significantly in the ovary of controls and treated groups when compared with the initial controls whereas there was no significant variation among the controls and the treated groups. The results indicate that stress dose not interfere with the progress of pre-pubertal follicular development. However, it causes increased loss of follicles by atretia.

  16. Development of chronic allograft rejection and arterial hypertension in Brown Norway rats after renal transplantation.

    Vaskonen, T; Mervaala, E; Nevala, R; Soots, A; Krogerus, L; Lähteenmäki, T; Karppanen, H; Vapaatalo, H; Ahonen, J


    The cardiovascular and renal pathophysiology associated with chronic renal allograft rejection under triple drug immunosuppressive treatment was studied using a recently developed model (Brown Norway (BN) rats) in a 6-week experiment. Renal transplantation was performed to 10-week-old rats in a rat strain combination of Dark Agouti (DA) --> BN. The right kidney was removed from another group of BN rats (uninephrectomized). A triple drug treatment comprising cyclosporine (10 mg/kg subcutaneously, s.c.), azathioprine (2 mg/kg s.c.) and methylprednisolone (1.6 mg/kg s.c.) was given to each rat daily for 6 weeks. A control group underwent no operations nor drug treatment. After the transplantation, the systolic blood pressure in this group was increased from 116 +/- 2 to 166 +/- 2 mmHg, while in the uninephrectomized group the rise was from 115 +/- 4 to 146 +/- 4 mmHg, and no change was observed in the blood pressures of the control group. The vascular relaxation responses of mesenteric arterial rings in vitro to acetylcholine were inhibited in both the transplantation group and the uninephrectomized group as compared with the control group, but few significant differences were found in the contraction responses to noradrenaline and potassium chloride. Graft histology was examined after 6 weeks, quantified by using the chronic allograft damage index (CADI). Changes specific to a chronic rejection reaction were observed in the allografts (CADI mean 6.0) but no injuries were seen in the rats' own kidneys (CADI mean 1.2). Our findings show that allograft rejection in BN rats after renal transplantation is associated with the development of arterial hypertension. The combination of cyclosporine, methylprednisolone and azathioprine also rises blood pressure in uninephrectomized BN rats. The hypertensive effects of the drug treatment and graft rejection are associated with endothelial dysfunction.

  17. Localization of tyrosine hydroxylase immunoreactive neurons in the forebrain of the guppy Poecilia reticulata.

    Parafati, M; Senatori, O; Nicotra, A


    The current study reports for the first time the distribution of tyrosine hydroxylase immunoreactive (TH-ir) neurons in the forebrain of the guppy Poecilia reticulata. Numerous small TH-ir neurons were observed in the olfactory bulbs, located mainly in the periphery of the bulbs. The TH-ir telencephalic neurons are localized in the ventral telencephalic area where they are grouped in three distinct nuclei (Vv,Vd and Vp) composed of a small number of cells forming a continuous strip. The largest number of forebrain TH-ir neurons was observed in the diencephalon where both small and larger neurons are present. Diencephalic TH-ir neurons are subdivided in large nuclei located in the preoptic region (nSC, nPOp and nPOm), the thalamus (nDM), the pretectal region (nPPv and nAP), the hypothalamus (nPP and nRP) and the posterior tuberculum (nPT). Many diencephalic nuclei are distributed in periventricular regions and no TH-ir cells were observed in the paraventricular organ. A comparative analysis indicates that the present observations are consistent with the general pattern of TH-ir neurons distribution reported for the forebrain of other teleosts, but with some interspecies variability present, mainly in the diencephalon. This paper also provides valuable neuroanatomical information for P. reticulata, a teleost frequently used in toxicological tests, for future studies investigating the effects of environmental pollutants on the catecholaminergic system.

  18. Quantitative analysis of development and aging of genital corpuscles in glans penis of the rat.

    Shiino, Mizuho; Hoshi, Hideo; Kawashima, Tomokazu; Ishikawa, Youichi; Takayanagi, Masaaki; Murakami, Kunio; Kishi, Kiyoshi; Sato, Fumi


    The aim of the present postnatal developmental study was to determine densities of unique genital corpuscles (GCs) in glans penis of developing and aged rats. GCs were identified as corpuscular endings consisting of highly branched and coiled axons with many varicosities, which were immunoreactive for protein gene product 9.5. In addition, GCs were immunoreactive for calcitonin gene-related peptide and substance P, but not for vasoactive intestinal polypeptide and neuropeptide Y. GCs were not found in the glans penis of 1 week old rats. Densities of GCs were low at 3 weeks, significantly increased at 5 and 10 weeks, reached the peak of density at 40 weeks, and tended to decrease at 70 and 100 weeks. Sizes of GCs were small in 3 weeks old rats, increased at 5 and 10 weeks, reached the peak-size at 40 weeks and reduced in size at 70 and 100 weeks. Considering sexual maturation of the rat, the results reveal that GCs of the rat begins to develop postnatal and reaches to the peak of their development after puberty and continues to exist until old age, in contrast to prenatal and early postnatal development of other sensory receptors of glabrous skin.

  19. [Effect of vincristine on molar development and jaw growth in rats].

    Sedlecki, S; Jakovljević, A; Pap, K


    A cystostatic of group Vinca-alcaloides, Vincristine, is often used in chemotherapy. As a microtubular poison it reacts with microtubular molecules of cell cytoplasma and in response to dose administrated decelerates or stops cell division. Since the information about the effect of this drug on molar teeth has not been found in available literature the aim of this study was to investigate the effect of vincristine on tooth development and jaw growth in rats. The experiment was carried out on Wistar rats of both sexes. Vincristine (Oncovin, "Lilly") was injected to animals in the dose of 0.1 mg/kg b.w. seven or eight days following birth. Treated and control animals were sacrificed on the 24th postnatal day. Radiographs of the mandibule were used to study tooth development. The morphometric examination concerned the following parameters: in maxillar frontal and posterior arc width and height; vertical and sagital dimension as well as length of incisive crown in the mandibule. The results of the analysis suggested that the teeth of treated rats were retarded in development compared to the control animals. Morphometric investigations showed that in treated rats both jaws were decelerated in growth in comparison to the control group but with no statistical significance. It should be emphasized that a 16-day-period was too short that full efficet of Vincristine should be established in rats and lead to a result which could suggest a certain molar development and jaw growth.

  20. Neurofilament localization and phosphorylation in the developing inner ear of the rat.

    Tonnaer, E.L.G.M.; Peters, T.A.; Curfs, J.H.A.J.


    Detailed understanding of neurofilament protein distribution in the inner ear can shed light on regulatory mechanisms involved in neuronal development of this tissue. We assessed the spatio-temporal changes in the distribution of neurofilaments in the developing rat inner ear between embryonic day

  1. Substantia nigra lesions attenuate the development of hypertension and behavioural hyperreactivity in spontaneously hypertensive rats

    Van den Buuse, M; Veldhuis, H D; Versteeg, D H; De Jong, W


    The possible relation between changes in behaviour and the development of hypertension was investigated. Depletion of striatal dopamine by lesions in the substantia nigra of Spontaneously Hypertensive Rats (SHR) was associated with an inhibition of the development of hypertension. In the open field

  2. Pax6 interactions with chromatin and identification of its novel direct target genes in lens and forebrain.

    Qing Xie

    Full Text Available Pax6 encodes a specific DNA-binding transcription factor that regulates the development of multiple organs, including the eye, brain and pancreas. Previous studies have shown that Pax6 regulates the entire process of ocular lens development. In the developing forebrain, Pax6 is expressed in ventricular zone precursor cells and in specific populations of neurons; absence of Pax6 results in disrupted cell proliferation and cell fate specification in telencephalon. In the pancreas, Pax6 is essential for the differentiation of α-, β- and δ-islet cells. To elucidate molecular roles of Pax6, chromatin immunoprecipitation experiments combined with high-density oligonucleotide array hybridizations (ChIP-chip were performed using three distinct sources of chromatin (lens, forebrain and β-cells. ChIP-chip studies, performed as biological triplicates, identified a total of 5,260 promoters occupied by Pax6. 1,001 (133 of these promoter regions were shared between at least two (three distinct chromatin sources, respectively. In lens chromatin, 2,335 promoters were bound by Pax6. RNA expression profiling from Pax6⁺/⁻ lenses combined with in vivo Pax6-binding data yielded 76 putative Pax6-direct targets, including the Gaa, Isl1, Kif1b, Mtmr2, Pcsk1n, and Snca genes. RNA and ChIP data were validated for all these genes. In lens cells, reporter assays established Kib1b and Snca as Pax6 activated and repressed genes, respectively. In situ hybridization revealed reduced expression of these genes in E14 cerebral cortex. Moreover, we examined differentially expressed transcripts between E9.5 wild type and Pax6⁻/⁻ lens placodes that suggested Efnb2, Fat4, Has2, Nav1, and Trpm3 as novel Pax6-direct targets. Collectively, the present studies, through the identification of Pax6-direct target genes, provide novel insights into the molecular mechanisms of Pax6 gene control during mouse embryonic development. In addition, the present data demonstrate that Pax6

  3. Forebrain deletion of αGDI in adult mice worsens the pre-synaptic deficit at cortico-lateral amygdala synaptic connections.

    Veronica Bianchi

    Full Text Available The GDI1 gene encodes αGDI, which retrieves inactive GDP-bound RAB from membranes to form a cytosolic pool awaiting vesicular release. Mutations in GDI1 are responsible for X-linked Intellectual Disability. Characterization of the Gdi1-null mice has revealed alterations in the total number and distribution of hippocampal and cortical synaptic vesicles, hippocampal short-term synaptic plasticity and specific short-term memory deficits in adult mice, which are possibly caused by alterations of different synaptic vesicle recycling pathways controlled by several RAB GTPases. However, interpretation of these studies is complicated by the complete ablation of Gdi1 in all cells in the brain throughout development. In this study, we generated conditionally gene-targeted mice in which the knockout of Gdi1 is restricted to the forebrain, hippocampus, cortex and amygdala and occurs only during postnatal development. Adult mutant mice reproduce the short-term memory deficit previously reported in Gdi1-null mice. Surprisingly, the delayed ablation of Gdi1 worsens the pre-synaptic phenotype at cortico-amygdala synaptic connections compared to Gdi1-null mice. These results suggest a pivotal role of αGDI via specific RAB GTPases acting specifically in forebrain regions at the pre-synaptic sites involved in memory formation.

  4. Effects of acute gamma-irradiation on extracellular adenine nucleotide hydrolysis in developing rat brain

    Stanojević, I.; Drakulić, D.; Veličković, N.; Milošević, M.; Petrović, S.; Horvat, A.


    Cell membrane is highly sensitive to irradiation which, acting directly or indirectly, may disturb functions of constitutive proteins including membrane enzymes. Plasma membrane surface-located enzyme chain of ecto-nucleotide triphospho diphosphohydrolases (NTPDases) and 5'-nucleotidase are involved in termination of cell purinergic signalization by hydrolyzing extracellular, excitatory adenosine triphosphate (ATP), as well as nucleotide di-, and mono-phosphate (ADP and AMP) to neuroprotective adenosine. Extracellular ATP, ADP, and AMP hydrolyzes were examined in purified synaptic plasma membranes after whole-body acute irradiation. All measurements were done 24 h after irradiation of developing (15-, 30-day-old) and adult (90-day-old) rats with low (50 cGy) and high (2 Gy) dose of gamma-rays. Both, high and low doses inhibited nucleotide hydrolyses in 15-day-old rats; in 30-day-old rats low dose of radiation inhibited ADP and AMP hydrolyses while high dose inhibited only ATP hydrolyse. In adult rats high dose induced no effects, while low dose stimulated nucleotides hydrolyses. According to obtained results it was concluded that ecto-nucleotidases of young rats are more sensitive to irradiation, since even low dose induces inhibition of ecto-nucleotidases activities. Ionizing radiation, by decreasing brain nucleotide hydrolyses in developing rats, induces accumulation of ATP and decreases production of adenosine in synaptic cleft which could be neurocytotoxic. On the contrary, in adult rats low dose of radiation stimulates NTPDase and 5'-nucleotidase activity and protective adenosine production which indicates protective and adaptive mechanisms developed in adult brain neuronal cells.


    秦玉明; 周爱卿; 贲晓明; 沈捷; 梁瑛; 李奋


    Objective To determine whether all-trans retinoic acid (atRA) affects the metabolism of collagen in main pulmonary artery and exerts an inhibitory effect in rats with pulmonary hypertension induced by monocrotaline . Methods All rats (n=72) were divided into 3 groups as control, model, and atRA . In model and atRA groups, rats (n=48) were assigned at random to be given a single subcutaneous injection of monocrotaline (60mgg/kg) and administrated with either atRA (30rng·kg-1·d-1) for atRA group or saline through oral-gastro intubation for model group. In control group, rats (n=24) received a single subcutaneous injection of an equal volume of 0. 9% saline. On day 7, 14,21 and 28 after monocrotaline or saline injection, cardiovascular catheters were inserted into the pulmonary artery of rats in each group to examine their mean pulmonary artery pressure, in addition with their hydroxyproline content determined by chromometry. Results In comparison with the control rats, the mean pulmonary artery pressure of rats in model group increased significantly on day 21 and up to the peak on day 28 (P<0.01), while their hydroxyproline contents decreased significantly on day 14 ( P < 0.05) and increased significantly on day 21 and 28. The atRA group when compared with the model group show reduction in the content of hydroxyproline and the mean pulmonary artery pressure ( P < 0.01 ). Conclusion The atRA inhibits the accumulation of collagen in main pulmonary artery and interferes the development of pulmonary hypertension which might elicit favorable geometric remodeling of rat pulmonary hypertension induced by monocrotaline.

  6. Pentylenetetrazole-induced seizures in developing rats prenatally exposed to valproic acid

    Angel A. Puig-Lagunes


    Full Text Available Background Epidemiological evidence indicates epilepsy is more common in patients with autism spectrum disorders (ASD (20–25% than in the general population. The aim of this project was to analyze seizure susceptibility in developing rats prenatally exposed to valproic acid (VPA as autism model. Methods Pregnant females were injected with VPA during the twelfth embryonic day. Seizures were induced in fourteen-days-old rat pups using two models of convulsions: pentylenetetrazole (PTZ and lithium-pilocarpine (Li-Pilo. Results Two subgroups with different PTZ-induced seizure susceptibility in rats exposed to VPA were found: a high susceptibility (VPA+ (28/42, seizure severity 5 and a low susceptibility (VPA− (14/42, seizure severity 2. The VPA+ subgroup exhibited an increased duration of the generalized tonic-clonic seizure (GTCS; 45 ± 2.7 min, a higher number of rats showed several GTCS (14/28 and developed status epilepticus (SE after PTZ injection (19/27 compared with control animals (36.6 ± 1.9 min; 10/39; 15/39, respectively. No differences in seizure severity, latency or duration of SE induced by Li-Pilo were detected between VPA and control animals. Discussion Prenatal VPA modifies the susceptibility to PTZ-induced seizures in developing rats, which may be linked to an alteration in the GABAergic transmission. These findings contribute to a better understanding of the comorbidity between autism and epilepsy.

  7. Retarded hippocampal development following prenatal exposure to ethanolic leaves extract of Datura metel in wistar rats

    Azeez Olakunle Ishola


    Full Text Available Background: Datura metel contains atropine alkaloids and has been used to treat complication like asthma and, bronchitis, because of its anticholinergic properties. Aim: This study aimed to determine the prenatal effects of ethanolic extract of D. metel leaves exposure on the development of hippocampus. Materials and Methods: Twenty rats (12 females and 8 males were purchased. The females were grouped into four groups (A_D. Group A were given 500 mg/kg body weight of the extract on the first day of fertilization to the end of gestation period, Group B were given 500 mg/kg body weight on the 8 th day of fertilization to the end of gestation period, Group C were given 500 mg/kg body weight on 15 th day of fertilization to the end of gestation period and Group D were given normal saline throughout the gestation period. Results: Rats in Group A showed no implantation, rats in Group B had abortion on the 7 th day after administration, and rats in Group C gave birth with their litters showing retarded hippocampus development and neural degeneration and rats in Group D (control showed normal development. Conclusion: Ethanolic extract of D. metel leaf is teratogenic in the late stage of pregnancy, is abortificient and can serve as a contraceptive.

  8. Non-signalling energy use in the developing rat brain.

    Engl, Elisabeth; Jolivet, Renaud; Hall, Catherine N; Attwell, David


    Energy use in the brain constrains its information processing power, but only about half the brain's energy consumption is directly related to information processing. Evidence for which non-signalling processes consume the rest of the brain's energy has been scarce. For the first time, we investigated the energy use of the brain's main non-signalling tasks with a single method. After blocking each non-signalling process, we measured oxygen level changes in juvenile rat brain slices with an oxygen-sensing microelectrode and calculated changes in oxygen consumption throughout the slice using a modified diffusion equation. We found that the turnover of the actin and microtubule cytoskeleton, followed by lipid synthesis, are significant energy drains, contributing 25%, 22% and 18%, respectively, to the rate of oxygen consumption. In contrast, protein synthesis is energetically inexpensive. We assess how these estimates of energy expenditure relate to brain energy use in vivo, and how they might differ in the mature brain.

  9. Impact of stress and levels of corticosterone on the development of breast cancer in rats

    De la Roca-Chiapas JM


    Full Text Available José María De la Roca-Chiapas,1 Gloria Barbosa-Sabanero,2 Jorge Antonio Martínez-García,3 Joel Martínez-Soto,1 Víctor Manuel Ramos-Frausto,1 Leivy Patricia González-Ramírez,1 Ken Nowack4 1Department of Psychology, 2Department of Medical Sciences, Division of Health Sciences, Campus Leon-University of Guanajuato, Guanajuato, 3General Regional Hospital of Leon, Guanajuato, Mexico; 4Envisia Learning, Inc., Santa Monica, CA, USA Abstract: Stress is experienced during cancer, and impairs the immune system's ability to protect the body. Our aim was to investigate if isolation stress has an impact on the development of tumors in rats, and to measure the size and number of tumors and the levels of corticosterone. Breast cancer was induced in two groups of female rats (N=20 by administration of a single dose of N-methyl-N-nitrosourea 50 mg/kg. Rats in the control group (cancer induction condition were allowed to remain together in a large cage, whereas in the second group, rats were also exposed to a stressful condition, that is, isolation (cancer induction and isolation condition, CIIC. The CIIC group displayed anxious behavior after 10 weeks of isolation. In the CIIC group, 16 tumors developed, compared with only eleven tumors in the control cancer induction condition group. In addition, compared with the control group, the volume of tumors in the CIIC group was greater, and more rats had more than one tumor and cells showed greater morphological damage. Levels of corticosterone were also significantly different between the two groups. This study supports the hypothesis that stress can influence the development of cancer, but that stress itself is not a sufficient factor for the development of cancer in rats. The study also provides new information for development of experimental studies and controlled environments. Keywords: breast cancer, corticosterone, isolation condition, psychoneuroimmunology, stress

  10. Effect of maternal obesity on diabetes development in adult rat offspring.

    de Campos, Kleber Eduardo; Sinzato, Yuri Karen; Pimenta, Walkyria de Paula; Rudge, Marilza Vieira Cunha; Damasceno, Débora Cristina


    This study aimed to evaluate whether maternal obesity leads to the onset of diabetes in adult Wistar rats offspring. MSG solution neonatally administration induced obesity in rats (F(1)MSG group, n=30); and saline solution was also administrated to control rats (F(1)CON group, n=13). In 3rd month of age, both control and MSG groups were mated for offspring (generation F(2)), named as F(2)CON, n=28 and F(2)MSG groups, n=15; and so both generations were studied until 7th month of life. Lee Index was measured for experimental obesity validation from 5th to 7th month. Glycemia was weekly determined during pregnancy and monthly from 3rd to 7th month. In the end of experimental period all rats were submitted to oral glucose tolerance test (OGTT), with estimation of total area under the curve (AUC); and insulin tolerance test (ITT). Rats were then anesthetized and killed. Data were statistically analyzed with significance level of pgenerations showed significant maternal interference in control and MSG groups. OGTT analysis showed higher glycemia in obese rats (F(1)MSG) and their offspring (F(2)MSG) as compared to their respective controls; and MSG groups increased AUC from OGTT. As regards ITT, F(2)MSG showed higher glycemia at 30 and 120 min, suggesting a delay of insulin action decreasing. Although glucose intolerance and insulin resistance clinical conditions represent as a factors for type 2 Diabetes mellitus development, this experimental model proposal was not efficient to induce type 2 Diabetes mellitus, but for obesity developing, glucose intolerance and insulin resistance in successive generations of rats.

  11. Disrupted social development enhances the motivation for cocaine in rats

    Baarendse, P.J.J.; Limpens, J.H.W.; Vanderschuren, L.J.M.J.


    for behavioural development. In particular, social play behaviour during post-weaning development is thought to facilitate the attainment of social, emotional and cognitive capacities. Conversely, social insults during development can cause longlasting behavioural impairments and increase the vulner

  12. Localization of Sonic hedgehog secreting and receiving cells in the developing and adult rat adrenal cortex.

    Guasti, Leonardo; Paul, Alex; Laufer, Ed; King, Peter


    Sonic hedgehog signaling was recently demonstrated to play an important role in murine adrenal cortex development. The organization of the rat adrenal differs from that of the mouse, with the zona glomerulosa and zona fasciculata separated by an undifferentiated zone in the rat, but not in the mouse. In the present study we aimed to determine the mRNA expression patterns of Sonic hedgehog and the hedgehog signaling pathway components Patched-1 and Gli1 in the developing and adult rat adrenal. Sonic hedgehog expression was detected at the periphery of the cortex in cells lacking CYP11B1 and CYP11B2 expression, while signal-receiving cells were localized in the overlying capsule mesenchyme. Using combined in situ hybridization and immunohistochemistry we found that the cells expressing Sonic hedgehog lie between the CYP11B2 and CYP11B1 layers, and thus Sonic hedgehog expression defines one cell population of the undifferentiated zone.

  13. Expression of Msx1 and Dlx1 during Dumbo rat head development: correlation with morphological features

    Suhair Katerji


    Full Text Available The Dumbo rat possesses some characteristics that evoke several human syndromes, such as Treacher-Collins: shortness of the maxillary, zygomatic and mandibular bones, and low position of the ears. Knowing that many homeobox genes are candidates in craniofacial development, we investigated the involvement of the Msx1 and Dlx1 genes in the Dumbo phenotype with the aim of understanding their possible role in abnormal craniofacial morphogenesis and examining the possibility of using Dumbo rat as an experimental model for understanding abnormal craniofacial development. We studied the expression of these genes during craniofacial morphogenesis by RT-PCR method. We used Dumbo embryos at E12 and E14 and included the Wistar strain as a control. Semi-quantitative PCR analysis demonstrated that Msx1 and Dlx1 are expressed differently between Dumbo and Wistar rats, indicating that their low expression may underly the Dumbo phenotype.

  14. Olanzapine-induced Fos expression in the rat forebrain; cross-tolerance with haloperidol and clozapine

    Sebens, JB; Koch, T; Ter Horst, GJ; Korf, J


    Acute administration of the atypical antipsychotic drug olanzapine (5 mg kg(-1) i.p.) increased the number of Fos-positive cells moderately in the prefrontal cortex and the striatum; more pronounced were the effects in the nucleus accumbens, the lateral septum, the hypothalamic paraventricular nucle

  15. Forebrain parasympathetic control of heart activity : retrograde transneuronal viral labeling in rats

    Ter Horst, GJ; Postema, F


    Dysfunction of parasympathetic command neurons may be a cause of cardiac autonomic imbalance, which has been implicated as a pathogenic mechanism of lethal arrhythmias. The locations in the brain of these command neurons are not known. The aim of this investigation is to identify selectively the par

  16. Brainstem Stimulation Increases Functional Connectivity of Basal Forebrain-Paralimbic Network in Isoflurane-Anesthetized Rats

    Pillay, Siveshigan; Liu, Xiping; Baracskay, Péter; Hudetz, Anthony G.


    Brain states and cognitive-behavioral functions are precisely controlled by subcortical neuromodulatory networks. Manipulating key components of the ascending arousal system (AAS), via deep-brain stimulation, may help facilitate global arousal in anesthetized animals. Here we test the hypothesis that electrical stimulation of the oral part of the pontine reticular nucleus (PnO) under light isoflurane anesthesia, associated with loss of consciousness, leads to cortical desynchronization and sp...

  17. Superoxide dismutase prevents development of adenocarcinoma in a rat model of Barrett's esophagus

    Elena Piazuelo; Carmelo Cebrián; Alfredo Escartín; Pilar Jiménez; Fernando Soteras; Javier Ortego; Angel Lanas


    AIM: To test whether antioxidant treatment could prevent the progression of Barrett's esophagus to adenocarcinoma.METHODS: In a rat model of gastroduodenoesophageal reflux by esophagojejunal anastomosis with gastric preservation, groups of 6-10 rats were randomized to receive treatment with superoxide dismutase (SOD) or vehicle and followed up for 4 mo. Rat's esophagus was assessed by histological analysis, superoxide anion and peroxinitrite generation, SOD levels and DNA oxidative damage.RESULTS: All rats undergoing esophagojejunostomy developed extensive esophageal mucosal ulceration and inflammation by mo 4. The process was associated with a progressive presence of intestinal metaplasia beyondthe anastomotic area (9% 1st mo and 50% 4th mo) (94% at the anastomotic level) and adenocarcinoma(11% 1st mo and 60% 4th mo). These changes were associated with superoxide anion and peroxinitrite mucosal generation, an early and significant increase of DNA oxidative damage and a significant decrease in SOD levels (P<0.05). Exogenous administration of SOD decreased mucosal superoxide levels, increased mucosal SOD levels and reduced the risk of developing intestinal metaplasia beyond the anastomotic area (odds ratio = 0.326; 95%CI: 0.108-0.981; P = 0.046),and esophageal adenocarcinoma (odds ratio = 0.243;95%CI: 0.073-0.804; P = 0.021).CONCLUSION: Superoxide dismutase prevents the progression of esophagitis to Barrett's esophagus and adenocarcinoma in this rat model of gastrointestinal reflux, supporting a role of antioxidants in the chemoprevention of esophageal adenocarcinoma.

  18. Development of telmisartan in the therapy of spinal cord injury: pre-clinical study in rats.

    Lin, Chien-Min; Tsai, Jo-Ting; Chang, Chen Kuei; Cheng, Juei-Tang; Lin, Jia-Wei


    Decrease of peroxisome proliferator-activated receptors-δ (PPARδ) expression has been observed after spinal cord injury (SCI). Increase of PPARδ may improve the damage in SCI. Telmisartan, the antihypertensive agent, has been mentioned to increase the expression of PPARδ. Thus, we are going to screen the effectiveness of telmisartan in SCI for the development of it in clinical application. In the present study, we used compressive SCI in rats. Telmisartan was then used to evaluate the influence in rats after SCI. Change in PPARδ expression was identified by Western blots. Also, behavioral tests were performed to check the recovery of damage. Recovery of damage from SCI was observed in telmisartan-treated rats. Additionally, this action of telmisartan was inhibited by GSK0660 at the dose sufficient to block PPARδ. However, metformin at the dose enough to activate adenosine monophosphate-activated protein kinase failed to produce similar action as telmisartan. Thus, mediation of adenosine monophosphate-activated protein kinase in this action of telmisartan can be rule out. Moreover, telmisartan reversed the expressions of PPARδ in rats with SCI. The obtained data suggest that telmisartan can improve the damage of SCI in rats through an increase in PPARδ expression. Thus, telmisartan is useful to be developed as an agent in the therapy of SCI.

  19. Development of T Lymphocytes in the Nasal-associated Lymphoid Tissue (NALT from Growing Wistar Rats

    Gustavo A. Sosa


    Full Text Available The aim of the present report was to study the development of several T-lymphocyte subsets in the nasal-associated lymphoid tissue (NALT of growing Wistar rats. CD5+ and CD4+ lymphocytes gradually increased with age. A predominance of CD8α+ over CD4+ T cells was found from 7 to 45 days but from 45 to 60 days of age T helper cells outnumbered the cytotoxic subpopulation. The majority of CD8+ T lymphocytes expressed the heterodimeric isoform. The most relevant findings by immunohistochemistry are: (1 the predominance of TCRγδ+ and CD8α+ cells at 7 days postpartum over all the other T-cell subpopulations; and (2 that TCRγβ+ outnumbered TCRαβ+ T cells from 7 to 45 days postpartum whereas αβ T cells predominated in 45- and 60-day-old rats. Besides, cytometric studies have shown that the percentages of TCRγ+, CD8+, as well as the population coexpressing both phenotypes (TCRγδ+CD8α+, were significantly higher in rats at 7 days postpartum when compared to 60 day-old rats. In the present study, the finding of a high number of γδ+ and CD8+ T cells early in NALT development may indicate the importance of these subpopulations in the protection of the nasal mucosa in suckling and weaning Wistar rats.

  20. Coping style predicts the (in)sensitivity for developing hyperinsulinemia on a high fat diet in rats

    Boersma, Gretha J.; Benthem, Lambertus; van Dijk, Gertjan; Steimer, Thierry J.; Scheurink, Anton J. W.


    The aim of this study was to explore interactions between coping style and diet as risk factors for developing insulin resistance in rats. We hypothesized that rats characterized by a passive coping strategy are more susceptible for developing insulin resistance and visceral obesity than proactively

  1. Coping style predicts the (in)sensitivity for developing hyperinsulinemia on a high fat diet in rats

    Boersma, Gretha J.; Benthem, Lambertus; van Dijk, Gertjan; Steimer, Thierry J.; Scheurink, Anton J. W.


    The aim of this study was to explore interactions between coping style and diet as risk factors for developing insulin resistance in rats. We hypothesized that rats characterized by a passive coping strategy are more susceptible for developing insulin resistance and visceral obesity than proactively

  2. Development of pulmonary oxygen toxicity in rats after hyperoxic exposure

    Siermontowski Piotr


    Full Text Available The aim of the study was to examine the effects of hyperbaric oxygen on lung aeration on an animal experimental model and compare the obtained results with the anticipated scope of damage to pulmonary parenchyma in humans under the same exposure conditions. The research was carried out on Black Hood rats that were kept in a hyperbaric chamber designed for animals in an atmosphere of pure oxygen and at overpressures of 0.15, 0.2, 0.3, 0.4, and 0.5 MPa for 1, 2 or 4 h. After sacrificing the animals, histopathological specimens were obtained encompassing cross-sections of entire lungs, which were subjected to qualitative and quantitative examination with the use of the 121-point Haug grid. A statistically significant decrease in pulmonary parenchyma was observed as a result of an increasing oxygen partial pressure as well as with prolonged exposure time. The intensification of changes observed was much higher than expected on the basis of calculations performed with the use of tables.

  3. In utero exposure to microwave radiation and rat brain development.

    Merritt, J H; Hardy, K A; Chamness, A F


    Timed-pregnancy rats were exposed in a circular waveguide system starting on day 2 of gestation. The system operated at 2,450 MHz (pulsed waves; 8 microseconds PW; 830 pps). Specific absorption rate (SAR) was maintained at 0.4 W/kg by increasing the input power as the animals grew in size. On day 18 of gestation the dams were removed from the waveguide cages and euthanized; the fetuses were removed and weighed. Fetal brains were excised and weighed, and brain RNA, DNA and protein were determined. Values for measured parameters of the radiated fetuses did not differ significantly from those of sham-exposed fetuses. A regression of brain weight on body weight showed no micrencephalous fetuses in the radiation group when using as a criterion a regression line based on two standard errors of the estimate of the sham-exposed group. In addition, metrics derived from brain DNA (ie, cell number and cell size) showed no significant differences when radiation was compared to sham exposure. We conclude that 2,450-MHz microwave radiation, at an SAR of 0.4 W/kg, did not produce significant alterations in brain organogenesis.

  4. The effects of lesions of the posterior piriform cortex on amygdala kindling in the rat.

    Wahnschaffe, U; Ebert, U; Löscher, W


    The piriform cortex (PC) is thought to be critically involved in the genesis of forebrain (limbic type) seizures, including limbic kindled seizures. More recent studies have shown that the posterior PC is particularly sensitive to kindling stimulation, suggesting that the posterior PC contains specific generating sites which may be important for the stepwise progression of kindling. In the present experiments, we used microinjections of ibotenate to study the effect of selective lesions of the posterior PC on amygdala kindling in rats. Large unilateral lesions of the posterior PC and adjacent endopiriform nucleus markedly decreased the susceptibility of the ipsilateral basolateral amygdala to electrical stimulation, thus indicating that the posterior PC may normally contribute to regulation of physiologic excitability in amygdala. During kindling, rats with large lesions of the PC stayed longer in the initial phase of kindling (stage 1) than sham-lesioned controls, consistent with involvement of the posterior PC in the early stages of seizure propagation during kindling acquisition. However, the PC lesions were not capable of blocking or even severely retarding kindling. Following kindling development, rats with large lesions of the posterior PC had significantly higher focal seizure thresholds than kindled rats without lesion or rats with only small PC lesions, which suggests that the posterior PC is involved in the mechanisms which are responsible for the marked increase in seizure susceptibility induced by kindling. Taken together, the data substantiate that PC structures play a facilitatory role in kindling.

  5. A remote control training system for rat navigation in complicated environment

    FENG Zhou-yan; LIU Chun-qing; LIU Fu-xin; LUO Jian-hong; ZHUANG Yue-ting; ZHENG Xiao-xiang; CHEN Wei-dong; YE Xue-song; ZHANG Shao-min; ZHENG Xiao-jing; WANG Peng; JIANG Jun; JIN Lin; XU Zhi-jian


    A remote control system has been developed to deliver stimuli into the rat brain through a wireless micro-stimulator for animal behavior training. The system consists of the following main components: an integrated PC control program, a transmitter and a receiver based on Bluetooth (BT) modules, a stimulator controlled by C8051 microprocessor, as well as an operant chamber and an eight-arm radial maze. The micro-stimulator is featured with its changeable amplitude of pulse output for both constant-voltage and constant-current mode, which provides an easy way to set the proper suitable stimulation intensity for different training. The system has been used in behavior experiments for monitoring and recording bar-pressing in the operant chamber, controlling rat roaming in the eight-arm maze, as well as navigating rats through a 3D obstacle route. The results indicated that the system worked stably and that the stimulation was effective for different types of rat behavior controls. In addition, the results showed that stimulation in the whisker barrel region of rat primary somatosensory cortex (SI) acted like a cue. The animals can be trained to take different desired turns upon the association between the SI cue stimulation and the reward stimulation in the medial forebrain bundle (MFB).

  6. Development of, and recovery from, activity-based anorexia in female rats.

    Dixon, Deann P; Ackert, Allison M; Eckel, Lisa A


    Activity-based anorexia occurs in rats maintained on a restricted-feeding schedule while given free access to running wheels. These conditions induce high levels of wheel running and rapid weight loss. Although this procedure was developed as an animal model of anorexia nervosa, it has been studied primarily in male rats. Our goal was to examine the development of, and recovery from, activity-based anorexia in female rats. Food intake, wheel running, body weight, and phase of the estrous cycle were monitored daily prior to, during, and after a period of restricted feeding in which access to food was limited to 2 h/day. Food intake, body weight, and estrous cyclicity were also monitored in a control group housed without access to running wheels. Prior to food restriction, rats with wheels displayed high levels of wheel running and consumed more food than rats without wheels. Despite that both groups consumed similar amounts of food during the restricted-feeding phase, only rats with wheels developed symptoms of activity-based anorexia, including increased wheel running, rapid weight loss, and disruptions in estrous cyclicity. Recovery from activity-based anorexia was associated with hypoactivity and hyperphagia. Resumption of estrous cycles occurred when the weight lost during food restriction was regained. Hyperphagia, but not hypoactivity, was maintained following resumption of estrous cycles; however, this hyperphagia was limited to nonestrous phases. Our findings suggest that recovery from activity-based anorexia is mediated primarily by an increase in orexigenic signaling that promotes pronounced hyperphagia, and that the increase in satiogenic signaling during estrus abolishes this compensatory hyperphagia.


    Rajesh Pandey et al


    Full Text Available The present study was designed to evaluate the impacts of high dietary fat on serum Total cholesterol and fatty liver syndrome in rats. Rats are fed on diets containing cholesterol; they develop fatty livers which are characterized by the presence in the liver of excessive amounts of cholesteryl esters, and glyceride. Increasement of glyceride content depend on a number of factors, such as the dietary contents of choline, While the nature of the "cholesterol" fatty liver and the effects on its composition of a number of dietary and other factors. In the present paper, we investigated the quantitative changes which occur in the "cholesterol" fatty liver, as a result of variations in the fat content of the diet, with particular reference to the deposition of cholesterol and of glyceride on diets of constant cholesterol content. Investigation was conducted on 90 day old Wister rats. It was observed that the serum TC values in rats of groups B and C were higher than control group. Furthermore, the serum TC and TG value was higher in rats of group C than group B. Grossly, the livers of rats of groups B and C were enlarged, pale in colour, soft in consistency and were having petechial haemorrhages with fat and fibrin deposits. Histopathologically, livers of groups B and C showed fatty infiltration, haemorrhages and mass of eosinophilic materials. The vacuoles coalesced to create clear space that displaced the nucleus to the periphery of the cell. The results suggested that addition of dietary fat from animal and vegetable sources in the diet of rats not only resulted in increase in serum TC and TG but also in marked macroscopic and microscopic changes in vital organ liver.

  8. HMGB1 promotes the development of pulmonary arterial hypertension in rats.

    Yukari Sadamura-Takenaka

    Full Text Available Pulmonary arterial hypertension (PAH is characterized by increased pulmonary vascular resistance leading to right ventricular failure and death. Recent studies have suggested that chronic inflammatory processes are involved in the pathogenesis of PAH. However, the molecular and cellular mechanisms driving inflammation have not been fully elucidated.To elucidate the roles of high mobility group box 1 protein (HMGB1, a ubiquitous DNA-binding protein with extracellular pro-inflammatory activity, in a rat model of PAH.Male Sprague-Dawley rats were administered monocrotaline (MCT. Concentrations of HMGB1 in bronchoalveolar lavage fluid (BALF and serum, and localization of HMGB1 in the lung were examined over time. The protective effects of anti-HMGB1 neutralizing antibody against MCT-induced PAH were tested.HMGB1 levels in BALF were elevated 1 week after MCT injection, and this elevation preceded increases of other pro-inflammatory cytokines, such as TNF-α, and the development of PAH. In contrast, serum HMGB1 levels were elevated 4 weeks after MCT injection, at which time the rats began to die. Immunohistochemical analyses indicated that HMGB1 was translocated to the extranuclear space in periarterial infiltrating cells, alveolar macrophages, and bronchial epithelial cells of MCT-injected rats. Anti-HMGB1 neutralizing antibody protected rats against MCT-induced lung inflammation, thickening of the pulmonary artery wall, and elevation of right ventricular systolic pressure, and significantly improved the survival of the MCT-induced PAH rats.Our results identify extracellular HMGB1 as a promoting factor for MCT-induced PAH. The blockade of HMGB1 activity improved survival of MCT-induced PAH rats, and thus might be a promising therapy for the treatment of PAH.

  9. Enzyme-histochemical study on postnatal development of rat stomach lymphatic vessels.

    Ji, R C; Kato, S


    Postnatal development of rat gastric lymphatics was studied by an enzyme-histochemical method to elucidate the morphological changes of lymphatics and their relationship to maturation and function, especially in the glandular portion. The significant features of 5'-Nase-positive lymphatics in distribution and structure were examined in different stages (within 24 hr, 4-21 days, and 2 months). Lymphatics in the greater curvature and anterior wall grew much slower than those in the lesser curvature and posterior wall of the stomach in newborn and infant rats. Lymphatic islands isolated from the primary lymphatic networks in the submucosa and subserosa underwent a morphological change during this early period. This is considered one of the basic steps in lymphatic development. Occurrence of lymphatic networks in the deep lamina propria indicates that development in the gastric wall is well characterized from Day 10. With further growth and modification of lymphatics, the networks in the different layers formed an extensive communication network and many lymphatic valves were found in the submucosa and subserosa. Pinocytotic vesicles, open junctions, and intraendothelial channels were frequently detected in the mucosal and submucosal lymphatic networks of the corpus-antrum and antrum-duodenum divisional zones in the adult rats. These findings suggest that developing lymphatics in the rat stomach may represent rapidly growing tissue not only with high 5'-Nase activity but also with high adaptability for future physiological demands.

  10. Extinction, Reacquisition, and Rapid Forgetting of Eyeblink Conditioning in Developing Rats

    Brown, Kevin L.; Freeman, John H.


    Eyeblink conditioning is a well-established model for studying the developmental neurobiology of associative learning and memory. However, age differences in extinction and subsequent reacquisition have yet to be studied using this model. The present study examined extinction and reacquisition of eyeblink conditioning in developing rats. In…

  11. Selenium prevents tumor development in a rat model for chemical carcinogenesis

    Bjorkhem-Bergman, L.; Torndal, U. B.; Eken, S.


    Previous studies in animals and humans have shown that selenium compounds can prevent cancer development. In this work we studied the tumor preventive effect of selenium supplementation, administrated as selenite, in the initiation, promotion and progression phases in a synchronized rat model for...


    Peripubertal DEHP exposure inhibits androgen-dependent development in Sprague-Dawley rats.N.C. Noriega, J. Furr, C. Lambright, V.S. Wilson and L.E. Gray.noriega.nigel@epa.govUS EPA, MD-72 RTD, NHEERL, ORD, RTP, NC 27711The plasticizer Di (2-ethylhe...

  13. Extinction, Reacquisition, and Rapid Forgetting of Eyeblink Conditioning in Developing Rats

    Brown, Kevin L.; Freeman, John H.


    Eyeblink conditioning is a well-established model for studying the developmental neurobiology of associative learning and memory. However, age differences in extinction and subsequent reacquisition have yet to be studied using this model. The present study examined extinction and reacquisition of eyeblink conditioning in developing rats. In…




    The development of the electromyogram (EMG) of tibialis anterior (TA) and medial gastrocnemius (GM) during locomotion was studied in normal rats from the onset of quadruped walking (postnatal day 10, P10) until P42. The objectives were to relate signal properties of the EMG and coordination of muscl

  15. Renal vascular dysfunction precedes the development of renal damage in the hypertensive Fawn-Hooded rat

    Ochodnicky, Peter; Henning, Robert H.; Buikema, Hendrik J.; de Zeeuw, Dick; Provoost, Abraham P.; van Dokkum, Richard P. E.


    Ochodnicky P, Henning RH, Buikema HJ, de Zeeuw D, Provoost AP, van Dokkum RP. Renal vascular dysfunction precedes the development of renal damage in the hypertensive Fawn-Hooded rat. Am J Physiol Renal Physiol 298: F625-F633, 2010. First published December 9, 2009; doi:10.1152/ajprenal.00289.2009.-I

  16. Behavioural factors contribute to the development of spontaneous hypertension in rats

    Van den Buuse, M; Veldhuis, H D; Versteeg, D H; de Jong, Wybren


    The relationship was studied between brain catecholamine systems, open-field behaviour and the development of hypertension in spontaneously hypertensive rats (SHR). Both the rise in blood pressure and the increased open-field rearing activity of SHR were inhibited by central dopamine depletion. Anti

  17. Behavioural factors contribute to the development of spontaneous hypertension in rats

    Van den Buuse, M; Veldhuis, H D; Versteeg, D H; de Jong, Wybren


    The relationship was studied between brain catecholamine systems, open-field behaviour and the development of hypertension in spontaneously hypertensive rats (SHR). Both the rise in blood pressure and the increased open-field rearing activity of SHR were inhibited by central dopamine depletion.

  18. Postnatal development and behaviour of Wistar rats after prenatal toluene exposure

    Thiel, R. [Fachbereich Humanmedizin, Universitaetsklinikum Benjamin Franklin, Inst. fuer Toxikologie und Embryopharmakologie, Freie Univ. Berlin (Germany); Chahoud, I. [Fachbereich Humanmedizin, Universitaetsklinikum Benjamin Franklin, Inst. fuer Toxikologie und Embryopharmakologie, Freie Univ. Berlin (Germany)


    Pregnant Wistar rats were treated with different concentrations of toluene by inhalation (300, 600, 1000 and 1200 ppm) from day 9 to day 21 of pregnancy for 6 h a day in a whole-body inhalation chamber (controls inhaled fresh air only). From day 22, rats were kept single-caged and were allowed to deliver. Besides a detailed evaluation of the physical development of the offspring we performed the following tests: forelimb-grasp reflex, righting reflex, cliff-drop aversion reflex, maintainance of balance on a rotating rod, measurement of locomotor activity and learning ability in a discrimination learning test. A toluene exposure of 1200 ppm resulted in a reduced body weight of rat dams and offspring and a higher mortality until weaning. The physical development (incisor eruption, eye opening and vaginal opening) was retarded in this group. There were no clear-cut and concentration-dependent differences in the development of reflexes, rota rod performance and locomotor activity between the offspring of animals exposed to toluene and the controls. Likewise, no effects were found on learning ability in the operant conditioning task. Compared to the controls there were no differences in mating, fertility and pregnancy indexes in the F{sub 1}-generation. The tests performed have provided no evidence that toluene exposures {<=} 1200 ppm induce adverse effects on the behaviour of rat offspring exposed during late embryonic and fetal development. (orig.). With 8 figs., 7 tabs.

  19. [Development and differentiation of the rat epididymis. I: ultrastructural aspects of the peritubular zone].

    Francavilla, S; Santiemma, V; Francavilla, F; Moscardelli, S; Forcella, G; Fabbrini, A


    We investigated the ultrastructural aspects of the peritubular cells of epididymis and their development from birth to adult age. At birth the peritubular zone consisted of polygonal cells which did not differ from other interstitial cells. Cytoplasmic filaments were visible in the cells of the inner layer at day 6. From day 22 the peritubular cells reached the adult aspect. The peritubular cells in the rat epididymis had aspects similar to those of peritubular smooth muscle cells of rat testis, with a more precocious appearance of cytoplasmic filaments. This finding concurs with the observed precocious contractility of epididymis.

  20. Curative effects of sodium fusidate on the development of dinitrobenzenesulfonic acid-induced colitis in rats

    Di Marco, Roberto; Mangano, Katia; Quattrocchi, Cinzia


    . These entailed a significant reduction in body weight loss, smaller increase in colon weights, milder macroscopic damage, and lower histological scores. In addition, when sacrificed at the end of the study, fusidin-treated rats had significantly lower blood levels of tumor necrosis factor alpha and interferon......Fusidic acid and sodium fusidate (fusidin) are antibiotics with low toxicity and powerful immunomodulatory activities in vitro and in vivo. In this study we have evaluated the effect of fusidin on the development of dinitrobenzenesulfonic acid (DNB)-induced colitis in rats that serves...

  1. Hazardous effects of fried potato chips on the development of retina in albino rats

    Hassan I El-Sayyad; Saber A Sakr; Gamal M Badawy; Hanaa S Afify


    Objective: To evaluate the hazardous effects of fried potato chips upon the retina of two developmental stages of the albino rats aged 7 and 14 days from parturition. Methods: Pregnant rats were arranged into two groups: control pregnant rats and consequently their delivered newborns until reaching 7 and 14 days old from parturition and fried potato chips group in which pregnant rats at the 6th day of gestation maintained on diet formed of fried potato chips supplied from the market mixed with standard diet at a concentration of 50% per each till 7 and 14 post-partum. Three fold integrated approaches were adopted, namely, histological, ultrastructural and proteomic analysis. Results: Histological examination of the retina of the experimental offsprings revealed many histopathological changes, including massive degeneration, vacuolization and cell loss in the ganglion cell layer, as well as general reduction in retinal size. At the ultrastructural level, the retina of experimental offsprings exhibited number of deformities, including ill differentiated and degenerated nuclear layer, malformed and vacuolated pigment epithelium with vesiculated and fragmented rough endoplasmic reticulum, degenerated outer segment of photoreceptors, as well as swollen choriocapillaris and loss of neuronal cells. Proteomic analysis of retina of the two experimental developmental stages showed variations in the expressed proteins as a result of intoxication which illustrated the adverse toxic effects of fried potato chips upon the retina. Conclusions: It can be concluded that the effect of fried potato chips on the development of retina in rats may be due to the presence of acrylamide or its metabolite.

  2. Alloxan-induced diabetes triggers the development of periodontal disease in rats.

    Marcela Claudino

    Full Text Available BACKGROUND: Periodontal disease in diabetic patients presents higher severity and prevalence; and increased severity of ligature-induced periodontal disease has been verified in diabetic rats. However, in absence of aggressive stimuli such as ligatures, the influence of diabetes on rat periodontal tissues is incompletely explored. The aim of this study was to evaluate the establishment and progression of periodontal diseases in rats only with diabetes induction. METHODOLOGY/PRINCIPAL FINDINGS: Diabetes was induced in Wistar rats (n = 25 by intravenous administration of alloxan (42 mg/kg and were analyzed at 1, 3, 6, 9 and 12 months after diabetes induction. The hemimandibles were removed and submitted to radiographical and histopathological procedures. A significant reduction was observed in height of bone crest in diabetic animals at 3, 6, 9 and 12 months, which was associated with increased numbers of osteoclasts and inflammatory cells. The histopathological analyses of diabetic rats also showed a reduction in density of collagen fibers, fibroblasts and blood vessels. Severe caries were also detected in the diabetic group. CONCLUSIONS/SIGNIFICANCE: The results demonstrate that diabetes induction triggers, or even co-induces the onset of alterations which are typical of periodontal diseases even in the absence of aggressive factors such as ligatures. Therefore, diabetes induction renders a previously resistant host into a susceptible phenotype, and hence diabetes can be considered a very important risk factor to the development of periodontal disease.

  3. Effect of methotrexate on cerebellar development in infant rats.

    Sugiyama, Akihiko; Sun, Jing; Ueda, Kota; Furukawa, Satoshi; Takeuchi, Takashi


    Six-day-old rats were treated intraperitoneal injections with methotrexate 1 mg/kg, and the cerebellum was examined. Both the length and width of the vermis decreased in the methotrexate-treated group instead of the control from 4 day after treatment (DAT) onward. A significant reduction in the width of the external granular layer was detected on 2 and 3 DAT in the methotrexate group. By 4 DAT, the width of the external granular layer of the methotrexate group was indistinguishable from the control, and by 8 DAT, it was greater than that of the control. The molecular layer of methotrexate group on 8 and 15 DAT was thinner than that of the control. On 1 DAT, in the methotrexate group, there were many TUNEL and cleaved caspase-3-positive granular cells throughout the external granular layer, and they decreased time-dependently. On 1 DAT, in the methotrexate group, phospho-histone H3-positive cells in the external granular layer were fewer than in the control and tended to increase on 2-4 DAT. The p21-positive-rate of the external granule cells in the MTX group was higher than in the control on 1-4 DAT. These results suggested that methotrexate exposure on postnatal day 6 induces a delay, slowing in the migration of external granular cells to the inner granular layer, attributed to decrease or inhibition in the production of external granular cells that had arisen from apoptosis and the decrease in cell proliferative activity, resulting in cerebellar hypoplasia.

  4. Detection of expressional changes induced by intrauterine growth restriction in the developing rat pancreas.

    Zhang, Lin; Chen, Wei; Dai, Yuee; Zhu, Ziyang; Liu, Qianqi


    Intrauterine growth retardation (IUGR) is a disorder that can result in permanent changes in the physiology and metabolism of the newborn, which increased the risk of disease in adulthood. Evidence supports IUGR as a risk factor for the development of diabetes mellitus, which could reflect changes in pancreas developmental pathways. We sought to characterize the IUGR-induced alterations of the complex pathways of pancreas development in a rat model of IUGR. We analyzed the pancreases of Sprague Dawley rats after inducing IUGR by feeding a maternal low calorie diet from gestational day 1 until term. IUGR altered the pancreatic structure, islet areas, and islet quantities and resulted in abnormal morphological changes during pancreatic development, as determined by HE staining and light microscopy. We identified multiple differentially expressed genes in the pancreas by RT-PCR. The genes of the insulin/FoxO1/Pdx1/MafA signaling pathway were first expressed at embryonic day 14 (E14). The expressions of insulin and MafA increased as the fetus grew while the expressions of FoxO1 and Pdx1 decreased. Compared with the control rats, the expressions of FoxO1, Pdx1, and MafA were lower in the IUGR rats, whereas insulin levels showed no change. Microarray profiling, in combination with quantitative real-time PCR, uncovered a subset of microRNAs that changed in their degree of expression throughout pancreatic development. In conclusion, our data support the hypothesis that IUGR influences the development of the rat pancreas. We also identified new pathways that appear to be programmed by IUGR. © 2016 by the Society for Experimental Biology and Medicine.

  5. Evaluation of bone targeting salmon calcitonin analogues in rats developing osteoporosis and adjuvant arthritis.

    Bhandari, Krishna H; Asghar, Waheed; Newa, Madhuri; Jamali, Fakhreddin; Doschak, Michael R


    Synthetic analogues of the peptide hormone calcitonin have been used in medicine as biologic drug therapies for decades, to treat pathological conditions of excessive bone turnover, such as osteoporosis, where more bones are removed than replaced during bone remodeling. Osteoporosis and other chronic skeletal diseases, including inflammatory arthritis, exact a substantial and growing toll on aging populations worldwide however they respond poor to synthetic biologic drug therapy, due in part to the rapid half-life of elimination, which for calcitonin is 43 minutes. To address those shortcomings, we have developed and synthesized bone-targeting variants of calcitonin as a targeted drug delivery strategy, by conjugation to bisphosphonate drug bone-seeking functional groups in highly specific reaction conditions. To evaluate their in vivo efficacy, bisphosphonate-mediated bone targeting with PEGylated (polyethylene glycol conjugated) and non-PEGylated salmon calcitonin analogues were synthesized and dose escalation was performed in female rats developing Osteoporosis. The bone-targeting calcitonin analogues were also tested in a separate cohort of male rats developing adjuvant-induced arthritis. Ovariectomized female rats developing Osteoporosis were administered daily sub-cutaneous injection of analogues equivalent to 5, 10 and 20 IU/kg of calcitonin for 3 months. Adjuvant arthritis was developed in male rats by administering Mycobacterium butyricum through tail base injection. Daily sub-cutaneous injection of analogues equivalent to 20 IU/kg of calcitonin was administered and the rats were measured for visible signs of inflammation to a 21 day endpoint. In both studies, the effect of drug intervention upon bone volume and bone mineral density (BMD) was assessed by measuring the trabecular bone volume percentage and BMD at the proximal tibial metaphysis using in vivo micro-computed tomography. With dose escalation studies, only bone targeting analogue dosed groups

  6. Neuronal-like differentiation of bone marrow-derived mesenchymal stem cells induced by striatal extracts from a rat model of Parkinson's disease

    Xiaoling Qin; Wang Han; Zhigang Yu


    A rat model of Parkinson's disease was established by 6-hydroxydopamine injection into the medial forebrain bundle. Bone marrow-derived mesenchymal stem cells (BMSCs) were isolated from the femur and tibia, and were co-cultured with 10% and 60% lesioned or intact striatal extracts. The results showed that when exposed to lesioned striatal extracts, BMSCs developed bipolar or multi-polar morphologies, and there was an increase in the percentage of cells that expressed glial fibrillary acidic protein (GFAP), nestin and neuron-specific enolase (NSE). Moreover, the percentage of NSE-positive cells increased with increasing concentrations of lesioned striatal extracts. However, intact striatal extracts only increased the percentage of GFAP-positive cells. The findings suggest that striatal extracts from Parkinson's disease rats induce BMSCs to differentiate into neuronal-like cells in vitro.

  7. Effects of induced maternal hypothyroidism on the ovarian development of offspring rats

    Radovanović Anita


    Full Text Available The effects of propylthyouracil (PTU induced hypothyroidism of rats during pregnancy and lactation on offspring ovarian development and maturation were studied. Thyroid hormones and thyroid stimulating hormone (TSH concentrations were determined using the radioimmunoassay method in order to verify the hypothyroid status of treated mothers and their two months old pups. The ovaries of the offspring were processed for light microscopy analysis on the day of the first estrus after the 60th day of age. Histological analysis including follicle count was performed on serial sections stained with haematoxyline/eosin and on semithin sections stained with methylene blue. A significant increase of serum TSH and decrease in T3 and T4 levels was observed in treated mothers compared to controls. The levels of measured hormones in the control and PTU-treated two months old rats were not significantly different. Ten percent of 60-dayold treated females did not reach estrus and they were sacrificed in diestrus. The secondary interstitial cells were the dominant structures in the ovaries. The number of healthy growing and early antral follicles was markedly decreased. Ovaries of treated rats contained relatively few antral follicles, significantly more atretic antral follicles and a decreased number of corpora lutea, compared to controls. These results indicate that lack of thyroid hormones during prenatal and early postnatal development impair ovarian development in rats. [Projekat Ministarstva nauke Republike Srbije, br. 175061

  8. Global expression analysis during late stage of embryonic pancreatic development of rats with microarray technique

    Qingxin Yuan; Chao Liu; Yan Zhong; Cuiping Liu; Li Yuan; Jinyong Zhou; Li-ping Teng; Jingjing Hu; Wei De


    Objective: To define gene expression profiles during late stage of embryonic pancreatic development of rats and to find out key genes in rat pancreatic functional development. Methods: Pancreata of rats in embryonic day 15.5(E15.5) and 18.5(E18.5)were dissected under microscope respectively. Genechips from Affymetrix company were applied to study gene expression profiles. Some differentially expressed genes were verified by RT-PCR. Results: Comparing El8.5 to El5.5, 8.3% genes were expressed differently 2-fold above, in which, 50.3% were up-regulated, including transcriptions related to metabolic development and various kinds of enzymes and hormones (both endocrine and exocrine) and 49.7% were down-regulated, including transcriptions related to cell differentiation. The percentage of genes having definite function was 63%, and that of expressed sequence tag(EST) was 37%. The result of RT-PCR is accordant to that of genechips. Conclusion: The metabolic function of rat pancreas may be further accomplished during late stage of embryonic day.

  9. Effects of iron supplementation on growth, gut microbiota, metabolomics and cognitive development of rat pups.

    Alexeev, Erica E; He, Xuan; Slupsky, Carolyn M; Lönnerdal, Bo


    Iron deficiency is common during infancy and therefore iron supplementation is recommended. Recent reports suggest that iron supplementation in already iron replete infants may adversely affect growth, cognitive development, and morbidity. Normal and growth restricted rat pups were given iron daily (30 or 150 μg/d) from birth to postnatal day (PD) 20, and followed to PD56. At PD20, hematology, tissue iron, and the hepatic metabolome were measured. The plasma metabolome and colonic microbial ecology were assessed at PD20 and PD56. T-maze (PD35) and passive avoidance (PD40) tests were used to evaluate cognitive development. Iron supplementation increased iron status in a dose-dependent manner in both groups, but no significant effect of iron on growth was observed. Passive avoidance was significantly lower only in normal rats given high iron compared with controls. In plasma and liver of normal and growth-restricted rats, excess iron increased 3-hydroxybutyrate and decreased several amino acids, urea and myo-inositol. While a profound difference in gut microbiota of normal and growth-restricted rats was observed, with iron supplementation differences in the abundance of strict anaerobes were observed. Excess iron adversely affects cognitive development, which may be a consequence of altered metabolism and/or shifts in gut microbiota.

  10. Method of Isolated Ex Vivo Lung Perfusion in a Rat Model: Lessons Learned from Developing a Rat EVLP Program

    Nelson, Kevin; Bobba, Christopher; Eren, Emre; Spata, Tyler; Tadres, Malak; Hayes,, Don; Black, Sylvester M.


    The number of acceptable donor lungs available for lung transplantation is severely limited due to poor quality. Ex-Vivo Lung Perfusion (EVLP) has allowed lung transplantation in humans to become more readily available by enabling the ability to assess organs and expand the donor pool. As this technology expands and improves, the ability to potentially evaluate and improve the quality of substandard lungs prior to transplant is a critical need. In order to more rigorously evaluate these approaches, a reproducible animal model needs to be established that would allow for testing of improved techniques and management of the donated lungs as well as to the lung-transplant recipient. In addition, an EVLP animal model of associated pathologies, e.g., ventilation induced lung injury (VILI), would provide a novel method to evaluate treatments for these pathologies. Here, we describe the development of a rat EVLP lung program and refinements to this method that allow for a reproducible model for future expansion. We also describe the application of this EVLP system to model VILI in rat lungs. The goal is to provide the research community with key information and “pearls of wisdom”/techniques that arose from trial and error and are critical to establishing an EVLP system that is robust and reproducible. PMID:25741794

  11. Relationship between neuronal loss and interictal glucose metabolism during the chronic phase of the lithium-pilocarpine model of epilepsy in the immature and adult rat.

    Dubé, C; Boyet, S; Marescaux, C; Nehlig, A


    The lithium-pilocarpine (Li-Pilo) model of epilepsy reproduces most of the features of human temporal lobe epilepsy. After having studied the metabolic changes occurring during the silent phase, in the present study, we explored the relationship between interictal metabolic changes and neuronal loss during the chronic phase following status epilepticus (SE) induced by Li-Pilo in 10-day-old (P10), 21-day-old (P21), and adult rats. Rats were observed and their EEG was recorded to detect the occurrence of spontaneous recurrent seizures (SRS). Local cerebral glucose utilization was measured during the interictal period of the chronic phase, between 2 and 7 months after SE, by the [(14)C]2-deoxyglucose method in rats subjected to SE at P10, P21, or as adults. Neuronal damage was assessed by cell counting on adjacent cresyl violet stained sections. When SE was induced at P10, rats did not become epileptic, did not develop lesions and cerebral glucose utilization was in the normal range 7 months later. When SE was induced in adult rats, they all became epileptic after a mean duration of 25 days and developed lesions in the forebrain limbic areas, which were hypometabolic during the interictal period of the chronic phase, 2 months after SE. When SE was induced in P21 rats, 24% developed SRS, and in 43% seizures could be triggered (TS) by handling, after a mean delay of 74 days in both cases. The remaining 33% did not become epileptic (NS). The three groups of P21 rats developed quite comparable lesions mainly in the hilus of the dentate gyrus, lateral thalamus, and entorhinal cortex; at 6 months after SE, the forebrain was hypometabolic in NS and TS rats while it was normo- to slightly hypermetabolic in SRS rats. These data show that interictal metabolic changes are age-dependent. Moreover, there is no obvious correlation, in this model, between interictal hypometabolism and neuronal loss, as reported previously in human temporal lobe epilepsy. Copyright 2000 Academic

  12. Song exposure regulates known and novel microRNAs in the zebra finch auditory forebrain

    Kim Jong H


    Full Text Available Abstract Background In an important model for neuroscience, songbirds learn to discriminate songs they hear during tape-recorded playbacks, as demonstrated by song-specific habituation of both behavioral and neurogenomic responses in the auditory forebrain. We hypothesized that microRNAs (miRNAs or miRs may participate in the changing pattern of gene expression induced by song exposure. To test this, we used massively parallel Illumina sequencing to analyse small RNAs from auditory forebrain of adult zebra finches exposed to tape-recorded birdsong or silence. Results In the auditory forebrain, we identified 121 known miRNAs conserved in other vertebrates. We also identified 34 novel miRNAs that do not align to human or chicken genomes. Five conserved miRNAs showed significant and consistent changes in copy number after song exposure across three biological replications of the song-silence comparison, with two increasing (tgu-miR-25, tgu-miR-192 and three decreasing (tgu-miR-92, tgu-miR-124, tgu-miR-129-5p. We also detected a locus on the Z sex chromosome that produces three different novel miRNAs, with supporting evidence from Northern blot and TaqMan qPCR assays for differential expression in males and females and in response to song playbacks. One of these, tgu-miR-2954-3p, is predicted (by TargetScan to regulate eight song-responsive mRNAs that all have functions in cellular proliferation and neuronal differentiation. Conclusions The experience of hearing another bird singing alters the profile of miRNAs in the auditory forebrain of zebra finches. The response involves both known conserved miRNAs and novel miRNAs described so far only in the zebra finch, including a novel sex-linked, song-responsive miRNA. These results indicate that miRNAs are likely to contribute to the unique behavioural biology of learned song communication in songbirds.

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

    Riedel, G


    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. Altered placental development in undernourished rats: role of maternal glucocorticoids

    Chen Chun-Hung


    Full Text Available Abstract Maternal undernutrition (MUN during pregnancy may lead to fetal intrauterine growth restriction (IUGR, which itself predisposes to adult risk of obesity, hypertension, and diabetes. IUGR may stem from insufficient maternal nutrient supply or reduced placental nutrient transfer. In addition, a critical role for maternal stress-induced glucocorticoids (GCs has been suggested to contribute to both IUGR and the ensuing risk of adult metabolic syndrome. While GC-induced fetal organ defects have been examined, there have been few studies on placental responses to MUN-induced maternal stress. Therefore, we hypothesize that 50% MUN associates with increased maternal GC levels and decreased placental HSD11B. This in turn leads to decreased placental and fetal growth, hence the need to investigate nutrient transporters. We measured maternal serum levels of corticosterone, and the placental basal and labyrinth zone expression of glucocorticoid receptor (NR3C1, 11-hydroxysteroid dehydrogenase B 1 (HSD11B-1 predominantly activates cortisone to cortisol and 11-dehydrocorticosterone (11-DHC to corticosterone, although can sometimes drive the opposing (inactivating reaction, and HSD11B-2 (only inactivates and converts corticosterone to 11-DHC in rodents in control and MUN rats at embryonic day 20 (E20. Moreover, we evaluated the expression of nutrient transporters for glucose (SLC2A1, SLC2A3 and amino acids (SLC38A1, 2, and 4. Our results show that MUN dams displayed significantly increased plasma corticosterone levels compared to control dams. Further, a reduction in fetal and placental weights was observed in both the mid-horn and proximal-horn positions. Notably, the placental labyrinth zone, the site of feto-maternal exchange, showed decreased expression of HSD11B1-2 in both horns, and increased HSD11B-1 in proximal-horn placentas, but no change in NR3C1. The reduced placental GCs catabolic capacity was accompanied by downregulation of SLC2A3, SLC

  15. Repercussions of mild diabetes on pregnancy in Wistar rats and on the fetal development

    Saito Felipe H


    Full Text Available Abstract Background Experimental models are necessary to elucidate diabetes pathophysiological mechanisms not yet understood in humans. Objective: To evaluate the repercussions of the mild diabetes, considering two methodologies, on the pregnancy of Wistar rats and on the development of their offspring. Methods In the 1st induction, female offspring were distributed into two experimental groups: Group streptozotocin (STZ, n = 67: received the β-cytotoxic agent (100 mg STZ/kg body weight - sc on the 1st day of the life; and Non-diabetic Group (ND, n = 14: received the vehicle in a similar time period. In the adult life, the animals were mated. After a positive diagnosis of pregnancy (0, female rats from group STZ presenting with lower glycemia than 120 mg/dL received more 20 mg STZ/kg (ip at day 7 of pregnancy (2nd induction. The female rats with glycemia higher than 120 mg/dL were discarded because they reproduced results already found in the literature. In the mornings of days 0, 7, 14 and 21 of the pregnancy glycemia was determined. At day 21 of pregnancy (at term, the female rats were anesthetized and killed for maternal reproductive performance and fetal development analysis. The data were analyzed using Student-Newman-Keuls, Chi-square and Zero-inflated Poisson (ZIP Tests (p Results STZ rats presented increased rates of pre (STZ = 22.0%; ND = 5.1% and post-implantation losses (STZ = 26.1%; ND = 5.7%, reduced rates of fetuses with appropriate weight for gestational age (STZ = 66%; ND = 93% and reduced degree of development (ossification sites. Conclusion Mild diabetes led a negative impact on maternal reproductive performance and caused intrauterine growth restriction and impaired fetal development.

  16. Ectopic development of skeletal muscle induced by subcutaneous transplant of rat satellite cells

    M.G. Fukushima


    Full Text Available The present study analyzes the ectopic development of the rat skeletal muscle originated from transplanted satellite cells. Satellite cells (10(6 cells obtained from hindlimb muscles of newborn female 2BAW Wistar rats were injected subcutaneously into the dorsal area of adult male rats. After 3, 7, and 14 days, the transplanted tissues (N = 4-5 were processed for histochemical analysis of peripheral nerves, inactive X-chromosome and acetylcholinesterase. Nicotinic acetylcholine receptors (nAChRs were also labeled with tetramethylrhodamine-labeled alpha-bungarotoxin. The development of ectopic muscles was successful in 86% of the implantation sites. By day 3, the transplanted cells were organized as multinucleated fibers containing multiple clusters of nAChRs (N = 2-4, resembling those from non-innervated cultured skeletal muscle fibers. After 7 days, the transplanted cells appeared as a highly vascularized tissue formed by bundles of fibers containing peripheral nuclei. The presence of X chromatin body indicated that subcutaneously developed fibers originated from female donor satellite cells. Differently from the extensor digitorum longus muscle of adult male rat (87.9 ± 1.0 µm; N = 213, the diameter of ectopic fibers (59.1 µm; N = 213 did not obey a Gaussian distribution and had a higher coefficient of variation. After 7 and 14 days, the organization of the nAChR clusters was similar to that of clusters from adult innervated extensor digitorum longus muscle. These findings indicate the histocompatibility of rats from 2BAW colony and that satellite cells transplanted into the subcutaneous space of adult animals are able to develop and fuse to form differentiated skeletal muscle fibers.

  17. Development of motor maps in rats and their modulation by experience.

    Young, Nicole A; Vuong, Jennifer; Teskey, G Campbell


    While a substantial literature demonstrates the effect of differential experience on development of mammalian sensory cortices and plasticity of adult motor cortex, characterization of differential experience on the functional development of motor cortex is meager. We first determined when forelimb movement representations (motor maps) could be detected in rats during postnatal development and then whether their motor map expression could be altered with rearing in an enriched environment consisting of group housing and novel toys or skilled learning by training on the single pellet reaching task. All offspring had high-resolution intracortical microstimulation (ICMS)-derived motor maps using methodologies previously optimized for the adult rat. First, cortical GABA-mediated inhibition was depressed by bicuculline infusion directly into layer V of motor cortex and ICMS-responsive points were first reliably detected on postnatal day (PND) 13. Without relying on bicuculline disinhibition of cortex, motor maps emerged on PND 35 and then increased in size until PND 60 and had progressively lower movement thresholds. Second, environmental enrichment did not affect initial detection of responsive points and motor maps in non-bicuculline-treated pups on PND 35. However, motor maps were larger on PND 45 in enriched rat pups relative to pups in the standard housing condition. Rats in both conditions had similar map sizes on PNDs 60, 75, and 90. Third, reach training in rat pups resulted in an internal reorganization of the map in the hemisphere contralateral, but not ipsilateral, to the trained forelimb. The map reorganization was expressed as proportionately more distal (digit and wrist) representations on PND 45. Our data indicate that both environmental enrichment and skilled reach training experience can differentially modify expression of motor maps during development.

  18. Physiology of Developing Gravity Receptors and Otolith-Ocular Reflexes in Rat

    Blanks, Robert H.


    This proposal had the long-term objective of examining the effects of microgravity on the physiology of the adult and developing mammalian gravity receptors. The grant outlined three-years of ground-based studies to examine. 1) the physiologic responses or otolith afferents in the adult rat and during postnatal development, and 2) the otolith organ contributions to the vertical vestibulo-ocular (VOR) and postural reflexes.

  19. The effect of morphine consumption on plasma corticosteron concentration and placenta development in pregnant rats

    Masoomeh Kazemi; Hedayat Sahraei; Mahnaz Azarnia; Leila Dehghani; Hossein Bahadoran; Elaheh Tekieh1


    Background: Previous studies have shown that morphine consumption during pregnancy may delay embryo development or cause abnormal nervous system function. Objective: The present study focused on the effect of maternal morphine consumption on development of placenta and blood corticosteron concentration in addictive pregnant mothers. Materials and Methods: 24 female rats, 170-200g weight, were used. The experimental groups after pregnancy received an oral dose of 0.05 mg/ml of morphine by tap ...

  20. The role of apoptosis in early embryonic development of the adenohypophysis in rats

    Gedrange Tomas; Kleinheinz Johannes; Driemel Oliver; Faltermeier Andreas; Lotz Kristina; Weingärtner Jens; Proff Peter


    Abstract Background Apoptosis is involved in fundamental processes of life, like embryonic development, tissue homeostasis, or immune defense. Defects in apoptosis cause or contribute to developmental malformation, cancer, and degenerative disorders. Methods The developing adenohypophysis area of rat fetuses was studied at the embryonic stage 13.5 (gestational day) for apoptotic and proliferative cell activities using histological serial sections. Results A high cell proliferation rate was ob...

  1. Changes in short-chain acyl-coA dehydrogenase during rat cardiac development and stress

    Huang, Jinxian; Xu, Lipeng; Huang, Qiuju; Luo, Jiani; Liu, Peiqing; Chen, Shaorui; Yuan, Xi; Lu, Yao; Wang, Ping; Zhou, Sigui


    This study was designed to investigate the expression of short-chain acyl-CoA dehydrogenase (SCAD), a key enzyme of fatty acid β-oxidation, during rat heart development and the difference of SCAD between pathological and physiological cardiac hypertrophy. The expression of SCAD was lowest in the foetal and neonatal heart, which had time-dependent increase during normal heart development. In contrast, a significant decrease in SCAD expression was observed in different ages of spontaneously hyp...

  2. Aberrant Lipid Metabolism in the Forebrain Niche Suppresses Adult Neural Stem Cell Proliferation in an Animal Model of Alzheimer's Disease.

    Hamilton, Laura K; Dufresne, Martin; Joppé, Sandra E; Petryszyn, Sarah; Aumont, Anne; Calon, Frédéric; Barnabé-Heider, Fanie; Furtos, Alexandra; Parent, Martin; Chaurand, Pierre; Fernandes, Karl J L


    Lipid metabolism is fundamental for brain development and function, but its roles in normal and pathological neural stem cell (NSC) regulation remain largely unexplored. Here, we uncover a fatty acid-mediated mechanism suppressing endogenous NSC activity in Alzheimer's disease (AD). We found that postmortem AD brains and triple-transgenic Alzheimer's disease (3xTg-AD) mice accumulate neutral lipids within ependymal cells, the main support cell of the forebrain NSC niche. Mass spectrometry and microarray analyses identified these lipids as oleic acid-enriched triglycerides that originate from niche-derived rather than peripheral lipid metabolism defects. In wild-type mice, locally increasing oleic acid was sufficient to recapitulate the AD-associated ependymal triglyceride phenotype and inhibit NSC proliferation. Moreover, inhibiting the rate-limiting enzyme of oleic acid synthesis rescued proliferative defects in both adult neurogenic niches of 3xTg-AD mice. These studies support a pathogenic mechanism whereby AD-induced perturbation of niche fatty acid metabolism suppresses the homeostatic and regenerative functions of NSCs. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. The primary brain vesicles revisited: are the three primary vesicles (forebrain/midbrain/hindbrain) universal in vertebrates?

    Ishikawa, Yuji; Yamamoto, Naoyuki; Yoshimoto, Masami; Ito, Hironobu


    It is widely held that three primary brain vesicles (forebrain, midbrain, and hindbrain vesicles) develop into five secondary brain vesicles in all vertebrates (von Baer's scheme). We reviewed previous studies in various vertebrates to see if this currently accepted scheme of brain morphogenesis is a rule applicable to vertebrates in general. Classical morphological studies on lamprey, shark, zebrafish, frog, chick, Chinese hamster, and human embryos provide only partial evidence to support the existence of von Baer's primary vesicles at early stages. Rather, they suggest that early brain morphogenesis is diverse among vertebrates. Gene expression and fate map studies on medaka, chick, and mouse embryos show that the fates of initial brain vesicles do not accord with von Baer's scheme, at least in medaka and chick brains. The currently accepted von Baer's scheme of brain morphogenesis, therefore, is not a universal rule throughout vertebrates. We propose here a developmental hourglass model as an alternative general rule: Brain morphogenesis is highly conserved at the five-brain vesicle stage but diverges more extensively at earlier and later stages. This hypothesis does not preclude the existence of deep similarities in molecular prepatterns at early stages.

  4. Expression of peroxisome proliferator-activated receptor γ in rat retina during development

    Ju-Ming Zhu


    Full Text Available AIM: To evaluate the spatiotemporal expression pattern of PPARγ in embryonic and early postnatal stages of rat retina. METHODS: Fetal rats were collected at 13-18d of gestation (GD from pregnant females and postnatal rats at 1d (P1 and 5d (P5 after birth were also used. We used RT-PCR to detect PPARγ mRNA and immunohistochemical to observe PPARγ protein. And at last, we chose HE staining showed the structural changes of rat retina during development. RESULTS: RT-PCR analysis showed that PPARγ mRNA was expressed as early as GD13 and gradually decreased as maturation continued. However, the PPARγ gene expression significantly increased after birth, especially in P5. Immunohistochemical analysis showed PPARγ protein was expressed throughout the retinal neuroepithelium at GD13 and GD14, and then decreased during late embryogenesis but remained relatively high in the predicted ganglion cell zone. During postnatal development, PPARγ protein was remarkably increased and the positive signals were mainly located in nerve fiber layer (NFL, ganglion cell layer (GCL and outer layers of the retina. CONCLUSION: The spatiotemporal changes of PPARγ expression demonstrated that PPARγ might play a role in regulating the differentiation and maturation of retinal cells.

  5. Effect of Marine Collagen Peptides on Physiological and Neurobehavioral Development of Male Rats with Perinatal Asphyxia

    Linlin Xu


    Full Text Available Asphyxia during delivery produces long-term deficits in brain development. We investigated the neuroprotective effects of marine collagen peptides (MCPs, isolated from Chum Salmon skin by enzymatic hydrolysis, on male rats with perinatal asphyxia (PA. PA was performed by immersing rat fetuses with uterine horns removed from ready-to-deliver rats into a water bath for 15 min. Caesarean-delivered pups were used as controls. PA rats were intragastrically administered with 0.33 g/kg, 1.0 g/kg and 3.0 g/kg body weight MCPs from postnatal day 0 (PND 0 till the age of 90-days. Behavioral tests were carried out at PND21, PND 28 and PND 90. The results indicated that MCPs facilitated early body weight gain of the PA pups, however had little effects on early physiological development. Behavioral tests revealed that MCPs facilitated long-term learning and memory of the pups with PA through reducing oxidative damage and acetylcholinesterase (AChE activity in the brain, and increasing hippocampus phosphorylated cAMP-response element binding protein (p-CREB and brain derived neurotrophic factor (BDNF expression.

  6. Aluminum chloride induces neuroinflammation, loss of neuronal dendritic spine and cognition impairment in developing rat.

    Cao, Zheng; Yang, Xu; Zhang, Haiyang; Wang, Haoran; Huang, Wanyue; Xu, Feibo; Zhuang, Cuicui; Wang, Xiaoguang; Li, Yanfei


    Aluminum (Al) is present in the daily life of humans, and the incidence of Al contamination increased in recent years. Long-term excessive Al intake induces neuroinflammation and cognition impairment. Neuroinflammation alter density of dendritic spine, which, in turn, influence cognition function. However, it is unknown whether increased neuroinflammation is associated with altered density of dendritic spine in Al-treated rats. In the present study, AlCl3 was orally administrated to rat at 50, 150 and 450 mg/kg for 90d. We examined the effects of AlCl3 on the cognition function, density of dendritic spine in hippocampus of CA1 and DG region and the mRNA levels of IL-1β, IL-6, TNF-α, MHC II, CX3CL1 and BNDF in developing rat. These results showed exposure to AlCl3 lead to increased mRNA levels of IL-1β, IL-6, TNF-α and MCH II, decreased mRNA levels of CX3CL1 and BDNF, decreased density of dendritic spine and impaired learning and memory in developing rat. Our results suggest AlCl3 can induce neuroinflammation that may result in loss of spine, and thereby leads to learning and memory deficits.

  7. Assessing Autophagy in Sciatic Nerves of a Rat Model that Develops Inflammatory Autoimmune Peripheral Neuropathies

    Susana Brun


    Full Text Available The rat sciatic nerve has attracted widespread attention as an excellent model system for studying autophagy alterations in peripheral neuropathies. In our laboratory, we have developed an original rat model, which we used currently in routine novel drug screening and to evaluate treatment strategies for chronic inflammatory demyelinating polyneuropathy (CIDP and other closely related diseases. Lewis rats injected with the S-palmitoylated P0(180-199 peptide develop a chronic, sometimes relapsing-remitting type of disease. Our model fulfills electrophysiological criteria of demyelination with axonal degeneration, confirmed by immunohistopathology and several typical features of CIDP. We have set up a series of techniques that led us to examine the failures of autophagy pathways in the sciatic nerve of these model rats and to follow the possible improvement of these defects after treatment. Based on these newly introduced methods, a novel area of investigation is now open and will allow us to more thoroughly examine important features of certain autophagy pathways occurring in sciatic nerves.

  8. Resistance of the rat to development of lead-induced renal functional deficits

    O' Flaherty, E.J.; Adams, W.D.; Hammond, P.B.; Taylor, E.


    Lead nephropathy, characterized functionally by depression of effective renal plasma flow (ERPF), glomerular filtration rate (GFR), and maximum glucose reabsorption rate, is associated with prolonged occupational exposure to lead. Production of comparable lead-related renal functional deficits in rats has been difficult to achieve. The authors have examined in rats some of the factors that might be expected to influence the development of lead-induced renal functional damage, using GFR (as inulin clearance). ERPF (as para-aminohippurate clearance), and maximum glucose readsorption rates as indices of renal functional competence. Although lead produces a significant weight loss, this can be accounted for by reduced food intake and is not associated with reduction in renal function. Even exposure to large amounts of lead in conjunction with other factors; such as controlled diet (NIH-07 and AIN-76) and early age of initial exposure, that might have been expected to increase the rats' susceptibility has not resulted in the development of renal functional deficits. It is unlikely that the rat can be successfully explored as an animal model of human lead nephropathy with accompanying functional deficits.

  9. Development of chemosensitivity in neurons from the nucleus tractus solitarii (NTS) of neonatal rats.

    Conrad, Susan C; Nichols, Nicole L; Ritucci, Nick A; Dean, Jay B; Putnam, Robert W


    We studied the development of chemosensitivity during the neonatal period in rat nucleus tractus solitarii (NTS) neurons. We determined the percentage of neurons activated by hypercapnia (15% CO(2)) and assessed the magnitude of the response by calculating the chemosensitivity index (CI). There were no differences in the percentage of neurons that were inhibited (9%) or activated (44.8%) by hypercapnia or in the magnitude of the activated response (CI 164+/-4.9%) in NTS neurons from neonatal rats of all ages. To assess the degree of intrinsic chemosensitivity in these neurons we used chemical synaptic block medium and the gap junction blocker carbenoxolone. Chemical synaptic block medium slightly decreased basal firing rate but did not affect the percentage of NTS neurons that responded to hypercapnia at any neonatal age. However, in neonates aged NTS neurons activated by hypercapnia in neonatal rats of any age. In summary, the response of NTS neurons from neonatal rats appears to be intrinsic and largely unchanged throughout early development. In young neonates (NTS neurons that respond to hypercapnia or the magnitude of that response.

  10. Nitrergic neurons during early postnatal development of the prefrontal cortex in the rat: histochemical study.

    Hvizdosova, Natalia; Tomasova, Lenka; Bolekova, Adriana; Kolesar, Dalibor; Kluchova, Darina


    The presence of nitrergic cells in the prefrontal cortex has been confirmed, however little is known about the postnatal development of these cells. Nitrergic neurons were studied histochemically by using NADPH-diaphorase staining in the prefrontal cortex of male Wistar rats from postnatal day 7-21 (P7-21). Neuronal NADPH-diaphorase is a nitric oxide synthase that provides a specific histochemical marker for neurons producing nitric oxide (NO). NO acts as a neurotransmitter and intracellular signaling molecule in the nervous system. We observed in 7 day old rats NADPH-d containing neurons that were intensely stained. These neurons were bipolar with a short dendrite with average length of 23 μm. During the second postnatal week, the neurons were mainly bipolar and were rarely multipolar. By P14 the cells were located primarily in cortical layers III-VI. Nitrergic neurons of the 21 day old rats were histochemically identified as multipolar cells with long radial extending dendrites. Dendrites of neurons in 14 and 21 day old rats were a similar length with an average of 57 μm. These results suggest that nitrergic neurons differentiate during a relatively short period of time and reach their structural maturity by the end of the second week of postnatal development.

  11. Development of Chemosensitivity in Neurons from the Nucleus Tractus Solitarii (NTS) of Neonatal Rats

    Conrad, Susan C.; Nichols, Nicole L.; Ritucci, Nick A.; Dean, Jay B.; Putnam, Robert W.


    We studied the development of chemosensitivity during the neonatal period in rat Nucleus tractus solitarii (NTS) neurons. We determined the percentage of neurons activated by hypercapnia (15% CO2) and assessed the magnitude of the response by calculating the chemosensitivity index (CI). There were no differences in the percentage of neurons that were inhibited (9%) or activated (44.8%) by hypercapnia or in the magnitude of the activated response (CI 164±4.9%) in NTS neurons from neonatal rats of all ages. To assess the degree of intrinsic chemosensitivity in these neurons we used chemical synaptic block medium and the gap junction blocker carbenoxolone. Chemical synaptic block medium slightly decreased basal firing rate but did not affect the percentage of NTS neurons that responded to hypercapnia at any neonatal age. However, in neonates aged rats of any age. In summary, the response of NTS neurons from neonatal rats appears to be intrinsic and largely unchanged throughout early development. In young neonates (

  12. Spinal Anesthesia in Infant Rats: Development of a Model and Assessment of Neurological Outcomes

    Yahalom, Barak; Athiraman, Umeshkumar; Soriano, Sulpicio G.; Zurakowski, David; Carpino, Elizabeth; Corfas, Gabriel; Berde, Charles B.


    Background Previous studies in infant rats and case-control studies of human infants undergoing surgery have raised concerns about potential neurodevelopmental toxicities of general anesthesia. Spinal anesthesia is an alternative to general anesthesia for some infant surgeries. To test for potential toxicity, we developed a spinal anesthesia model in infant rats. Methods Rats of postnatal ages 7, 14, and 21 days were assigned to: no treatment; 1% isoflurane for either 1 h or 6 h, or lumbar spinal injection of saline or bupivacaine, at doses of 3.75 mg/kg (low dose) or 7.5 mg/kg (high dose). Subgroups of animals underwent neurobehavioral testing and blood gas analysis. Brain and lumbar spinal cord sections were examined for apoptosis using cleaved caspase-3 immunostaining. Lumbar spinal cord was examined histologically. Rats exposed to spinal or general anesthesia as infants underwent Rotarod testing of motor performance as adults. Data were analyzed using analysis of variance (ANOVA) using general linear models, Friedman Tests, and Mann–Whitney U tests, as appropriate. Results Bupivacaine 3.75 mg/kg was effective for spinal anesthesia in all age groups, and produced sensory and motor function recovered in 40 to 60 min. Blood gases were similar among groups. Brain and spinal cord apoptosis increased in rats receiving 6 h of 1% isoflurane, but not among the other treatments. All groups showed intact motor performance at adulthood. Conclusions Spinal anesthesia is technically feasible in infant rats, and appears benign in terms of neuroapoptotic and neuromotor sequelae. PMID:21555934

  13. Asthma pregnancy alters postnatal development of chromaffin cells in the rat adrenal medulla.

    Xiu-Ming Wu

    Full Text Available BACKGROUND: Adrenal neuroendocrine plays an important role in asthma. The activity of the sympathoadrenal system could be altered by early life events. The effects of maternal asthma during pregnancy on the adrenal medulla of offspring remain unknown. METHODOLOGY/PRINCIPAL FINDINGS: This study aims to explore the influence of maternal asthma during pregnancy on the development and function of adrenal medulla in offspring from postnatal day 3 (P3 to postnatal day 60 (P60. Asthmatic pregnant rats (AP, nerve growth factor (NGF-treated pregnant rats (NP and NGF antibody-treated pregnant rats (ANP were sensitized and challenged with ovalbumin (OVA; NP and ANP were treated with NGF and NGF antibody respectively. Offspring rats from the maternal group were divided into four groups: offspring from control pregnant rats (OCP, offspring from AP (OAP, offspring from NP (ONP, and offspring from ANP (OANP. The expressions of phenylethanolamine N-methyltransferase (PNMT protein in adrenal medulla were analyzed. The concentrations of epinephrine (EPI, corticosterone and NGF in serum were measured. Adrenal medulla chromaffin cells (AMCC were prone to differentiate into sympathetic nerve cells in OAP and ONP. Both EPI and PNMT were decreased in OAP from P3 to P14, and then reached normal level gradually from P30 to P60, which were lower from birth to adulthood in ONP. Corticosterone concentration increased significantly in OAP and ONP. CONCLUSION/SIGNIFICANCE: Asthma pregnancy may promote AMCC to differentiate into sympathetic neurons in offspring rats and inhibit the synthesis of EPI, resulting in dysfunction of bronchial relaxation.


    ZHONG Yi-sheng; LIU Xiao-hong; HUANG Ping; CHENG Yu


    Objective To investigate the distribution of erythropoietin (EPO) and erythropoietin receptor (EPOR) expression in the postnatal rat retina development.Methods Forty-two male Sprague-Dawley rats were divided into 7 groups according to their various postnatal days: postnatal 1 d (D1 group), 3 d (D3 group), 1 week (W1 group), 2 weeks (W2 group), 3 weeks (W3 group), 4 weeks (W4 group) and 8 weeks (W8 group) (n=6). Single eye was randomly chosen from each rat for the study. The retinal sections were stained with hematoxylin and eosin (HE) and used for the retina development observation. Immunohistochemical staining was used to localize EPO and EPOR expressions in retinas of different stages of development, and the expression intensities were determined by an image plus 4 program.Results The retinal inner nuclear layer (INL) and outer nuclear layer (ONL) were mixed together and had not yet fully differentiated in D1 and D3 groups. The INL and ONL formed their own independent regions and the outer plexiform layer (OPL) appeared between two layers in W1 group. With the postnatal retinal development, the inner plexiform layer (IPL), rods and cones layer (RCL), and OPL were gradually widened and stabilized in W2 to W3 groups. EPO/EPOR expressions located prominently in the inner part of the postnatal rat developing retinas. The expression of EPO in GCL and INL gradually increased from D1 to W4, then the expression decreased in W8. Expression of EPOR in GCL gradually increased from D1 to W1, then decreased in W2; and it gradually increased again from W3 to W8. Expression of EPOR in INL gradually increased from D1 to W1, then decreased in W2; and it continued to decrease from W3 to W8. Expression of EPOR in the external segment of RCL gradually increased from D1 to W8. However, expression in the internal segment of RCL gradually decreased from D1 to W3, then no obvious expression was seen in the internal segment of RCL in W4 and W8.Conclusion EPO/EPOR expressions locate

  15. Distinct Correlation Structure Supporting a Rate-Code for Sound Localization in the Owl’s Auditory Forebrain


    Abstract While a topographic map of auditory space exists in the vertebrate midbrain, it is absent in the forebrain. Yet, both brain regions are implicated in sound localization. The heterogeneous spatial tuning of adjacent sites in the forebrain compared to the midbrain reflects different underlying circuitries, which is expected to affect the correlation structure, i.e., signal (similarity of tuning) and noise (trial-by-trial variability) correlations. Recent studies have drawn attention to the impact of response correlations on the information readout from a neural population. We thus analyzed the correlation structure in midbrain and forebrain regions of the barn owl’s auditory system. Tetrodes were used to record in the midbrain and two forebrain regions, Field L and the downstream auditory arcopallium (AAr), in anesthetized owls. Nearby neurons in the midbrain showed high signal and noise correlations (RNCs), consistent with shared inputs. As previously reported, Field L was arranged in random clusters of similarly tuned neurons. Interestingly, AAr neurons displayed homogeneous monotonic azimuth tuning, while response variability of nearby neurons was significantly less correlated than the midbrain. Using a decoding approach, we demonstrate that low RNC in AAr restricts the potentially detrimental effect it can have on information, assuming a rate code proposed for mammalian sound localization. This study harnesses the power of correlation structure analysis to investigate the coding of auditory space. Our findings demonstrate distinct correlation structures in the auditory midbrain and forebrain, which would be beneficial for a rate-code framework for sound localization in the nontopographic forebrain representation of auditory space. PMID:28674698

  16. Changing bone marrow micro-environment during development of acute myeloid leukaemia in rats

    Mortensen, B T; Jensen, P O; Helledie, N;


    cells (from about 45% to 25%), evidently as a result of the severely changed microenvironment. In this study we have demonstrated in vivo the development of an acidic and hypoxic bone marrow hampering normal haemopoiesis during leukaemic growth. Our data support the notion of BNML as a valuable tool......The Brown Norwegian rat transplanted with promyelocytic leukaemic cells (BNML) has been used as a model for human acute myeloid leukaemia. We have previously shown that both the blood supply to the bone marrow and the metabolic rate decrease in relation to the leukaemic development in these rats....... Here we have investigated how the development and progression of this leukaemia affect oxygenation, pH and proliferation of normal and leukaemic cells in vivo. Bone marrow pH was measured by a needle electrode. Nitroimidazol-theophylline (NITP) was used to identify hypoxic cells, and we applied...

  17. The importance of dietary control in the development of a peanut allergy model in Brown Norway rats

    Jonge, J.D. de; Knippels, L.M.J.; Ezendam, J.; Odink, J.; Penninks, A.H.; Loveren, H. van


    This report describes the further development of a peanut allergy model in Brown Norway (BN) rats and in particular the importance of allergen-free breeding of the laboratory animals for the allergen to be used. For this purpose BN rats were bred for 3 generations on soy- and peanut-free feed since




    The morphological development of motoneuron pools of two hindlimb muscles of the rat, soleus (SOL) and tibialis anterior (TA), was studied in rats ranging in age between 8 and 30 postnatal days (P8-P30). Motoneurons were retrogradely labelled by injecting a cholera toxin B subunit solution directly

  19. Mammary gland development and response to prenatal atrazine exposure in the Sprague Dawley and Long-Evans rats.

    Mammary gland (MG) tumor development in Sprague Dawley (SD) rats is increased by longterm dietary exposure to the chlorotriazine herbicide atrazine (ATR). ATR is proposed to cause these changes in the adult SD rat by altering hormonally-regulated estrous cyclicity. In Long-Evans...

  20. Expression and localization of Wolfram syndrome 1 gene in the developing rat pancreas

    Rong Xu; Biao Xia; Jie Geng; Jing Shi; Hui Shi; Li Yuan; Wei De


    AIM: To investigate the expression and function of Wolfram syndrome 1 gene ( WFS1) during the development of normal pancreas.METHODS: Pancreas from SpragueDawley Rat fetuses, embryos, young and adult animals were used in this study.Expression levels of WFS1 in pancreas of different development stages were detected by reverse transcriptionpolymerase chain reation (RTPCR) and Western blotting.To identify the cell location of WFS1 in the developing rat pancreas, double-immunofluorescent staining was performed using antibodies to specific cell markers and WFS1, respectively.RESULTS: Compared to E15.5, the highest level of WFS1 mRNA was detected at E18.5, the level of WFS1 mRNA in E15.5 and P0 was less, and at a lowest at adult ( P < 0.05 vs P0 and adult), respectively.Compare to E15.5, the highest level of WFS1 was at P14 and lowest at P21 ( P < 0.05 vs P14 and P21), respectively.The WFS1 positive staining is expressed in the normal developing rat pancreas mainly in the islet betacells and mesenchyme at each stage tested.CONCLUSION: These results indicate that WFS1 may be involved in some aspects of pancreatic development and further research on WFS1 may provide new evidences to prove the interactions between mesenchyma and epithelia at the same time.

  1. Quantitative in situ hybridization analysis of glutamic acid decarboxylase messenger RNA in developing rat cerebellum.

    Willcutts, M D; Morrison-Bogorad, M


    The appearance and relative amounts of GAD mRNA in rat cerebellar neurons during postnatal development was studied by in situ hybridization. GAD mRNA content within all GABAergic neurons increased during the first month of postnatal development, but the degree and time course of the increase varied among different neuronal types. In newborn rats, GAD mRNA was present only in the prenatally-formed Purkinje and Golgi cells. GAD mRNA in Golgi cells had reached adult levels by postnatal day 14, while GAD mRNA levels in Purkinje cells reached adult levels one week later. Most basket cells expressed GAD mRNA by postnatal day 14, and final levels were attained one week later. Stellate cells in the bottom two-thirds of the molecular layer attained their final GAD mRNA content by postnatal day 21 whereas stellate cells in close proximity to the pial surface were not yet mature at this age. No GAD mRNA was detected within the external granular layer at any time during development. In adult rat, approximately 40% of cerebellar GAD mRNA was contained within the Purkinje cell population, 38% within the stellate cells, 17% within the basket cells, and only 5% within the Golgi cells. Increases in GAD mRNA within GABAergic neurons during cerebellar development correlated with the timing of neuronal maturation and synaptogenesis in these cell populations, suggesting that synaptic activity affects GAD gene expression in developing cerebellum.

  2. Modulation of mammary gland development in prepubertal male rats exposed to genistein and methoxychlor.

    You, Li; Sar, Madhabananda; Bartolucci, Erika J; McIntyre, Barry S; Sriperumbudur, Rajagopal


    The estrogenic isoflavone genistein is a common dietary component that has been shown to affect reproductive development in experimental animals at high doses. The objective of the present study was to examine interactions of genistein and the hormonally active pesticide methoxychlor on mammary gland development in juvenile rats. Timed-pregnant Sprague-Dawley rats were fed a soy- and alfalfa-free diet containing different combinations of genistein (300 and 800 ppm) and methoxychlor (800 ppm). Rats were fed these diets starting on gestation day (GD)1 and continuing through pregnancy and lactation until postnatal day (PND) 22, when the pups were killed. Inguinal mammary glands from both female and male pups were processed as whole-mount preparations for morphometric analysis. The total glandular area and the numbers of branch points, lateral buds, and terminal end buds in the male rats were found to be significantly greater in the groups exposed to methoxychlor than those exposed to genistein only. These effects were not observed in the female rats. In the male rats, methoxychlor had the most prominent effect on elongating the glandular ducts, while genistein enhanced the ductile branching. The 2 compounds in combination promoted the development of alveolar-lobular structure, an effect not observed with either compound alone. Immunostaining for proliferating cell nuclear antigen revealed a high percentage of immunopositive cells in the mammary epithelia of the males exposed to methoxychlor and genistein (800 ppm) compared to the controls. While no significant changes in serum levels of mammotrophic hormones were detected, increased immunostaining for insulin-like growth factor-1 receptor, estrogen receptor alpha, and progesterone receptor in the genistein + methoxychlor group suggested that local factors involved in regulating mammary growth may have played a role in propagating the endocrine effects of these two compounds. These results indicated that the mammary

  3. Effects of the masticatory demand on the rat mandibular development

    Hichijo, N.; Kawai, N.; Mori, H.; Sano, R.; Ohnuki, Y.; Okumura, S.; Langenbach, G.E.J.; Tanaka, E.


    The influence of masticatory loading stimulus on mandibular development is not fully clear. In this paper, experimental alterations in the daily muscle use, caused by a changed diet consistency, were continuously monitored, while adaptations in bone and cartilage were examined. It is hypothesised th

  4. Partial sympathetic denervation of the rat epididymis permits fertilization but inhibits embryo development.

    Ricker, D D; Crone, J K; Chamness, S L; Klinefelter, G R; Chang, T S


    ovulated oocytes following IUI with spermatozoa from sham-operated controls and from 1- and 4-week IMG-denervated rats, respectively. To determine whether the reduction in implantation sites following IUI with spermatozoa from IMG-denervated rats resulted from impaired oocyte fertilization, studies were performed in which oocytes were retrieved and stained 24 hours after IUI. Comparable fertilization rates of 76.5% and 89.0% were observed using cauda epididymal spermatozoa from IMG-denervated and sham-operated control males, respectively, indicating that oocyte fertilization was not affected by the loss of innervation. These studies establish the importance of innervation from the IMG for ejaculatory competence and sperm reproductive capacity in the male rat. These data further suggest that sympathetic innervation in the epididymis critically influences paternal factors associated with embryonic development.

  5. Expression of glutamic acid decarboxylase and identification of GABAergic cells in the ischemic rat dentate gyrus

    Müller, Georg Johannes; Dogonowski, Anne-Marie; Finsen, Bente


    We have investigated the glutamic acid dexcarboxylase (GAD) mRNA and protein isoforms as markers for ischemic loss of GABAergic neurons in the dentate hilus. Stereological counts of these neurons were performed in rats surviving 8 days after 10 min of transient forebrain ischemia, and in control...

  6. Expression of glutamic acid decarboxylase and identification of GABAergic cells in the ischemic rat dentate gyrus

    Müller, Georg Johannes; Dogonowski, Anne-Marie; Finsen, Bente


    We have investigated the glutamic acid dexarboxylase (GAD) mRNA and protein isoforms as markers for ischemic loss of GABAergic neurons in the dentate hilus. Stereological counts of these neurons were performed in rats surviving 8 days after 10 min of transient forebrain ischemia, and in control...

  7. Expression of glutamic acid decarboxylase and identification of GABAergic cells in the ischemic rat dentate gyrus

    Müller, Georg Johannes; Dogonowski, Anne-Marie; Finsen, Bente;


    We have investigated the glutamic acid dexarboxylase (GAD) mRNA and protein isoforms as markers for ischemic loss of GABAergic neurons in the dentate hilus. Stereological counts of these neurons were performed in rats surviving 8 days after 10 min of transient forebrain ischemia, and in control...

  8. Acoustic imprinting leads to differential 2-deoxy-D-glucose uptake in the chick forebrain.

    Maier, V; Scheich, H


    This report describes experiments in which successful acoustic imprinting correlates with differential uptake of D-2-deoxy[14C]glucose in particular forebrain areas that are not considered primarily auditory. Newly hatched guinea chicks (Numida meleagris meleagris) were imprinted by playing 1.8-kHz or 2.5-kHz tone bursts for prolonged periods. Those chicks were considered to be imprinted who approached the imprinting stimulus (emitted from a loudspeaker) and preferred it over a new stimulus in a simultaneous discrimination test. In the 2-deoxy-D-glucose experiment all chicks, imprinted and naive, were exposed to 1.8-kHz tone bursts for 1 hr. As shown by the autoradiographic analysis of the brains, neurons in the 1.8-kHz isofrequency plane of the auditory "cortex" (field L) were activated in all chicks, whether imprinted or not. However, in the most rostral forebrain striking differences were found. Imprinted chicks showed an increased 2-deoxy-D-glucose uptake in three areas, as compared to naive chicks: (i) the lateral neostriatum and hyperstriatum ventrale, (ii) a medial magnocellular field (medial neostriatum/hyperstriatum ventrale), and (iii) the most dorsal layers of the hyperstriatum. Based on these findings we conclude that these areas are involved in the processing of auditory stimuli once they have become meaningful by experience. Images PMID:6574519

  9. Conservation of spatial memory function in the pallial forebrain of reptiles and ray-finned fishes.

    Rodríguez, Fernando; López, J Carlos; Vargas, J Pedro; Gómez, Yolanda; Broglio, Cristina; Salas, Cosme


    The hippocampus of mammals and birds is critical for spatial memory. Neuroanatomical evidence indicates that the medial cortex (MC) of reptiles and the lateral pallium (LP) of ray-finned fishes could be homologous to the hippocampus of mammals and birds. In this work, we studied the effects of lesions to the MC of turtles and to the LP of goldfish in spatial memory. Lesioned animals were trained in place, and cue maze tasks and crucial probe and transfer tests were performed. In experiment 1, MC-lesioned turtles in the place task failed to locate the goal during trials in which new start positions were used, whereas sham animals navigated directly to the goal independently of start location. In contrast, no deficit was observed in cue learning. In experiment 2, LP lesion produced a dramatic impairment in goldfish trained in the place task, whereas medial and dorsal pallium lesions did not decrease accuracy. In addition, none of these pallial lesions produced deficits in cue learning. These results indicate that lesions to the MC of turtles and to the LP of goldfish, like hippocampal lesions in mammals and birds, selectively impair map-like memory representations of the environmental space. Thus, the forebrain structures of reptiles and teleost fish neuroanatomically equivalent to the mammalian and avian hippocampus also share a central role in spatial cognition. Present results suggest that the presence of a hippocampus-dependent spatial memory system is a primitive feature of the vertebrate forebrain that has been conserved through evolution.

  10. Developmental activity variations of DNA polymerase α,δ,ε in mouse forebrains and spleens

    杨荣武; 陆长德


    The levels of DNA polymerase α,δ,ε were examined in the neonatal mouse forebrains andspleens.The levels of DNA polymerase α were determined by the difference of polymerase activity in theabsence and the presence of α specific inhibitor,BuPdGTP,or its monoclonal antibody.The levels of DNApolymerase δ were determined in H · A fractions after separating it from the other two enzymes.The levelsof DNA polymerase ε were identified in H · A fractions by the use of α-monoclonal antibody or BuPdGTP.Results showed that in the mouse forebrain DNA polymerase α,δ,ε activities are the highest before birth,decline sharply following birth and are very low on the 8th day and hardly detectable on the 17th day;as forthe mouse spleen,however,DNA polymerase α,δ,ε activities are the lowest at birth,increase rapidly afterbirth and reach their maxima on the 8th day and then decline gradually but remain in higher levels.Theseresults not only prove that DNA polymerase α and δ take part in cell DNA replication but also suggest thatDNA polymerase ε is involved in DNA replication.

  11. Hierarchical prediction errors in midbrain and basal forebrain during sensory learning.

    Iglesias, Sandra; Mathys, Christoph; Brodersen, Kay H; Kasper, Lars; Piccirelli, Marco; den Ouden, Hanneke E M; Stephan, Klaas E


    In Bayesian brain theories, hierarchically related prediction errors (PEs) play a central role for predicting sensory inputs and inferring their underlying causes, e.g., the probabilistic structure of the environment and its volatility. Notably, PEs at different hierarchical levels may be encoded by different neuromodulatory transmitters. Here, we tested this possibility in computational fMRI studies of audio-visual learning. Using a hierarchical Bayesian model, we found that low-level PEs about visual stimulus outcome were reflected by widespread activity in visual and supramodal areas but also in the midbrain. In contrast, high-level PEs about stimulus probabilities were encoded by the basal forebrain. These findings were replicated in two groups of healthy volunteers. While our fMRI measures do not reveal the exact neuron types activated in midbrain and basal forebrain, they suggest a dichotomy between neuromodulatory systems, linking dopamine to low-level PEs about stimulus outcome and acetylcholine to more abstract PEs about stimulus probabilities.

  12. Shp2 in forebrain neurons regulates synaptic plasticity, locomotion, and memory formation in mice.

    Kusakari, Shinya; Saitow, Fumihito; Ago, Yukio; Shibasaki, Koji; Sato-Hashimoto, Miho; Matsuzaki, Yasunori; Kotani, Takenori; Murata, Yoji; Hirai, Hirokazu; Matsuda, Toshio; Suzuki, Hidenori; Matozaki, Takashi; Ohnishi, Hiroshi


    Shp2 (Src homology 2 domain-containing protein tyrosine phosphatase 2) regulates neural cell differentiation. It is also expressed in postmitotic neurons, however, and mutations of Shp2 are associated with clinical syndromes characterized by mental retardation. Here we show that conditional-knockout (cKO) mice lacking Shp2 specifically in postmitotic forebrain neurons manifest abnormal behavior, including hyperactivity. Novelty-induced expression of immediate-early genes and activation of extracellular-signal-regulated kinase (Erk) were attenuated in the cerebral cortex and hippocampus of Shp2 cKO mice, suggestive of reduced neuronal activity. In contrast, ablation of Shp2 enhanced high-K(+)-induced Erk activation in both cultured cortical neurons and synaptosomes, whereas it inhibited that induced by brain-derived growth factor in cultured neurons. Posttetanic potentiation and paired-pulse facilitation were attenuated and enhanced, respectively, in hippocampal slices from Shp2 cKO mice. The mutant mice also manifested transient impairment of memory formation in the Morris water maze. Our data suggest that Shp2 contributes to regulation of Erk activation and synaptic plasticity in postmitotic forebrain neurons and thereby controls locomotor activity and memory formation.

  13. Fine-Tuning Circadian Rhythms: The Importance of Bmal1 Expression in the Ventral Forebrain

    Mieda, Michihiro; Hasegawa, Emi; Kessaris, Nicoletta; Sakurai, Takeshi


    Although, the suprachiasmatic nucleus (SCN) of the hypothalamus acts as the central clock in mammals, the circadian expression of clock genes has been demonstrated not only in the SCN, but also in peripheral tissues and brain regions outside the SCN. However, the physiological roles of extra-SCN circadian clocks in the brain remain largely elusive. In response, we generated Nkx2.1-Bmal1−/− mice in which Bmal1, an essential clock component, was genetically deleted specifically in the ventral forebrain, including the preoptic area, nucleus of the diagonal band, and most of the hypothalamus except the SCN. In these mice, as expected, PER2::LUC oscillation was drastically attenuated in the explants of mediobasal hypothalamus, whereas it was maintained in those of the SCN. Although, Nkx2.1-Bmal1−/− mice were rhythmic and nocturnal, they showed altered patterns of locomotor activity during the night in a 12:12-h light:dark cycle and during subjective night in constant darkness. Control mice were more active during the first half than the second half of the dark phase or subjective night, whereas Nkx2.1-Bmal1−/− mice showed the opposite pattern of locomotor activity. Temporal patterns of sleep-wakefulness and feeding also changed accordingly. Such results suggest that along with mechanisms in the SCN, local Bmal1–dependent clocks in the ventral forebrain are critical for generating precise temporal patterns of circadian behaviors.

  14. Origin and immunolesioning of cholinergic basal forebrain innervation of cat primary auditory cortex.

    Kamke, Marc R; Brown, Mel; Irvine, Dexter R F


    Numerous studies have implicated the cholinergic basal forebrain (cBF) in the modulation of auditory cortical responses. This study aimed to accurately define the sources of cBF input to primary auditory cortex (AI) and to assess the efficacy of a cholinergic immunotoxin in cat. Three anaesthetized cats received multiple injections of horseradish-peroxidase conjugated wheatgerm-agglutin into physiologically identified AI. Following one to two days survival, tetramethylbenzidine histochemistry revealed the greatest number of retrogradely labeled cells in ipsilateral putamen, globus pallidus and internal capsule, and smaller numbers in more medial nuclei of the basal forebrain (BF). Concurrent choline acetyltransferase immunohistochemistry showed that almost 80% of the retrogradely labeled cells in BF were cholinergic, with the vast majority of these cells arising from the more lateral BF nuclei identified above. In the second part of the study, unilateral intraparenchymal injections of the cholinergic immunotoxin ME20.4-SAP were made into the putamen/globus pallidus nuclei of six cats. Immuno- and histochemistry revealed a massive reduction in the number of cholinergic cells in and around the targeted area, and a corresponding reduction in the density of cholinergic fibers in auditory cortex. These results are discussed in terms of their implications for investigations of the role of the cBF in cortical plasticity.

  15. Apoptosis in the early developing periodontium of rat molars

    Cerri, Paulo Sérgio; Freymüller, Edna; Katchburian, Eduardo


    Development of the periodontium involves a series of complex steps that result in the formation of root dentine, cementum, bone and fibres of the ligament. These precisely controlled and timed events require the participation of the enamel organ derived epithelial cells of Hertwig's (HRS) and ectomesenchymal cells of the dental follicle. These events involve rapid turnover of the tissues and cells, including disappearance of epithelial cells of HRS. Thus, it seemed likely to us that programme...

  16. Behavioral effects of bovine lactoferrin administration during postnatal development of rats.

    Shumake, Jason; Barrett, Douglas W; Lane, Michelle A; Wittke, Anja J


    We tested the hypothesis that rats consuming bovine lactoferrin (bLf) during postnatal development would show better performance of stressful tasks during adolescence. In the first study, we orally administered bLf (750 mg/kg) once daily between postnatal days 16-34. Rats then underwent a battery of behavioral tests: open field (forced exploration of risky environment), light-dark emergence (voluntary exploration of risky environment), baited holeboard (working and reference memory), food neophobia (preference for familiar versus novel food), forced swim (test for antidepressant efficacy), and shuttle-box escape (learning to escape footshock). bLf-supplemented rats showed less exploration of the risky environment, greater preference for the familiar food odor, and faster escape responses. The effect of bLf on forced-swim behavior depended on sex: immobility increased for males and decreased for females. In the next study, we replaced the forced-swim test with an escape-swim test in which rats learned to use a visual cue to locate an escape platform, and we tested the dose response of bLf on this and the shuttle-box escape test, with subjects receiving vehicle or bLf at 500, 1,000, or 2,000 mg/kg. Under this modified testing battery, improvement of escape from footshock was not observed at any dose. However, males, but not females, showed a significant dose-dependent effect of bLf on acquisition of the water-escape task. On average, males receiving a higher dose mastered the task 20-25 % sooner than rats receiving a lower dose or vehicle. These results offer preliminary evidence that bLf supplementation during development can improve subsequent cognitive performance during stress.

  17. Relationship between monocularly deprivation and amblyopia rats and visual system development

    Yu Ma


    Objective:To explore the changes of lateral geniculate body and visual cortex in monocular strabismus and form deprived amblyopic rat, and visual development plastic stage and visual plasticity in adult rats.Methods:A total of60SD rats ages13 d were randomly divided intoA, B,C three groups with20 in each group, groupA was set as the normal control group without any processing, groupB was strabismus amblyopic group, using the unilateral extraocular rectus resection to establish the strabismus amblyopia model, groupC was monocular form deprivation amblyopia group using unilateral eyelid edge resection+ lid suture.At visual developmental early phase(P25), meta phase(P35), late phase(P45) and adult phase(P120), the lateral geniculate body and visual cortex area17 of five rats in each group were exacted forC-fosImmunocytochemistry. Neuron morphological changes in lateral geniculate body and visual cortex was observed, the positive neurons differences ofC-fos expression induced by light stimulation was measured in each group, and the condition of radiation development ofP120 amblyopic adult rats was observed.Results:In groupsB andC,C-fos positive cells were significantly lower thanthe control group atP25(P0.05),C-fos protein positive cells level of groupB was significantly lower than that of groupA(P<0.05).The binoculusC-fos protein positive cells level of groupsB andC were significantly higher than that of control group atP35,P45 andP120 with statistically significant differences(P<0.05).Conclusions:The increasing ofC-fos expression in geniculate body and visual cortex neurons of adult amblyopia suggests the visual cortex neurons exist a certain degree of visual plasticity.

  18. Development of nNOS-positive neurons in the rat sensory ganglia after capsaicin treatment.

    Masliukov, Petr M; Moiseev, Konstantin Y; Korzina, Marina B; Porseva, Valentina V


    To gain a better understanding of the neuroplasticity of afferent neurons during postnatal ontogenesis, the distribution of neuronal nitric oxide synthase (nNOS) immunoreactivity was studied in the nodose ganglion (NG) and Th2 and L4 dorsal root ganglia (DRG) from vehicle-treated and capsaicin-treated female Wistar rats at different ages (10-day-old, 20-day-old, 30-day-old, and two-month-old). The percentage of nNOS-immunoreactive (IR) neurons decreased after capsaicin treatment in all studied ganglia in first 20 days of life, from 55.4% to 36.9% in the Th2 DRG, from 54.6% to 26.1% in the L4 DRG and from 37.1% to 15.0% in the NG. However, in the NG, the proportion of nNOS-IR neurons increased after day 20, from 11.8% to 23.9%. In the sensory ganglia of all studied rats, a high proportion of nNOS-IR neurons bound isolectin B4. Approximately 90% of the sensory nNOS-IR neurons bound to IB4 in the DRG and approximately 80% in the NG in capsaicin-treated and vehicle-treated rats. In 10-day-old rats, a large number of nNOS-IR neurons also expressed TrkA, and the proportion of nNOS(+)/TrkA(+) neurons was larger in the capsaicin-treated rats compared with the vehicle-treated animals. During development, the percentage of nNOS(+)/TrkA(+) cells decreased in the first month of life in both groups. The information provided here will also serve as a basis for future studies investigating mechanisms of sensory neuron development.

  19. Development of telmisartan in the therapy of spinal cord injury: pre-clinical study in rats

    Lin CM


    Full Text Available Chien-Min Lin,1,* Jo-Ting Tsai,2,* Chen Kuei Chang,1 Juei-Tang Cheng,3 Jia-Wei Lin11Department of Neurosurgery, 2Department of Radiation Oncology, Shuang Ho Hospital-Taipei Medical University, 3Institute of Medical Science, College of Health Science, Chang Jung Christian University, Tainan City, Taiwan*These authors contributed equally to this workBackground: Decrease of peroxisome proliferator-activated receptors-δ (PPARδ expression has been observed after spinal cord injury (SCI. Increase of PPARδ may improve the damage in SCI. Telmisartan, the antihypertensive agent, has been mentioned to increase the expression of PPARδ. Thus, we are going to screen the effectiveness of telmisartan in SCI for the development of it in clinical application.Methods: In the present study, we used compressive SCI in rats. Telmisartan was then used to evaluate the influence in rats after SCI. Change in PPARδ expression was identified by Western blots. Also, behavioral tests were performed to check the recovery of damage.Results: Recovery of damage from SCI was observed in telmisartan-treated rats. Additionally, this action of telmisartan was inhibited by GSK0660 at the dose sufficient to block PPARδ. However, metformin at the dose enough to activate adenosine monophosphate-activated protein kinase failed to produce similar action as telmisartan. Thus, mediation of adenosine monophosphate-activated protein kinase in this action of telmisartan can be rule out. Moreover, telmisartan reversed the expressions of PPARδ in rats with SCI.Conclusion: The obtained data suggest that telmisartan can improve the damage of SCI in rats through an increase in PPARδ expression. Thus, telmisartan is useful to be developed as an agent in the therapy of SCI.Keywords: PPARδ, AMPK, spinal cord injury, angiotensin receptor blocker, metformin

  20. Development of UDP-glucuronosyltransferase activity toward digitoxigenin-monodigitoxoside in neonatal rats.

    Watkins, J B; Klaassen, C D


    Glucuronidation is low or undetectable in embryonic and early fetal tissues and changes to adult levels at rates depending on the acceptor, tissue, and species. Because other data indicate there may be a specific UDP-glucuronosyltransferase (GT) in the liver of adult rats that glucuronidates digitoxigenin-monodigitoxoside (DIG), the development of GT activity in neonatal rats toward DIG was compared with that of other acceptors. Conjugation of p-nitrophenol and 1-naphthol was higher at birth and decreased to adult levels by 20 days of age. Glucuronidation of chloramphenicol, morphine, valproic acid, and bilirubin increased from birth to adult activity by 20 days of age. Conjugation of phenolphthalein, estrone, and diethylstilbestrol was low in 1-day-old rats and higher than adult in 20-day-old animals. In contrast, glucuronidation of DIG was barely detectable (9% of adult) in 20-day-old rats. The concentration of UDP-glucuronic acid was 50% of adult levels at birth and increased to adult values by 10 days of age. Administration of 3-methylcholanthrene on days 6 to 9 after birth significantly stimulated GT activity toward 1-naphthol, p-nitrophenol, and morphine, whereas phenobarbital precociously increased conjugation of chloramphenicol, valproic acid, morphine, and diethylstilbestrol. Pregnenolone-16 alpha-carbonitrile enhanced the development of GT activity toward morphine, chloramphenicol, valproic acid, bilirubin, diethylstilbestrol, and estrone. Glucuronidation of DIG was not increased after 3-methylcholanthrene or phenobarbital, but could be induced after pregnenolone-16 alpha-carbonitrile to 7% of adult values in 10-day-old rats.(ABSTRACT TRUNCATED AT 250 WORDS)

  1. An interneuron progenitor maintains neurogenic potential in vivo and differentiates into GABAergic interneurons after transplantation in the postnatal rat brain.

    Wang, Qi; Hong, Peiwei; Gao, Hui; Chen, Yuntian; Yang, Qi; Jiang, Mei; Li, Hedong


    Dysfunction of cortical GABAergic interneurons are involved in numerous neurological disorders including epilepsy, schizophrenia and autism; and replenishment of these cells by transplantation strategy has proven to be a feasible and effective method to help revert the symptoms in several animal models. To develop methodology of generating transplantable GABAergic interneurons for therapy, we previously reported the isolation of a v-myc-induced GABAergic interneuron progenitor clone GE6 from embryonic ganglionic eminence (GE). These cells can proliferate and form functional inhibitory synapses in culture. Here, we tested their differentiation behavior in vivo by transplanting them into the postnatal rat forebrain. We found that GE6 cells migrate extensively in the neonatal forebrain and differentiate into both neurons and glia, but preferentially into neurons when compared with a sister progenitor clone CTX8. The neurogenic potential of GE6 cells is also maintained after transplantation into a non-permissive environment such as adult cortex or when treated with inflammatory cytokine in culture. The GE6-derived neurons were able to mature in vivo as GABAergic interneurons expressing GABAergic, not glutamatergic, presynaptic puncta. Finally, we propose that v-myc-induced human interneuron progenitor clones could be an alternative cell source of transplantable GABAergic interneurons for treating related neurological diseases in future clinic.

  2. Postdependent state in rats as a model for medication development in alcoholism.

    Meinhardt, Marcus W; Sommer, Wolfgang H


    Rational development of novel therapeutic strategies for alcoholism requires understanding of its underlying neurobiology and pathophysiology. Obtaining this knowledge largely relies on animal studies. Thus, choosing the appropriate animal model is one of the most critical steps in pre-clinical medication development. Among the range of animal models that have been used to investigate excessive alcohol consumption in rodents, the postdependent model stands out. It was specifically developed to test the role of negative affect as a key driving force in a perpetuating addiction cycle for alcoholism. Here, we will describe our approach to make rats dependent via chronic intermittent exposure to alcohol, discuss the validity of this model, and compare it with other commonly used animal models of alcoholism. We will summarize evidence that postdependent rats fulfill several criteria of a 'Diagnostic and Statistical Manual of Mental Disorders IV/V-like' diagnostic system. Importantly, these animals show long-lasting excessive consumption of and increased motivation for alcohol, and evidence for loss of control over alcohol intake. Our conclusion that postdependent rats are an excellent model for medication development for alcoholism is underscored by a summary of more than two dozen pharmacological tests aimed at reversing these abnormal alcohol responses. We will end with open questions on the use of this model. In the tradition of the Sanchis-Segura and Spanagel review, we provide comic strips that illustrate the postdependent procedure and relevant phenotypes in this review.

  3. Effect of Retinoic acid on Platelet-derived Growth Factor and Lung Development in Newborn Rats

    陈红兵; 常立文; 刘汉楚; 容志惠; 祝华平; 张谦慎; 李文斌


    Summary: The influence of platelet-derived growth factor (PDGF) on lung development in newborn rats and the effect of retinoic acid (RA) on PDGF in lung development were investigated. Newborn Sprague-Dawley (SD) rats were randomly assigned to two groups: control group and RA group.The rats in RA group was intraperitoneally injected with all trans-retinoic acid (500 μg/kg every day) for consecutive 3 days after birth, while those in the control group were not subjected to intervention, Immunohistochemical assay was performed to locate the expression of PDGF. mRNA levels of PDGF were measured by reverse transcription polymerase chain reaction (RT-PCR) at age of 1, 3, 5, 7, 10, 14, 21 days. The method of radial alveolar counts (RAC) was used to measure the amount of the alveoli of the lungs. It was found that with increasing days, levels of PDGF-A and PDGF-B changed to verying degrees. RA could elevate significantly the expression levels of PDGF A mRNA and protein (P<0.01), but not affect the expression levels of PDGF-B mRNA and pro tein markedly (P>0.05). It is suggested that PDGF might play an important role in lung development. RA can stimulate lung development through increasing the expression levels of PDGF-A mRNA and protein.

  4. Stress induced alterations in pre-pubertal ovarian follicular development in rat

    Yajurvedi H.N.


    Full Text Available The objective of the study was to find out whether stress experienced during neo-natal period alters the timing of formation of pre-antral and antral follicles and if so, whether pre-treatment with CRH receptor antagonist prevents these effects in rats. New born rat pups (n= 15 were exposed to maternal separation (6 hours/ day from post-natal day (PND 1 to 7 and were killed on PND 8, 11 and 15. The time of exposure was randomly changed every day during light phase (7Am to 7Pm of the day to avoid habituation. There was a significant increase in serum corticosterone levels on PND 8 and 11 in stress group rats compared to controls indicating stress response in these pups. The ovary of both control and stressed rats contained oocytes and primary follicles on PND 8 and 11 and in showed progress of follicular development upto to pre-antral and early antral follicle formation on PND 11 and 15. However, mean number of healthy oocytes and all categories of follicles at all ages studied were significantly lower in stressed rats compared to controls. Concomitant with these changes, number of atreatic follicles showed an increase over control values in stressed rats. The increase in atresia of follicles was due to apoptosis as shown by increase in the percentage of granulosa cells showing TUNEL positive staining and caspase 3 activity. On the other hand, pre-treatment with CRH- receptor antagonist (CRH 9-41 2ng/ 0.1 ml/ rat prior to undergoing stress regime on PND 1 to 7, prevented alterations in pre- pubertal follicular development thereby indicating that the ovarian changes were due to effects of stress induced activation of HPA axis. The results indicate that, stress during neonatal phase, though does not affect timing of formation of pre-antral and antral follicles, it does enhance atresia of follicles of all categories, including follicular reserve, which may affect the reproductive potential of adults. The results, for the first time reveal that CRF

  5. Effects of lead exposure on dendrite and spine development in hippocampal dentate gyrus areas of rats.

    Hu, Fan; Ge, Meng-Meng; Chen, Wei-Heng


    Lead exposure has been implicated in the impairment of synaptic plasticity in the hippocampal dentate gyrus (DG) areas of rats. However, whether the degradation of physiological properties is based on the morphological alteration of granule neurons in DG areas remains elusive. Here, we examined the dendritic branch extension and spine formation of granule neurons after lead exposure during development in rats. Dendritic morphology was studied using Golgi-Cox stain method, which was followed by Sholl analysis at postnatal days 14 and 21. Our results indicated that, for both ages, lead exposure significantly decreased the total dendritic length and spine density of granule neurons in the DG of the rat hippocampus. Further branch order analysis revealed that the decrease of dendritic length was observed only at the second branch order. Moreover, there were obvious deficits in the proportion and size of mushroom-type spines. These deficits in spine formation and maturity were accompanied by a decrease in Arc/Arg3.1 expression. Our present findings are the first to show that developmental lead exposure disturbs branch and spine formation in hippocampal DG areas. Arc/Arg3.1 may have a critical role in the disruption of neuronal morphology and synaptic plasticity in lead-exposed rats. © 2016 Wiley Periodicals, Inc.

  6. Effects of lead on central nervous system development of the cat and rat

    Patrick, G.W.


    This study utilizes the kitten as an experimental model because the neuroanatomical development of the cat more closely resembles that of the human, more so than the rat. Each kitten, except one control per litter, was given 20 mg/kg lead acetate daily by esophageal intubation for 35 days. At 35 days of age the kittens were sacrificed and prepared by standard methods for light or Golgi analysis. Body weight, but not brain weight, was reduced in lead-treated cats. However, Golgi-Cox stained material revealed a significant reduction in size and density of the Purkinje cell dendritic arborization in lead-treated animals. The width of the molecular layer was reduced reflecting this reduction in Purkinje cell dendritic field. The granule cell layer was reduced in width, while granule cell density was increased, indicating no reduction in cell number. The pyramidal cells from the motor cortex of lead-treated cats showed a reduction in secondary dendritic branching and a phenomenal increase in spine density on apical and basal dendrites. A series of studies using rats was also performed similar to those described by Pentschew and Garro (1966) for comparative purposes. Exposure to lead pre- and postnatally only caused changes in Purkinje cells similar to those seen in the lead-treated kittens. Histological changes were seen in pre- and postnatally exposed rat pups only. Esophageal intubation of high doses of lead solutions in newborn rat pups produced hemorrhagic lesions in both cerebellar and cerebral hemispheres within 24 hours after lead treatment.

  7. Study on development and localization of CTGF-immunoreactive cells in central nervous system of rats

    SU Bing-yin; CAI Wen-qin; ZHANNG Cheng-gang; B.Perbal


    Objective: To study the development of connective tissue growth factor(CTGF) immunoreactive cells in the central nervous system (CNS) of E8-P300 rats. Methods: Immunocytochemistry was employed in our study. Results: No CTGF-immunoreactive cells were detected in the CNS of rats during prenatal stages. A few of CTGF-positive cells were detected in the early postnatal stage. However, the positive cells increased gradually in later stages. CTGF-immunoreactive cells widely distributed in the CNS of rats in the first 30 to 60 days postnatally, and the density of immunoreactive products was the highest in these days. The number and staining intensity of CTGF-positive cells decreased and their area of distribution diminished gradually with age. The positive cells included neurons mainly located in the cingulate cortex,striatum, hippocampus, hypothalamus and cerebellum, and astrocytes in white matter of the spinal cord and ependymal cells of the brain. Most of CTGF-immunoreactive cells were quite big in size with a long process. Conclusion: CTGF-immunoreactive cells were found in the CNS of rats, and their numbers and positive signal decreased with the age.

  8. The effect of a hyperdynamic environment on the development of the rat retina

    Murakami, D. M.; Fuller, C. A.


    The effects of a 2 G field on the retinal development of the layers in the rat and central visual system nuclei are investigated. The thickness of the retinal layers, ganglion cells, and brains of male and female Wistar rats suspended from an 18 foot diameter centrifuge creating a 2 G field are evaluated and compared with a control group. A decrease in the thickness of the outer nuclear layer (ONL) of 37.1 percent, of 58.5 percent in the inner nuclear layer (INL), and of 28.8 percent in the inner plexiform layer (IPL), and a reduction in body weight are observed in the 2-G rats. The data reveal that the ganglion cells and visual system nuclei activity correspond well with the control data; however, the medial terminal nucleus (MTN) activity is inhibited in the 2-G rats. It is concluded that the differences in ONL and IPL are attributed to body weight reduction, but the INL and MTN are affected by the 2-G conditions.

  9. Nicotine Exposure Exacerbates Development of Cataracts in a Type 1 Diabetic Rat Model

    Nima Tirgan


    Full Text Available Diabetes and smoking are known risk factors for cataract development. In this study, we evaluated the effect of nicotine on the progression of cataracts in a type 1 diabetic rat model. Diabetes was induced in Sprague-Dawley rats by a single injection of 65 mg/kg streptozotocin. Daily nicotine injections were administered subcutaneously. Forty-five rats were divided into groups of diabetics with and without nicotine treatment and controls with and without nicotine treatment. Progression of lens opacity was monitored using a slit lamp biomicroscope and scores were assigned. To assess whether systemic inflammation played a role in mediating cataractogenesis, we studied serum levels of eotaxin, IL-6, and IL-4. The levels of the measured cytokines increased significantly in nicotine-treated and untreated diabetic animals versus controls and demonstrated a positive trend in the nicotine-treated diabetic rats. Our data suggest the presence of a synergistic relationship between nicotine and diabetes that accelerated cataract formation via inflammatory mediators.

  10. Fibronectin distribution during the development of fetal rat skin

    Gibson, W T; Couchman, J R; Weaver, A C


    revealed fibronectin on the surface of many of these cells and in association with the surrounding fine collagen fibrils. At the dermal-epidermal junction, both follicular and interfollicular, fibronectin was localized mainly in the plasma membrane and lamina lucida regions of the basement membrane......, and there was also staining associated with the underlying fine collagen fibrils. These observations are further evidence for the proposed role of fibronectin as a mediator of the cell-matrix interactions which are of importance for tissue development and maintenance....

  11. Citric acid inhibits development of cataracts, proteinuria and ketosis in streptozotocin (type1) diabetic rats

    Nagai, Ryoji; Nagai, Mime; Shimasaki, Satoko; Baynes, John W.; Fujiwara, Yukio


    Although many fruits such as lemon and orange contain citric acid, little is known about beneficial effects of citric acid on health. Here we measured the effect of citric acid on the pathogenesis of diabetic complications in streptozotocin-induced diabetic rats. Although oral administration of citric acid to diabetic rats did not affect blood glucose concentration, it delayed the development of cataracts, inhibited accumulation of advanced glycation end products (AGEs) such as Nε-(carboxyethyl)lysine (CEL) and Nε-(carboxymethyl)lysine (CML) in lens proteins, and protected against albuminuria and ketosis . We also show that incubation of protein with acetol, a metabolite formed from acetone by acetone monooxygenase, generate CEL, suggesting that inhibition of ketosis by citric acid may lead to the decrease in CEL in lens proteins. These results demonstrate that the oral administration of citric acid ameliorates ketosis and protects against the development of diabetic complications in an animal model of type 1 diabetes. PMID:20117096

  12. Matricaria chamomilla extract inhibits both development of morphine dependence and expression of abstinence syndrome in rats.

    Gomaa, Adel; Hashem, Tahia; Mohamed, Mahmoud; Ashry, Esraa


    The effect of Matricaria chamomilla (M. chamomilla) on the development of morphine dependence and expression of abstinence was investigated in rats. The frequencies of withdrawal behavioral signs (paw tremor, rearing, teeth chattering, body shakes, ptosis, diarrhea, and urination) and weight loss induced by naloxone challenge were demonstrated in morphine-dependent rats receiving M. chamomilla extract or saline. The withdrawal behavioral manifestations and weight loss were inhibited significantly by chronic co-administration of M. chamomilla extract with morphine. Administration of a single dose of M. chamomilla before the naloxone challenge in morphine-dependent animals abolished the withdrawal behavioral manifestations. The dramatic increase of plasma cAMP induced by naloxone-precipitated abstinence was prevented by chronic co-administration of M. chamomilla extract with morphine. These results suggest that M. chamomilla extract inhibits the development of morphine dependence and expression of abstinence syndrome.

  13. Isoforms of agrin are widely expressed in the developing rat and may function as protease inhibitors.

    Biroc, S L; Payan, D G; Fisher, J M


    The agrin family of extracellular matrix proteins may be important in the formation of the neuromuscular junction. Using in situ hybridization with a probe recognizing all agrin isoforms, we demonstrate that it is widely expressed during mammalian embryogenesis. In the developing rat, particularly high levels of expression are found in the dorsal root and cranial ganglia, gut, whisker rudiments, penis, snout, teeth, retina, hippocampus, cerebral cortex and the lining of brain ventricles. Functional analysis of the recombinant rat protein shows that it is a potent inhibitor of the proteases trypsin, chymotrypsin and plasmin but not thrombin or the plasminogen activators. We conclude that agrin and its isoforms may play multiple roles in mammalian development including the regulation of proteolysis in the extracellular matrix.

  14. Toxic effects of maternal zearalenone exposure on uterine capacity and fetal development in gestation rats.

    Zhang, Yuanyuan; Jia, Zhiqiang; Yin, Shutong; Shan, Anshan; Gao, Rui; Qu, Zhe; Liu, Min; Nie, Shaoping


    The objectives of this study were to determine the effects of high-dose and early gestational exposure to zearalenone (ZEN) in female Sprague-Dawley (SD) rats, to correlate the maternal uterus with the fetus, and to explore the development and malformation of fetuses. Pregnant female SD rats were fed diets containing 0.3, 48.5, 97.6, or 146.0 mg/kg ZEN on gestational days (GDs) 0 through 7. All the females survived until GD 20, at which point a cesarean section was performed to harvest the organs, blood, and fetuses. The results indicated that exposure to ZEN during early gestation can impact the maternal reproductive capability. Delayed fetal development was directly linked to maternal toxicity. The toxic effects of ZEN caused early deaths more frequently than late deaths, and the deleterious effects lasted through the end of pregnancy.

  15. Changing bone marrow micro-environment during development of acute myeloid leukaemia in rats

    Mortensen, B T; Jensen, P O; Helledie, N;


    The Brown Norwegian rat transplanted with promyelocytic leukaemic cells (BNML) has been used as a model for human acute myeloid leukaemia. We have previously shown that both the blood supply to the bone marrow and the metabolic rate decrease in relation to the leukaemic development in these rats....... Here we have investigated how the development and progression of this leukaemia affect oxygenation, pH and proliferation of normal and leukaemic cells in vivo. Bone marrow pH was measured by a needle electrode. Nitroimidazol-theophylline (NITP) was used to identify hypoxic cells, and we applied...... bromodeoxyuridine (BrdUrd) to identify DNA replicating cells. The leukaemia progressed slowly until day 27 after which a rapid deterioration could be observed leading to severe changes over the following 5 d. In whole blood there was evidence of progressing metabolic acidosis. In bone marrow the fraction...

  16. A quantitative magnetic resonance histology atlas of postnatal rat brain development with regional estimates of growth and variability.

    Calabrese, Evan; Badea, Alexandra; Watson, Charles; Johnson, G Allan


    There has been growing interest in the role of postnatal brain development in the etiology of several neurologic diseases. The rat has long been recognized as a powerful model system for studying neuropathology and the safety of pharmacologic treatments. However, the complex spatiotemporal changes that occur during rat neurodevelopment remain to be elucidated. This work establishes the first magnetic resonance histology (MRH) atlas of the developing rat brain, with an emphasis on quantitation. The atlas comprises five specimens at each of nine time points, imaged with eight distinct MR contrasts and segmented into 26 developmentally defined brain regions. The atlas was used to establish a timeline of morphometric changes and variability throughout neurodevelopment and represents a quantitative database of rat neurodevelopment for characterizing rat models of human neurologic disease. Published by Elsevier Inc.

  17. The role of transforming growth factor alpha in rat craniofacial development and chondrogenesis.

    Huang, L; Solursh, M; Sandra, A


    To explore the possible role of transforming growth factor alpha (TGF-alpha) in craniofacial development, its expression in the craniofacial region of rat embryos from embryonic day (d) 9 to d 20 was examined by in situ hybridisation and immunostaining. The TGF-alpha transcripts were first detected in the neural fold of embryonic d 9 and 10 embryos. In the craniofacial region, the TGF-alpha transcripts were not detected until embryonic d 16 in mesenchyme surrounding the olfactory bulb, within...

  18. Localization and regulation of dopamine receptor D4 expression in the adult and developing rat retina

    Klitten, Laura L; Rath, Martin F; Coon, Steven L


    Levels of dopamine and melatonin exhibit diurnal rhythms in the rat retina. Dopamine is high during daytime adapting the retina to light, whereas melatonin is high during nighttime participating in the adaptation of the retina to low light intensities. Dopamine inhibits the synthesis of melatonin....... The sharp increase of Drd4 expression at a specific postnatal time suggests that dopamine is involved in retinal development....

  19. Immunolocalization of Sprouty-1 and Sprouty-2 in Developing Rat Lung

    Hashimoto, Shuichi; Nakano, Hiroshi; Suguta, Yuko; Singh, Gurmukh; Katyal, Sikandar L.


    Objective Sprouty, a common antagonist of fibroblast growth factor (FGF) and epidermal growth factor signaling, is a key player regulating tracheal branching and eye development in Drosophila. Four Sprouty homologs have been identified in vertebrates and all share a cysteine-rich region. However, the physiological function(s) of the individual Sprouty homologs is unknown. mRNA of Sprouty homologs is expressed during mouse lung development. In the present study, we investigated the immunolocalization of Sprouty proteins in rat lung at different stages of development. Methods Rabbit antibodies were raised against peptides derived from rat Sprouty-1 and Sprouty-2 and were used in Western blot analysis to determine Sprouty distribution in subcellular fractions (pellets and supernatant centrifuged at 5,000 and 20,000 g) and bronchoalveolar lavage fluid (BAL) from adult rat lungs or used in immunohistochemistry. Results Western blot analysis revealed a 30-kDa Sprouty-1 band and a 34-kDa Sprouty-2 band in the supernatant and pellet fractions centrifuged at 20,000 g. BAL contained a band of approximately 16 kDa with Sprouty-1 antibody derived from proteolytic fragmentation of Sprouty-1. In embryonic day (E) 14 and E16 lungs, Sprouty-1 and Sprouty-2 were expressed both in epithelial and peripheral mesenchymal cells. In adult rat lung, bronchiolar and alveolar type II epithelial cells showed staining for both Sprouty-1 and Sprouty-2. Sprouty-1 expression was also seen in alveolar type I epithelial cells. Conclusion In light of the proximity of the distribution of Sprouty to that of FGF-10 (peripheral mesenchyme) and its receptor FGFR2IIIb (distal tubular epithelium) in lung development, and the finding that FGF-9, which is expressed in mesothelial cells, upregulates FGF-10, it appears that Sprouty expression in epithelial and mesenchymal cells during branching morphogenesis is closely related to signaling by FGF-9 and FGF-10. PMID:22236546

  20. Morphology and ontogeny of dendritic cells in rats at different development periods

    Juan Gao; Hua-Mei Yang; Jian-Xin Zhu; Tong-Xin Chen; Zhen-Juan He


    AIM: To study the morphology and ontogeny of dendritic cells of Peyer's patches in rats at different development periods.METHODS: The morphometric and flow cytometric analyses were performed to detect all the parameters of villous-crypts axis and the number of OX62+DC,OX62+CD4+SIRP+DC, and OX62+CD4-SIRP-DC in the small intestine in different groups of rats. The relationship between the parameters of villous-axis and the number of DC and DC subtype were analyzed.RESULTS: All morphometric parameters changed significantly with the development of pups in the different age groups ( F = 10.751, 12.374, 16.527,5.291, 3.486; P = 0.000, 0.000, 0.000, 0.001, 0.015).Villous height levels were unstable and increased from 115.24 μm to 140.43 μm as early as 3 wk postpartum.Villous area increased significantly between 5 and 7 wk postpartum, peeked up to 13 817.60 μm2 at 7 wk postpartum. Villous height and crypt depth ratios were relatively stable and increased significantly from 5.536, P = 0.0013). OX62+CD4+SIRP+DC subset levels detected in single-cell suspensions of rat total Peyer's patch dendritic cells (PP-DCs) increased significantly 2.07% 9-11 wk postpartum ( F = 7.216, P = 0.005).CONCLUSION: This study confirms the agerelated changes in villous-crypt axis differentiation in the small intestine. Simultaneously, there are also development and maturation in rat PP-DCs phenotypic expression. Furthermore, the morphological changes of intestinal mucosa and the development of immune cells (especially DC) peaked at 9-11 wk postpartum,indicating that the intestinal mucosae reached a relatively mature state at 11 wk postpartum.

  1. In vitro translation of RNA to lactase during postnatal development of rat intestine

    Jaspreet Kaur; Kamaljit Kaur; Akhtar Mahmood; Safrun Mahmood


    mRNA levels encoding lactase were detected by Northern blot analysis using two different probes in developing rat intestine. Probe I and probe II corresponding to second half of prolactase gene showed a 6.8 kb mRNA transcript in 7, 14, 21 and 30 day old rat intestine. There was no change in quantity of lactase mRNA detected using probe II, but hybridization with probe I showed a progressive decrease in mRNA transcript encoding lactase with age. At day 7 and 14 of postnatal development, the lactase mRNA was quite high, but it reduced upon weaning. The in vitro translation products of RNA detected by Western blot analysis using brush border lactase antibodies showed several isoforms of lactase antigen with molecular weight ranging from 100–220 kDa. Analysed at days 7 and 30 of postnatal development, lactase isoforms of molecular weight 130 kDa and 220 kDa were similar to those found in purified brush border membranes. The translation of RNA to 220 kDa lactase protein was high in 7 and 14 day old pups, but it was markedly reduced in 30 day old animals. These findings support the contention that translation of mRNA to lactase is impaired in weaned animals, which may also be responsible for the maturational decline in lactase activity in adult rat intestine.

  2. Enhancing effects of mustard oil on preneoplastic hepatic foci development in Wistar rats.

    Shukla, Yogeshwer; Arora, Annu


    Dietary habits are known to be the major contributory factor in the development of cancer. Mustard oil, which is extensively used in India and elsewhere as a flying and cooking medium, is reported to induce an inflammatory response. The development of altered hepatic foci is an early carcinogenic change in rat liver in diethylnitrosamine (DEN)-induced hepatocarcinogenesis. In the present study, the development of preneoplastic lesions was observed following administration of mustard oil (0.5 mL/day for 8 weeks) in DEN-initiated and partially hepatomized Wistar rats. A significant decrease in the relative and absolute liver weight of mustard oil-exposed rats was recorded. The results revealed a significant increase in the number and area of placental glutathione-S-transferase (GST-P) and gamma-glutamyl transpeptidase (GGT)-positive foci in mustard oil-administered animals. The GST-P- and GGT-positive foci were more prominent in the animals given boiled (up to 300 degrees C for 3 hours) mustard oil in comparison to the animals given fresh mustard oil. These results indicate the possible tumourigenic risk associated with mustard oil consumption.

  3. Changes in Rat Brain Tissue Microstructure and Stiffness during the Development of Experimental Obstructive Hydrocephalus.

    Jugé, Lauriane; Pong, Alice C; Bongers, Andre; Sinkus, Ralph; Bilston, Lynne E; Cheng, Shaokoon


    Understanding neural injury in hydrocephalus and how the brain changes during the course of the disease in-vivo remain unclear. This study describes brain deformation, microstructural and mechanical properties changes during obstructive hydrocephalus development in a rat model using multimodal magnetic resonance (MR) imaging. Hydrocephalus was induced in eight Sprague-Dawley rats (4 weeks old) by injecting a kaolin suspension into the cisterna magna. Six sham-injected rats were used as controls. MR imaging (9.4T, Bruker) was performed 1 day before, and at 3, 7 and 16 days post injection. T2-weighted MR images were collected to quantify brain deformation. MR elastography was used to measure brain stiffness, and diffusion tensor imaging (DTI) was conducted to observe brain tissue microstructure. Results showed that the enlargement of the ventricular system was associated with a decrease in the cortical gray matter thickness and caudate-putamen cross-sectional area (P hydrocephalus development, increased space between the white matter tracts was observed in the CC+PVWM (P hydrocephalus development.

  4. Non-alcoholic steatohepatitis and preneoplastic lesions develop in the liver of obese and hypertensive rats: suppressing effects of EGCG on the development of liver lesions.

    Kochi, Takahiro; Shimizu, Masahito; Terakura, Daishi; Baba, Atsushi; Ohno, Tomohiko; Kubota, Masaya; Shirakami, Yohei; Tsurumi, Hisashi; Tanaka, Takuji; Moriwaki, Hisataka


    Non-alcoholic steatohepatitis (NASH), which involves hepatic inflammation and fibrosis, is associated with liver carcinogenesis. The activation of the renin-angiotensin system (RAS), which plays a key role in blood pressure regulation, promotes hepatic fibrogenesis. In this study, we investigated the effects of (-)-epigallocatechin-3-gallate (EGCG), a major component of green tea catechins, on the development of glutathione S-transferase placental form (GST-P)-positive (GST-P(+)) foci, a hepatic preneoplastic lesion, in SHRSP.Z-Lepr(fa)/IzmDmcr (SHRSP-ZF) obese and hypertensive rats. Male 7-week-old SHRSP-ZF rats and control non-obese and normotensive WKY rats were fed a high fat diet and received intraperitoneal injections of carbon tetrachloride twice a week for 8weeks. The rats were also provided tap water containing 0.1% EGCG during the experiment. SHRSP-ZF rats presented with obesity, insulin resistance, dyslipidemia, an imbalance of adipokines in the serum, and hepatic steatosis. The development of GST-P(+) foci and liver fibrosis was markedly accelerated in SHRSP-ZF rats compared to that in control rats. Additionally, in SHRSP-ZF rats, RAS was activated and inflammation and oxidative stress were induced. Administration of EGCG, however, inhibited the development of hepatic premalignant lesions by improving liver fibrosis, inhibiting RAS activation, and attenuating inflammation and oxidative stress in SHRSP-ZF rats. In conclusion, obese and hypertensive SHRSP-ZF rats treated with a high fat diet and carbon tetrachloride displayed the histopathological and pathophysiological characteristics of NASH and developed GST-P(+) foci hepatic premalignant lesions, suggesting the model might be useful for the evaluation of NASH-related liver tumorigenesis. EGCG might also be able to prevent NASH-related liver fibrosis and tumorigenesis. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  5. Flor-Essence? Herbal Tonic Promotes Mammary Tumor Development in Sprague Dawley Rats

    Bennett, L; Montgomery, J; Steinberg, S; Kulp, K


    Background: Women who are diagnosed with breast cancer often self-administer complementary and alternative medicines to augment their conventional treatments, improve health, or prevent recurrence. Flor-Essence{reg_sign} Tonic is a complex mixture of herbal extracts used by cancer patients because of anecdotal evidence that it can treat or prevent disease. Methods: Female Sprague Dawley rats were given water or exposed to 3% or 6% Flor-Essence{reg_sign} beginning at one day of age. Mammary tumors were induced with a single oral 40 mg/kg/bw dose of dimethylbenz(a)anthracene at 50 days of age and sacrificed at 23 weeks. Rats were maintained on AIN-76A diet. Results: Control rats had palpable mammary tumor incidence of 51.0% at 19 weeks of age compared to 65.0% and 59.4% for the 3% and 6% Flor-Essence{reg_sign} groups respectively. Overall, no significant difference in time until first palpable tumor was detected among any of the groups. At necropsy, mammary tumor incidence was 82.5% for controls compared to 90.0% and 97.3% for rats consuming 3% and 6% Flor-Essence{reg_sign}, respectively. Mean mammary tumor multiplicity ({+-}SES) for the controls was 2.8 ({+-} 0.5) and statistically different from the 3% or 6% Flor- Essence{reg_sign} groups with 5.2 ({+-} 0.7), and 4.8 ({+-} 0.6), respectively (p{<=}0.01). As expected, the majority of isolated tumors were diagnosed as adenocarcinomas. Conclusions: Flor-Essence{reg_sign} can promote mammary tumor development in the Sprague Dawley rat model. This observation is contrary to widely available anecdotal evidence as well as the desire of the consumer that this commercially available herbal tonic will suppress and/or inhibit tumor growth.

  6. Development of a bio-magnetic measurement system and sensor configuration analysis for rats

    Kim, Ji-Eun; Kim, In-Seon; Kim, Kiwoong; Lim, Sanghyun; Kwon, Hyukchan; Kang, Chan Seok; Ahn, San; Yu, Kwon Kyu; Lee, Yong-Ho


    Magnetoencephalography (MEG) based on superconducting quantum interference devices enables the measurement of very weak magnetic fields (10-1000 fT) generated from the human or animal brain. In this article, we introduce a small MEG system that we developed specifically for use with rats. Our system has the following characteristics: (1) variable distance between the pick-up coil and outer Dewar bottom (˜5 mm), (2) small pick-up coil (4 mm) for high spatial resolution, (3) good field sensitivity (45 ˜ 80 fT /cm/√{Hz} ) , (4) the sensor interval satisfies the Nyquist spatial sampling theorem, and (5) small source localization error for the region to be investigated. To reduce source localization error, it is necessary to establish an optimal sensor layout. To this end, we simulated confidence volumes at each point on a grid on the surface of a virtual rat head. In this simulation, we used locally fitted spheres as model rat heads. This enabled us to consider more realistic volume currents. We constrained the model such that the dipoles could have only four possible orientations: the x- and y-axes from the original coordinates, and two tangentially layered dipoles (local x- and y-axes) in the locally fitted spheres. We considered the confidence volumes according to the sensor layout and dipole orientation and positions. We then conducted a preliminary test with a 4-channel MEG system prior to manufacturing the multi-channel system. Using the 4-channel MEG system, we measured rat magnetocardiograms. We obtained well defined P-, QRS-, and T-waves in rats with a maximum value of 15 pT/cm. Finally, we measured auditory evoked fields and steady state auditory evoked fields with maximum values 400 fT/cm and 250 fT/cm, respectively.

  7. Incorporation of radioactive polyunsaturated fatty acids into liver and brain of developing rat.

    Sinclair, A J


    The incorporation of radioactivity from orally administered linoleic acid-1-14C, linolenic acid-1-14C, arachidonic acid-3H8, and docosahexaenoic acid-14C into the liver and brain lipids of suckling rats was studied. In both tissues, 22 hr after dosing, 2 distinct levels of incorporation were observed: a low uptake (from 18:2-1-14C and 18:3-1-14C) and a high uptake (from 20:4-3H8 and 22:6-14C). In adult rats, the incorporation of radioactivity into brain lipids from 18:2-1-14C and 20:4-3H was considerably lower than the incorporation into the brains of the young rats. In the livers of the suckling rats, the activity from the 18 carbon acids was associated mostly with the triglyceride fraction, whereas the activity from the 20:4-3H8 and 22:6-14C was concentrated in the phospholipid fraction. In the brain lipids, the activity from the different fatty apid fatty acids, some of the activity in the 18:2-1-14C and 18:3-1-14C experiments was associated with 20 and 22 carbon polyunsaturated fatty acids; however, radioactivity from orally administered 20:4-3H8 and 22:6-14C was incorporated intact into the tissue phospholipid to a much greater extent compared with the incorporation of radioactivity into 20:4 and 22:6 in the experiments where 18:2-1-14C and 18:3-1-14C, respectively, were administered. Possible reasons for these differences are discussed. Rat milk contains a wide spectrum of polyunsaturated fatty acids, including linoleate, linolenate, arachidonate, and docosahexaenoate. During the suckling period in the rat, there is a rapid deposition of 20:4 and 22:6 in the brain. The results of the present experiments suggested that dietary 20:4 and 22:6 were important sources of brain 20:4 and 22:6 in the developing rat.

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

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


    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.

  9. Wnt3 and Wnt3a are required for induction of the mid-diencephalic organizer in the caudal forebrain

    Mattes Benjamin


    Full Text Available Abstract Background A fundamental requirement for development of diverse brain regions is the function of local organizers at morphological boundaries. These organizers are restricted groups of cells that secrete signaling molecules, which in turn regulate the fate of the adjacent neural tissue. The thalamus is located in the caudal diencephalon and is the central relay station between the sense organs and higher brain areas. The mid-diencephalic organizer (MDO orchestrates the development of the thalamus by releasing secreted signaling molecules such as Shh. Results Here we show that canonical Wnt signaling in the caudal forebrain is required for the formation of the Shh-secreting MD organizer in zebrafish. Wnt signaling induces the MDO in a narrow time window of 4 hours - between 10 and 14 hours post fertilization. Loss of Wnt3 and Wnt3a prevents induction of the MDO, a phenotype also observed upon blockage of canonical Wnt signaling per se. Pharmaceutical activation of the canonical Wnt pathways in Wnt3/Wnt3a compound morphant embryos is able to restore the lack of the MDO. After blockage of Wnt signaling or knock-down of Wnt3/Wnt3a we find an increase of apoptotic cells specifically within the organizer primordium. Consistently, blockage of apoptosis restores the thalamus organizer MDO in Wnt deficient embryos. Conclusion We have identified canonical Wnt signaling as a novel pathway, that is required for proper formation of the MDO and consequently for the development of the major relay station of the brain - the thalamus. We propose that Wnt ligands are necessary to maintain the primordial tissue of the organizer during somitogenesis by suppressing Tp53-mediated apoptosis.

  10. Effects of the phytoestrogen genistein on the development of the reproductive system of Sprague Dawley rats

    Siti Rosmani Md Zin


    Full Text Available OBJECTIVES: Genistein is known to influence reproductive system development through its binding affinity for estrogen receptors. The present study aimed to further explore the effect of Genistein on the development of the reproductive system of experimental rats. METHODS: Eighteen post-weaning female Sprague Dawley rats were divided into the following groups: (i a control group that received vehicle (distilled water and Tween 80; (ii a group treated with 10 mg/kg body weight (BW of Genistein (Gen 10; and (iii a group treated with a higher dose of Genistein (Gen 100. The rats were treated daily for three weeks from postnatal day 22 (P22 to P42. After the animals were sacrificed, blood samples were collected, and the uteri and ovaries were harvested and subjected to light microscopy and immunohistochemical study. RESULTS: A reduction of the mean weekly BW gain and organ weights (uteri and ovaries were observed in the Gen 10 group compared to the control group; these findings were reversed in the Gen 100 group. Follicle stimulating hormone and estrogen levels were increased in the Gen 10 group and reduced in the Gen 100 group. Luteinizing hormone was reduced in both groups of Genistein-treated animals, and there was a significant difference between the Gen 10 and control groups (p<0.05. These findings were consistent with increased atretic follicular count, a decreased number of corpus luteum and down-regulation of estrogen receptors-a in the uterine tissues of the Genistein-treated animals compared to the control animals. CONCLUSION: Post-weaning exposure to Genistein could affect the development of the reproductive system of ovarian-intact experimental rats because of its action on the hypothalamic-pituitary-gonadal axis by regulating hormones and estrogen receptors.

  11. Extract of Adenanthera pavonina L. seed reduces development of diabetic nephropathy in streptozotocin-induced diabetic rats

    Ramdas Pandhare


    Conclusion: These results suggested that APSAE has reduced development of diabetic nephropathy in streptozotocin-induced diabetic rats and could have beneficial effect in reducing the progression of diabetic nephropathy.

  12. Impaired brain development in the rat following prenatal exposure to methylazoxymethanol acetate at gestational day 17 and neurotrophin distribution

    Fiore, M; Grace, AA; Korf, J; Stampachiacchiere, B; Aloe, L


    Several neuropsychiatric disorders, including schizophrenia, are the consequence of a disrupted development of the CNS. Accordingly, intrauterine exposure to toxins may increase the risk for psychopathology. We investigated whether prenatal exposure of rats to the neurotoxin methylaxoxymethanol acet

  13. Forebrain overexpression of CaMKII abolishes cingulate long term depression and reduces mechanical allodynia and thermal hyperalgesia

    Tsien Joe Z


    Full Text Available Abstract Activity-dependent synaptic plasticity is known to be important in learning and memory, persistent pain and drug addiction. Glutamate NMDA receptor activation stimulates several protein kinases, which then trigger biochemical cascades that lead to modifications in synaptic efficacy. Genetic and pharmacological techniques have been used to show a role for Ca2+/calmodulin-dependent kinase II (CaMKII in synaptic plasticity and memory formation. However, it is not known if increasing CaMKII activity in forebrain areas affects behavioral responses to tissue injury. Using genetic and pharmacological techniques, we were able to temporally and spatially restrict the over expression of CaMKII in forebrain areas. Here we show that genetic overexpression of CaMKII in the mouse forebrain selectively inhibits tissue injury-induced behavioral sensitization, including allodynia and hyperalgesia, while behavioral responses to acute noxious stimuli remain intact. CaMKII overexpression also inhibited synaptic depression induced by a prolonged repetitive stimulation in the ACC, suggesting an important role for CaMKII in the regulation of cingulate neurons. Our results suggest that neuronal CaMKII activity in the forebrain plays a role in persistent pain.

  14. Lhx2 and Lhx9 determine neuronal differentiation and compartition in the caudal forebrain by regulating Wnt signaling.

    Daniela Peukert


    Full Text Available 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.

  15. The basal forebrain cholinergic system in aging and dementia : Rescuing cholinergic neurons from neurotoxic amyloid-beta 42 with memantine

    Nyakas, Csaba; Granic, Ivica; Halmy, Laszlo G.; Banerjee, Pradeep; Luiten, Paul G. M.


    The dysfunction and loss of basal forebrain cholinergic neurons and their cortical projections are among the earliest pathological events in the pathogenesis of Alzheimer's disease (AD). The evidence pointing to cholinergic impairments come from studies that report a decline in the activity of choli

  16. Food-associated cues alter forebrain functional connectivity as assessed with immediate early gene and proenkephalin expression

    Landry Charles F


    Full Text Available Abstract Background Cues predictive of food availability are powerful modulators of appetite as well as food-seeking and ingestive behaviors. The neurobiological underpinnings of these conditioned responses are not well understood. Monitoring regional immediate early gene expression is a method used to assess alterations in neuronal metabolism resulting from upstream intracellular and extracellular signaling. Furthermore, assessing the expression of multiple immediate early genes offers a window onto the possible sequelae of exposure to food cues, since the function of each gene differs. We used immediate early gene and proenkephalin expression as a means of assessing food cue-elicited regional activation and alterations in functional connectivity within the forebrain. Results Contextual cues associated with palatable food elicited conditioned motor activation and corticosterone release in rats. This motivational state was associated with increased transcription of the activity-regulated genes homer1a, arc, zif268, ngfi-b and c-fos in corticolimbic, thalamic and hypothalamic areas and of proenkephalin within striatal regions. Furthermore, the functional connectivity elicited by food cues, as assessed by an inter-regional multigene-expression correlation method, differed substantially from that elicited by neutral cues. Specifically, food cues increased cortical engagement of the striatum, and within the nucleus accumbens, shifted correlations away from the shell towards the core. Exposure to the food-associated context also induced correlated gene expression between corticostriatal networks and the basolateral amygdala, an area critical for learning and responding to the incentive value of sensory stimuli. This increased corticostriatal-amygdalar functional connectivity was absent in the control group exposed to innocuous cues. Conclusion The results implicate correlated activity between the cortex and the striatum, especially the nucleus

  17. Differential effects of exercise intensities in hippocampal BDNF, inflammatory cytokines and cell proliferation in rats during the postnatal brain development.

    de Almeida, Alexandre Aparecido; Gomes da Silva, Sérgio; Fernandes, Jansen; Peixinho-Pena, Luiz Fernando; Scorza, Fulvio Alexandre; Cavalheiro, Esper Abrão; Arida, Ricardo Mario


    It has been established that low intensities of exercise produce beneficial effects for the brain, while high intensities can cause some neuronal damage (e.g. exacerbated inflammatory response and cell death). Although these effects are documented in the mature brain, the influence of exercise intensities in the developing brain has been poorly explored. To investigate the impact of exercise intensity in developing rats, we evaluated the hippocampal level of brain derived neurotrophic factor (BDNF), inflammatory cytokines (TNFα, IL6 and IL10) and the occurrence of hippocampal cell degeneration and proliferation at different stages of postnatal brain development of rats submitted to two physical exercise intensities. To this point, male rats were divided into different age groups: P21, P31, P41 and P51. Each age group was submitted to two exercise intensities (low and high) on a treadmill over 10 consecutive days, except the control rats. We verified that the density of proliferating cells was significantly higher in the dentate gyrus of rats submitted to low-intensity exercise from P21 to P30 compared with high-intensity exercise and control rats. A significant increase of proliferative cell density was found in rats submitted to high-intensity exercise from P31 to P40 when compared to low-intensity exercise and control rats. Elevated hippocampal levels of IL6 were detected in rats submitted to high-intensity exercise from P21 to P30 compared to control rats. From P41 to P50 period, higher levels of BDNF, TNFα and IL10 were found in the hippocampal formation of rats submitted to high-intensity exercise in relation to their control rats. Our data show that exercise-induced neuroplastic effects on BDNF levels and cellular proliferation in the hippocampal region are dependent on exercise intensity and developmental period. Thus, exercise intensity is an inflammation-inducing factor and exercise-induced inflammatory response during the postnatal brain development is

  18. Effect of water temperature on exercise-induced maternal hyperthermia on fetal development in rats.

    Mottola, M F; Fitzgerald, H M; Wilson, N C; Taylor, A W


    The objective of this study was to determine if water temperature influenced exercise-induced hyperthermia in swim-trained pregnant rats and the resulting fetal development. Pregnant Sprague-Dawley rats with 6 weeks pre-pregnancy training were exercised daily from day 1 to day 18 of gestation in water that was 34.6 +/- 0.4 degrees C (Cool Water Swimmers--CWS) or 37.6 +/- 0.1 degrees C (Warm Water Swimmers--WWS), for one hour/day. During this time period another group of pregnant rats was immersed to the neck in warm water (37.6 +/- 0.2 degrees C) (Warm Water Controls--WWC). On day 19 of gestation all animals were sacrificed and fetal development assessed. Maternal exercise in warm water elevated maternal body core temperature by 2.3 +/- 0.1 degrees C above resting values, with an increase in fetal abnormalities compared to the same exercise intensity in cool water. Fifty-eight percent of the abnormal fetuses and 60% of the resorption sites were found in the WWS group. Of the abnormalities determined, 65% were from the WWS group and 45% of these fetuses showed micrencephaly. Results suggest cool water may regulate maternal body temperature during swimming exercise and that swimming in warm water should be avoided during gestation because of potential teratogenic effects.

  19. Expression and localization of versican during postnatal development of rat temporomandibular joint disc.

    Toriya, Naoko; Takuma, Taishin; Arakawa, Toshiya; Abiko, Yoshihiro; Sasano, Yasuyuki; Takahashi, Ichiro; Sakakura, Yasunori; Rahemtulla, Firoz; Mizoguchi, Itaru


    To analyze the growth-related changes in extracellular matrix components in temporomandibular joint (TMJ) discs, the expression and localization of the core protein of a large chondroitin sulphate proteoglycan, versican, in rat TMJ discs during postnatal development (2-32 weeks) were examined using Western blot analysis, real-time quantitative PCR and immunohistochemistry. Western blot analysis showed that rat TMJ discs predominantly expressed one isoform (V1) and the core protein sharply increased after birth, reached a peak at 8 weeks, and then gradually decreased up to 32 weeks. Real-time quantitative PCR with TaqMan probes indicated that mRNA expression of versican was highest at 2 weeks and gradually decreased with growth. An immunohistochemical study showed that staining for versican was weak and evenly distributed in TMJ discs at 2 weeks. Regional differences in staining for versican became prominent after 8 weeks; staining was intense in the anterior and posterior peripheral attachments, and weak in the central part of the discs. These results demonstrate that growth-related changes and regional differences exist in the expression of versican in the TMJ discs of growing rats, and these probably reflect the changes in the biomechanical environment caused by the development of orofacial functions.

  20. Progressive development of pulmonary hypertension leading to right ventricular hypertrophy assessed by echocardiography in rats.

    Kato, Yosuke; Iwase, Mitsunori; Kanazawa, Hiroaki; Kawata, Natsuki; Yoshimori, Yukie; Hashimoto, Katsunori; Yokoi, Toyoharu; Noda, Akiko; Takagi, Kenzo; Koike, Yasuo; Nishizawa, Takao; Nishimura, Masahiko; Yokota, Mitsuhiro


    The present study aimed to evaluate the development of pulmonary hypertension by serial echocardiography, including measurements of pulmonary artery (PA) flow velocities, and correlate echocardiographic indices with pathological findings in rats administered monocrotaline (MCT). MCT (60 mg/kg body weight) or physiologic saline was administered to a total of 9 male Wistar rats at the age of 4 weeks (MCT group: n = 4, control group: n = 5, respectively). Echocardiography was performed serially until the age of 8 weeks. The ratio of right ventricular (RV) outflow tract dimensions to aortic dimensions increased progressively in the MCT group and became significantly greater than that of the control group after the age of 6 weeks. Peak PA velocity (Peak V) in the MCT group was significantly less than that of the control group at the ages of 7 and 8 weeks. The ratio of acceleration time to ejection time (AT/ET) in PA flow waveforms declined progressively and was significantly less than that of the control group after the age of 6 weeks. The ratio of RV weight to body weight (RVW/BW) in the MCT group was significantly greater than that of the control group. Both AT/ET ratio and Peak V were significantly inversely correlated with RVW/BW ratio. Furthermore, these echocardiographic findings were also significantly inversely correlated with the mean cross-sectional RV myocyte area. In conclusion, the progressive development of pulmonary hypertension leading to RV hypertrophy can be evaluated appropriately by echocardiography including PA flow Doppler indices in rats.

  1. Metformin regulates ovarian angiogenesis and follicular development in a female polycystic ovary syndrome rat model.

    Di Pietro, Mariana; Parborell, Fernanda; Irusta, Griselda; Pascuali, Natalia; Bas, Diana; Bianchi, María Silvia; Tesone, Marta; Abramovich, Dalhia


    Polycystic ovary syndrome (PCOS) is a frequent pathology that affects more than 5% of women of reproductive age. Among other heterogeneous symptoms, PCOS is characterized by abnormalities in angiogenesis. Metformin has been introduced in the treatment of PCOS to manage insulin resistance and hyperglycemia. Besides its metabolic effects, metformin has been shown to improve ovulation, pregnancy and live birth rates in PCOS patients. In the present study, we used a dehydroepiandrosterone-induced PCOS rat model to analyze the effect of metformin administration on ovarian angiogenesis. We found that metformin was able to restore the increased levels of vascular endothelial growth factor, angiopoietin (ANGPT)1, and ANGPT1/ANGPT2 ratio and the decreased levels of platelet-derived growth factor B and platelet-derived growth factor D observed in the dehydroepiandrosterone-treated rats. These effects could take place, at least in part, through a decrease in the levels of serum insulin. We also found an improvement in follicular development, with a lower percentage of small follicles and cysts and a higher percentage of antral follicles and corpora lutea after metformin administration. The improvement in ovarian angiogenesis is likely to restore the accumulation of small follicles observed in PCOS rats and to reduce cyst formation, thus improving follicular development and the percentage of corpora lutea. These results open new insights into the study of metformin action not only in glucose metabolism but also in ovarian dysfunction in PCOS women.

  2. [The development of grooming in the ontogeny of rats and mice].

    Sviderskaia, G E; Dmitrieva, L E


    Experiments have been made on rats and mice within the first month of postnatal life. Common age dynamics of grooming reactions for these animals was shown which consists of a sharp intensification of grooming movements at the 3rd week, i.e. at the period of "behavioral arousal", as well as of heterochronous onset of different types of movements which results from successive maturation of the brain structures in which rhythmic centres of these movements are located. Quantitative differences in grooming of rats and mice are presumably due to ecological peculiarities of these animals. Periodic pattern of realization of grooming, as well as the parameters of its rhythmic components suggests that stereotype behavioural reactions are governed by mechanisms of autorhythmic excitation which are typical for the early stages of the development of the nervous system.

  3. Morphological and Histopathological Changes in Orofacial Structures of Experimentally Developed Acromegaly-Like Rats: An Overview

    Masahiro Iikubo


    Full Text Available Tongue enlargement and mandibular prognathism are clinically recognized in almost all patients with acromegaly. An acromegaly-like rat model recently developed by exogenous administration of insulin-like growth factor I (IGF-I was used to investigate morphological and histopathological changes in orofacial structures and to clarify whether these changes were reversible. Exogenous administration of IGF-I evoked specific enlargement of the tongue with identifiable histopathological changes (increased muscle bundle width, increased space between muscle bundles, and increased epithelial thickness, elongation of the mandibular alveolar bone and ascending ramus, and lateral expansion of the mandibular dental arch. Regarding histopathological changes in the mandibular condyle, the cartilaginous layer width, bone matrix ratio, and number of osteoblasts were all significantly greater in this rat model. After normalization of the circulating IGF-I level, tongue enlargement and histopathological changes in the tongue and mandibular condyle were reversible, whereas morphological skeletal changes in the mandible remained.

  4. Morphological and histopathological changes in orofacial structures of experimentally developed acromegaly-like rats: an overview.

    Iikubo, Masahiro; Kojima, Ikuho; Sakamoto, Maya; Kobayashi, Akane; Ikeda, Hidetoshi; Sasano, Takashi


    Tongue enlargement and mandibular prognathism are clinically recognized in almost all patients with acromegaly. An acromegaly-like rat model recently developed by exogenous administration of insulin-like growth factor I (IGF-I) was used to investigate morphological and histopathological changes in orofacial structures and to clarify whether these changes were reversible. Exogenous administration of IGF-I evoked specific enlargement of the tongue with identifiable histopathological changes (increased muscle bundle width, increased space between muscle bundles, and increased epithelial thickness), elongation of the mandibular alveolar bone and ascending ramus, and lateral expansion of the mandibular dental arch. Regarding histopathological changes in the mandibular condyle, the cartilaginous layer width, bone matrix ratio, and number of osteoblasts were all significantly greater in this rat model. After normalization of the circulating IGF-I level, tongue enlargement and histopathological changes in the tongue and mandibular condyle were reversible, whereas morphological skeletal changes in the mandible remained.

  5. Curative effects of sodium fusidate on the development of dinitrobenzenesulfonic acid-induced colitis in rats

    Di Marco, Roberto; Mangano, Katia; Quattrocchi, Cinzia


    . These entailed a significant reduction in body weight loss, smaller increase in colon weights, milder macroscopic damage, and lower histological scores. In addition, when sacrificed at the end of the study, fusidin-treated rats had significantly lower blood levels of tumor necrosis factor alpha and interferon......Fusidic acid and sodium fusidate (fusidin) are antibiotics with low toxicity and powerful immunomodulatory activities in vitro and in vivo. In this study we have evaluated the effect of fusidin on the development of dinitrobenzenesulfonic acid (DNB)-induced colitis in rats that serves...... as a preclinical model of human inflammatory bowel disease (IBD). The data show that when administered orally at the dose of 80 (but not 40) mg/kg body wt under a "therapeutic" regimen soon after DNB application, fusidin significantly ameliorates clinical, histological, and seroimmunological signs of disease...

  6. Serotonin 5-HT7 receptor increases the density of dendritic spines and facilitates synaptogenesis in forebrain neurons.

    Speranza, Luisa; Labus, Josephine; Volpicelli, Floriana; Guseva, Daria; Lacivita, Enza; Leopoldo, Marcello; Bellenchi, Gian Carlo; di Porzio, Umberto; Bijata, Monika; Perrone-Capano, Carla; Ponimaskin, Evgeni


    Precise control of dendritic spine density and synapse formation is critical for normal and pathological brain functions. Therefore, signaling pathways influencing dendrite outgrowth and remodeling remain a subject of extensive investigations. Here, we report that prolonged activation of the serotonin 5-HT7 receptor (5-HT7R) with selective agonist LP-211 promotes formation of dendritic spines and facilitates synaptogenesis in postnatal cortical and striatal neurons. Critical role of 5-HT7R in neuronal morphogenesis was confirmed by analysis of neurons isolated from 5-HT7R-deficient mice and by pharmacological inactivation of the receptor. Acute activation of 5-HT7R results in pronounced neurite elongation in postnatal striatal and cortical neurons, thus extending previous data on the morphogenic role of 5-HT7R in embryonic and hippocampal neurons. We also observed decreased number of spines in neurons with either genetically (i.e. 5-HT7R-knock-out) or pharmacologically (i.e. antagonist treatment) blocked 5-HT7R, suggesting that constitutive 5-HT7R activity is critically involved in the spinogenesis. Moreover, cyclin-dependent kinase 5 and small GTPase Cdc42 were identified as important downstream effectors mediating morphogenic effects of 5-HT7R in neurons. Altogether, our data suggest that the 5-HT7R-mediated structural reorganization during the postnatal development might have a crucial role for the development and plasticity of forebrain areas such as cortex and striatum, and thereby can be implicated in regulation of the higher cognitive functions. Read the Editorial Highlight for this article on page 644. © 2017 International Society for Neurochemistry.

  7. Intact neurobehavioral development and dramatic impairments of procedural-like memory following neonatal ventral hippocampal lesion in rats.

    Lecourtier, L; Antal, M-C; Cosquer, B; Schumacher, A; Samama, B; Angst, M-J; Ferrandon, A; Koning, E; Cassel, J-C; Nehlig, A


    Neonatal ventral hippocampal lesions (NVHL) in rats are considered a potent developmental model of schizophrenia. After NVHL, rats appear normal during their preadolescent time, whereas in early adulthood, they develop behavioral deficits paralleling symptomatic aspects of schizophrenia, including hyperactivity, hypersensitivity to amphetamine (AMPH), prepulse and latent inhibition deficits, reduced social interactions, and spatial working and reference memory alterations. Surprisingly, the question of the consequences of NVHL on postnatal neurobehavioral development has not been addressed. This is of particular importance, as a defective neurobehavioral development could contribute to impairments seen in adult rats. Therefore, at several time points of the early postsurgical life of NVHL rats, we assessed behaviors accounting for neurobehavioral development, including negative geotaxis and grip strength (PD11), locomotor coordination (PD21), and open-field (PD25). At adulthood, the rats were tested for anxiety levels, locomotor activity, as well as spatial reference memory performance. Using a novel task, we also investigated the consequences of the lesions on procedural-like memory, which had never been tested following NVHL. Our results point to preserved neurobehavioral development. They also confirm the already documented locomotor hyperactivity, spatial reference memory impairment, and hyperresponsiveness to AMPH. Finally, our rseults show for the first time that NVHL disabled the development of behavioral routines, suggesting dramatic procedural memory deficits. The presence of procedural memory deficits in adult rats subjected to NHVL suggests that the lesions lead to a wider range of cognitive deficits than previously shown. Interestingly, procedural or implicit memory impairments have also been reported in schizophrenic patients.

  8. Effects of melamine and cyanuric acid on embryo-fetal development in rats.

    Kim, Sung-Hwan; Lee, In-Chul; Baek, Hyung-Seon; No, Kyeong-Woo; Shin, Dong-Ho; Moon, Changjong; Kim, Sung-Ho; Park, Seung-Chun; Kim, Jong-Choon


    After the outbreak of acute renal failure associated with melamine-contaminated pet food, melamine and melamine-related compounds have become of great interest from a toxicologic perspective. We investigated the potential effects of melamine in combination with cyanuric acid (M + CA, 1:1) on pregnant dams and embryo-fetal development in rats. M + CA was orally administered to pregnant rats from gestational days 6 through 19 at doses of 0, 3, 10, and 30 mg/kg/day of both melamine and cyanuric acid. Maternal toxicity of rats administered 30 mg/kg/day M + CA was manifested as increased incidences of clinical signs and death; gross pathologic findings; higher blood urea nitrogen and creatinine levels; lower body weight gain and food intake; decreased thymus weight; and increased heart, lung, and kidney weights. Histopathological examinations revealed an increase in the incidence of congestion, tubular necrosis/degeneration, crystals, casts, mineralization, inflammatory cells in tubules, tubular dilation, and atrophy of glomeruli in maternal kidneys, whereas fetal kidneys did not show any histopathological changes. Developmental toxicity included a decrease in fetal (28%) and placental weights and a delay in fetal ossification (n = 7). Increased incidence of gross and histopathological changes in the maternal kidney was also found in the middle dose group (n = 12). No treatment-related maternal or developmental effects were observed in the low dose group (n = 12). Under these experimental conditions, M + CA is embryotoxic at an overt maternotoxic dose in rats and the no-observed-adverse-effect level of M + CA is considered to be 3 mg/kg/day for pregnant dams and 10 mg/kg/day for embryo-fetal development.

  9. Moderate recurrent hypoglycemia during early development leads to persistent changes in affective behavior in the rat.

    Moore, Holly; Craft, Tara K S; Grimaldi, Lisa M; Babic, Bruna; Brunelli, Susan A; Vannucci, Susan J


    Recurrent hypoglycemia is a common problem among infants and children that is associated with several metabolic disorders and insulin-dependent diabetes mellitus. Although studies have reported a relationship between a history of juvenile hypoglycemia and psychological health problems, the direct effects of recurrent moderate hypoglycemia have not been fully determined. Thus, in this study, we used an animal model to examine the effects of recurrent hypoglycemia during the juvenile period on affective, social, and motor function (assessed under euglycemic conditions) across development. To model recurrent hypoglycemia, rats were administered 5 U/kg of insulin or saline twice per day from postnatal day (P)10 to P19. Body weight gain was retarded in insulin-treated rats during the treatment period, but recovered by the end of treatment. However, insulin-treated rats displayed increases in affective reactivity that emerged early during treatment and persisted after treatment into early adulthood. Specifically, insulin-treated pups showed increased maternal separation-induced vocalizations as infants, and an exaggerated acoustic startle reflex as juveniles and young adults. Moreover, young adult rats with a history of recurrent juvenile hypoglycemia exhibited increased fear-potentiated startle and increases in behavioral and hormonal responses to restraint stress. Some of these effects were sex-dependent. The changes in affective behavior in insulin-exposed pups were accompanied by decreases in adolescent social play behavior. These results provide evidence that recurrent, transient hypoglycemia during juvenile development can lead to increases in fear-related behavior and stress reactivity. Importantly, these phenotypes are not reversed with normalization of blood glucose and may persist into adulthood.

  10. Glycine receptor α3 and α2 subunits mediate tonic and exogenous agonist-induced currents in forebrain.

    McCracken, Lindsay M; Lowes, Daniel C; Salling, Michael C; Carreau-Vollmer, Cyndel; Odean, Naomi N; Blednov, Yuri A; Betz, Heinrich; Harris, R Adron; Harrison, Neil L


    Neuronal inhibition can occur via synaptic mechanisms or through tonic activation of extrasynaptic receptors. In spinal cord, glycine mediates synaptic inhibition through the activation of heteromeric glycine receptors (GlyRs) composed primarily of α1 and β subunits. Inhibitory GlyRs are also found throughout the brain, where GlyR α2 and α3 subunit expression exceeds that of α1, particularly in forebrain structures, and coassembly of these α subunits with the β subunit appears to occur to a lesser extent than in spinal cord. Here, we analyzed GlyR currents in several regions of the adolescent mouse forebrain (striatum, prefrontal cortex, hippocampus, amygdala, and bed nucleus of the stria terminalis). Our results show ubiquitous expression of GlyRs that mediate large-amplitude currents in response to exogenously applied glycine in these forebrain structures. Additionally, tonic inward currents were also detected, but only in the striatum, hippocampus, and prefrontal cortex (PFC). These tonic currents were sensitive to both strychnine and picrotoxin, indicating that they are mediated by extrasynaptic homomeric GlyRs. Recordings from mice deficient in the GlyR α3 subunit (Glra3(-/-)) revealed a lack of tonic GlyR currents in the striatum and the PFC. In Glra2(-/Y) animals, GlyR tonic currents were preserved; however, the amplitudes of current responses to exogenous glycine were significantly reduced. We conclude that functional α2 and α3 GlyRs are present in various regions of the forebrain and that α3 GlyRs specifically participate in tonic inhibition in the striatum and PFC. Our findings suggest roles for glycine in regulating neuronal excitability in the forebrain.

  11. Influence of oxygen tension on dopaminergic differentiation of human fetal stem cells of midbrain and forebrain origin.

    Krabbe, Christina; Bak, Sara Thornby; Jensen, Pia; von Linstow, Christian; Martínez Serrano, Alberto; Hansen, Claus; Meyer, Morten


    Neural stem cells (NSCs) constitute a promising source of cells for transplantation in Parkinson's disease (PD), but protocols for controlled dopaminergic differentiation are not yet available. Here we investigated the influence of oxygen on dopaminergic differentiation of human fetal NSCs derived from the midbrain and forebrain. Cells were differentiated for 10 days in vitro at low, physiological (3%) versus high, atmospheric (20%) oxygen tension. Low oxygen resulted in upregulation of vascular endothelial growth factor and increased the proportion of tyrosine hydroxylase-immunoreactive (TH-ir) cells in both types of cultures (midbrain: 9.1 ± 0.5 and 17.1 ± 0.4 (Pcells). Regardless of oxygen levels, the content of TH-ir cells with mature neuronal morphologies was higher for midbrain as compared to forebrain cultures. Proliferative Ki67-ir cells were found in both types of cultures, but the relative proportion of these cells was significantly higher for forebrain NSCs cultured at low, as compared to high, oxygen tension. No such difference was detected for midbrain-derived cells. Western blot analysis revealed that low oxygen enhanced β-tubulin III and GFAP expression in both cultures. Up-regulation of β-tubulin III was most pronounced for midbrain cells, whereas GFAP expression was higher in forebrain as compared to midbrain cells. NSCs from both brain regions displayed less cell death when cultured at low oxygen tension. Following mictrotransplantation into mouse striatal slice cultures predifferentiated midbrain NSCs were found to proliferate and differentiate into substantial numbers of TH-ir neurons with mature neuronal morphologies, particularly at low oxygen. In contrast, predifferentiated forebrain NSCs microtransplanted using identical conditions displayed little proliferation and contained few TH-ir cells, all of which had an immature appearance. Our data may reflect differences in dopaminergic differentiation capacity and region-specific requirements

  12. Development of the glucocorticoid receptor system in the rat limbic brain. 2. An autoradiographic study

    Meaney, M.J.; Sapolsky, R.M.; McEwen, B.S. (Rockefeller Univ., New York (USA))


    The authors report the results of an autoradiographic analysis of the postnatal development of the hippocampal glucocorticoid receptor system in the rat brain. Quantitative analysis of the autoradiograms revealed a varied pattern of gradual development towards adult receptor concentrations during the second week of life. Receptor concentrations in the dentate gyrus increased dramatically between Days 9 and 15, while the changes during this period in the pyramidal layers of Ammon's horn seemed to reflect both structural changes in these regions as well as increases in receptor concentrations.

  13. Hippocampal Sclerosis but Not Normal Aging or Alzheimer Disease Is Associated With TDP-43 Pathology in the Basal Forebrain of Aged Persons.

    Cykowski, Matthew D; Takei, Hidehiro; Van Eldik, Linda J; Schmitt, Frederick A; Jicha, Gregory A; Powell, Suzanne Z; Nelson, Peter T


    Transactivating responsive sequence (TAR) DNA-binding protein 43-kDa (TDP-43) pathology has been described in various brain diseases, but the full anatomical distribution and clinical and biological implications of that pathology are incompletely characterized. Here, we describe TDP-43 neuropathology in the basal forebrain, hypothalamus, and adjacent nuclei in 98 individuals (mean age, 86 years; median final mini-mental state examination score, 27). On examination blinded to clinical and pathologic diagnoses, we identified TDP-43 pathology that most frequently involved the ventromedial basal forebrain in 19 individuals (19.4%). As expected, many of these brains had comorbid pathologies including those of Alzheimer disease (AD), Lewy body disease (LBD), and/or hippocampal sclerosis of aging (HS-Aging). The basal forebrain TDP-43 pathology was strongly associated with comorbid HS-Aging (odds ratio = 6.8, p = 0.001), whereas there was no significant association between basal forebrain TDP-43 pathology and either AD or LBD neuropathology. In this sample, there were some cases with apparent preclinical TDP-43 pathology in the basal forebrain that may indicate that this is an early affected area in HS-Aging. We conclude that TDP-43 pathology in the basal forebrain is strongly associated with HS-Aging. These results raise questions about a specific pathogenetic relationship between basal forebrain TDP-43 and non-HS-Aging comorbid diseases (AD and LBD).

  14. Calcium imaging of basal forebrain activity during innate and learned behaviors

    Thomas Clarke Harrison


    Full Text Available 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.

  15. Enhanced inhibitory effects of TBT chloride on the development of F1 rats.

    Asakawa, H; Tsunoda, M; Kaido, T; Hosokawa, M; Sugaya, C; Inoue, Y; Kudo, Y; Satoh, T; Katagiri, H; Akita, H; Saji, M; Wakasa, M; Negishi, T; Tashiro, T; Aizawa, Y


    Neurotoxicity is one of the major effects of tributyltin (TBT). The effects on the next generation of F(1) rats exposed to TBT via the placenta and their dams' milk may be stronger than those on adults. Pregnant Wister rats were exposed to TBT at 0 and 125 ppm in their food. Half of the female F(1) rats in both groups were exposed to TBT at 125 ppm in their food from 9 to 15 weeks of age. Female F(1) rats were divided into the following groups: the control-control (CC) group, with no exposure; the TBT-control (TC) group, exposed to TBT via the placenta and their dams' milk; the control-TBT (CT) group, exposed to TBT via their food from 9 to 15 weeks of age; and the TBT-TBT (TT) group, exposed to TBT via the placenta, their dams' milk, and their food (n = 10/group). After administration, an open-field test and prepulse inhibition (PPI) test were performed at 15 weeks of age. The mean body weights of the TC and TT groups were significantly lower than that of the CC group from 9 to 15 weeks of age. The mean relative thymus weight of the TC and TT groups was significantly lower than that of the CC group. In the open-field test, a marked decrease in the total locomotion distance was observed in the TT group. The mean values in the TT and TC groups were significantly lower than that in the CC group. For the locomotion distance between 15 and 20 min, the mean values in the CT, TC, and TT groups were significantly lower than that in the CC group. The mean locomotor distance between 25 and 30 min in the TT group was significantly lower than that in the CC and TC groups. The mean values of instances of wall rearing in the TC, CT, and TT groups were significantly lower than that in the CC group. The mean value of face washing or body washing in the TT group was significantly lower than that in the CT group. There were no significant differences in indexes of the PPI test. Exposure to TBT via the placenta and their dams' milk inhibited the development of F(1) rats, which

  16. Learning-related changes in Fos-like immunoreactivity in the chick forebrain after imprinting.

    McCabe, B J; Horn, G


    The intermediate and medial part of the hyperstriatum ventrale (IMHV) is a part of the chick forebrain that is critical for the learning process of imprinting and may be a site of information storage. Chicks were either trained on an imprinting stimulus or dark-reared. Trained chicks were classified as good or poor learners by their preference score (a measure of the strength of imprinting). A monoclonal antibody against the immediate early gene product Fos was applied to sections through IMHV and other forebrain regions. In the IMHV, significantly more immunopositive nuclei were counted in good learners than in poor learners or dark-reared chicks. There was a positive correlation between counts of labeled nuclei and preference score that was not attributable to sensory activity per se, locomotor activity during training, or a predisposition to learn well; rather, the results indicated that the change in Fos immunoreactivity in the IMHV was related to learning. In the hyperstriatum accessorium, significantly fewer immunopositive nuclei were counted in good learners than in poor learners or in dark-reared chicks. In the dorsolateral hippocampal region, more immunopositive nuclei were counted in trained than in dark-reared chicks. No significant effects of training were found in the anterior hyperstriatum ventrale, lobus parolfactorius, neostriatum, medial hippocampal region, or ventrolateral hippocampal region, but counts in this last region were positively correlated with training approach. The results for IMHV implicate Fos or Fos-related proteins in memory processes and pave the way for the identification of the cell types that show the learning-related increase in gene expression. Images PMID:7972076

  17. Forebrain-specific ablation of phospholipase Cγ1 causes manic-like behavior.

    Yang, Y R; Jung, J H; Kim, S-J; Hamada, K; Suzuki, A; Kim, H J; Lee, J H; Kwon, O-B; Lee, Y K; Kim, J; Kim, E-K; Jang, H-J; Kang, D-S; Choi, J-S; Lee, C J; Marshall, J; Koh, H-Y; Kim, C-J; Seok, H; Kim, S H; Choi, J H; Choi, Y-B; Cocco, L; Ryu, S H; Kim, J-H; Suh, P-G


    Manic episodes are one of the major diagnostic symptoms in a spectrum of neuropsychiatric disorders that include schizophrenia, obsessive-compulsive disorder and bipolar disorder (BD). Despite a possible association between BD and the gene encoding phospholipase Cγ1 (PLCG1), its etiological basis remains unclear. Here, we report that mice lacking phospholipase Cγ1 (PLCγ1) in the forebrain (Plcg1(f/f); CaMKII) exhibit hyperactivity, decreased anxiety-like behavior, reduced depressive-related behavior, hyperhedonia, hyperphagia, impaired learning and memory and exaggerated startle responses. Inhibitory transmission in hippocampal pyramidal neurons and striatal dopamine receptor D1-expressing neurons of Plcg1-deficient mice was significantly reduced. The decrease in inhibitory transmission is likely due to a reduced number of γ-aminobutyric acid (GABA)-ergic boutons, which may result from impaired localization and/or stabilization of postsynaptic CaMKII (Ca(2+)/calmodulin-dependent protein kinase II) at inhibitory synapses. Moreover, mutant mice display impaired brain-derived neurotrophic factor-tropomyosin receptor kinase B-dependent synaptic plasticity in the hippocampus, which could account for deficits of spatial memory. Lithium and valproate, the drugs presently used to treat mania associated with BD, rescued the hyperactive phenotypes of Plcg1(f/f); CaMKII mice. These findings provide evidence that PLCγ1 is critical for synaptic function and plasticity and that the loss of PLCγ1 from the forebrain results in manic-like behavior.Molecular Psychiatry advance online publication, 31 January 2017; doi:10.1038/mp.2016.261.

  18. Multiple Mechanisms for Processing Reward Uncertainty in the Primate Basal Forebrain.

    Ledbetter, Noah M; Chen, Charles D; Monosov, Ilya E


    The ability to use information about the uncertainty of future outcomes is critical for adaptive behavior in an uncertain world. We show that the basal forebrain (BF) contains at least two distinct neural-coding strategies to support this capacity. The dorsal-lateral BF, including the ventral pallidum (VP), contains reward-sensitive neurons, some of which are selectively suppressed by uncertain-reward predictions (U(-)). In contrast, the medial BF (mBF) contains reward-sensitive neurons, some of which are selectively enhanced (U(+)) by uncertain-reward predictions. In a two-alternative choice-task, U(-) neurons were selectively suppressed while monkeys chose uncertain options over certain options. During the same choice-epoch, U(+) neurons signaled the subjective reward value of the choice options. Additionally, after the choice was reported, U(+) neurons signaled reward uncertainty until the choice outcome. We suggest that uncertainty-related suppression of VP may participate in the mediation of uncertainty-seeking actions, whereas uncertainty-related enhancement of the mBF may direct cognitive resources to monitor and learn from uncertain-outcomes. To survive in an uncertain world, we must approach uncertainty and learn from it. Here we provide evidence for two mostly distinct mechanisms for processing uncertainty about rewards within different subregions of the primate basal forebrain (BF). We found that uncertainty suppressed the representation of certain (or safe) reward values by some neurons in the dorsal-lateral BF, in regions occupied by the ventral pallidum. This uncertainty-related suppression was evident as monkeys made risky choices. We also found that uncertainty-enhanced the activity of many medial BF neurons, most prominently after the monkeys' choices were completed (as they awaited uncertain outcomes). Based on these findings, we propose that different subregions of the BF could support action and learning under uncertainty in distinct but

  19. Immunohistochemical organization of the forebrain in the white sturgeon, Acipenser transmontanus.

    Piñuela, Carmen; Northcutt, R Glenn


    The distribution of substance P (SP), leucine-enkephalin (LENK), serotonin (5HT), dopamine (DA), and tyrosine hydroxylase (TH) was examined in the forebrain of the white sturgeon in order to evaluate several anatomical hypotheses based on cytoarchitectonics, and to gain a better understanding of the evolution of the forebrain in ray-finned fishes. The subpallium of the telencephalon has the highest concentration of the neuropeptides SP and LENK, allowing the pallial-subpallial border to be easily distinguished. The distribution of dopamine is similar to that of serotonin in the subpallium, fibers positive for these transmitters are particularly dense in the dorsal and ventral divisions of the subpallium. In addition, a small population of DA- and 5HT-positive cell bodies--which appear to be unique to sturgeons--was identified at the level of the anterior commissure. The internal granular layer of the olfactory bulbs had large numbers of TH-positive cell bodies and fibers, as did the rostral subpallium. The occurrence of cell bodies positive for LENK in the dorsal nucleus of the rostral subpallium supports the hypothesis that this nucleus is homologous to the striatum in other vertebrates. This is further reinforced by the apparent origin of an ascending dopaminergic pathway from cells in the posterior tubercle that are likely homologous to the ventral tegmental area/substantia nigra in land vertebrates. Finally, the differential distribution of SP and TH in the pallium supports the hypothesis that the pallium, or area dorsalis, can be divided medially into a rostral division (Dm), a caudal division (Dp) that is the main pallial target of secondary olfactory projections, and a narrow lateral division (Dd+Dl) immediately adjacent to the attachment of the tela choroidea along the entire rostrocaudal length of the telencephalic hemisphere.

  20. Development of nNOS-positive neurons in the rat sensory and sympathetic ganglia.

    Masliukov, P M; Emanuilov, A I; Madalieva, L V; Moiseev, K Y; Bulibin, A V; Korzina, M B; Porseva, V V; Korobkin, A A; Smirnova, V P


    Neurochemical features in sympathetic and afferent neurons are subject to change during development. Nitric oxide (NO) plays a developmental role in the nervous system. To better understand the neuroplasticity of sympathetic and afferent neurons during postnatal ontogenesis, the distribution of neuronal NO synthase (nNOS) immunoreactivity was studied in the sympathetic para- and prevertebral, nodose ganglion (NG) and Th2 and L4 dorsal root ganglia (DRG) from female Wistar rats of different ages (newborn, 10-day-old, 20-day-old, 30-day-old, 2-month-old, 6-month-old, 1-year-old, and 3-year-old). nNOS-positive neurons were revealed in all sensory ganglia but not in sympathetic ones from birth onward. The percentage of nNOS-immunoreactive (IR) neurons increased during first 10 days of life from 41.3 to 57.6 in Th2 DRG, from 40.9 to 59.1 in L4 DRG and from 31.6 to 38.5 in NG. The percentage of nNOS-IR neurons did not change in the NG later during development and senescence. However, in Th2 and L4 DRG the proportion of nNOS-IR neurons was high in animals between 10 and 30days of life and decreased up to the second month of life. In 2-month-old rats, the percentage of nNOS-IR neurons was 52.9 in Th2 DRG and 51.3 in L4 DRG. We did not find statistically significant differences in the percentage of nNOS-IR neurons between Th2 and L4 DRG and between young and aged rats. In NG and DRG of 10-day-old and older rats, a high proportion of nNOS-IR neurons binds isolectin B4. In newborn animals, only 41.3%, 45.3% and 28.4% of nNOS neuron profiles bind to IB4 in Th2, L4 DRG and NG, respectively. In 10-day-old and older rats, the number of sensory nNOS-IR neurons binding IB4 reached more than 90% in DRG and more than 80% in NG. Only a small number of nNOS-positive cells showed immunoreactivity to calcitonin gene-related peptide, neurofilament 200, calretinin. The information provided here will also serve as a basis for future studies investigating mechanisms of the development of

  1. Identification of QTLs involved in the development of amygdala kindling in the rat.

    Hashimoto, Ryoko; Voigt, Birger; Ishimaru, Yuji; Hokao, Ryoji; Chiba, Shigeru; Serikawa, Tadao; Sasa, Masashi; Kuramoto, Takashi


    Amygdala kindling is useful for modeling human epilepsy development. It has been known that genetic factors are involved in the development of amygdala kindling. The purpose of this study was to identify the loci that are responsible for the development of amygdala kindling. To achieve this, rat strains from a LEXF/FXLE recombinant inbred (RI) strain panel were used. The phenotypes of amygdala kindling-related parameters for seven RI strains and parental LE/Stm and F344/Stm strains were determined. They included the afterdischarge threshold (ADT), the afterdischarge duration (ADD), and the kindling rate, an incidence of development of kindling. Quantitative trait loci (QTL) analysis was performed to identify linkage relationships between these phenotypes and 1,033 SNP markers. Although no significant differences in pre-kindling ADT and ADD were observed, a significant difference in the kindling rate was found for the LEXF/FXLE RI strain. Two QTLs for the amygdala kindling rate (Agkr1 and Agkr2) were identified on rat chromosome 2. These findings clearly prove the existence of genetic influences that are involved in kindling development and suggest that substantial genetic components contribute to the progression of partial seizures into generalized seizures.

  2. Perinatal ethinyl oestradiol alters mammary gland development in male and female Wistar rats

    Mandrup, Karen; Hass, Ulla; Christiansen, Sofie


    Increased attention is being paid to human mammary gland development because of concerns for environmental influences on puberty onset and breast cancer development. Studies in rodents have showed a variety of changes in the mammary glands after perinatal exposure to endocrine disrupting chemical...... exposures may alter mammary gland development, disrupt lactation and alter susceptibility to breast cancer.......Increased attention is being paid to human mammary gland development because of concerns for environmental influences on puberty onset and breast cancer development. Studies in rodents have showed a variety of changes in the mammary glands after perinatal exposure to endocrine disrupting chemicals......, Wistar rats were exposed to 0, 5, 15 or 50 μg/kg of ethinyl oestradiol per day during gestation and lactation. A wide range of morphological parameters were evaluated in whole mounts of mammary glands from male and female offspring PD21–22. This study showed that in both male and female pre...

  3. MiR-200a is involved in rat epididymal development by targeting β-catenin mRNA

    Xiaojiang Wu; Botao Zhao; Wei Li; Yue Chen; Ruqiang Liang; Lin Li; Youxin Jin; Kangcheng Ruan


    The expression of 350 microRNAs (miRNAs) in epididymis of rat from postnatal development to adult (from postnatal days 7-70) was profiled with home-made miRNA microarray.Among them,48 miRNAs changed significantly, in which the expression of miR-200a increased obviously with time,in a good agreement with that obtained from northern blot analysis.The real-time quantitative-polymerase chain reaction result indicated that temporal expression of rat β-catenin was exactly inversed to that of miR-200a during rat epididymal development,implying that miR-200a might also target β-catenin mRNA in rat epididymis as reported by Saydam et humans.The bioinformatic analysis indicated that 3' untranslated region of rat β-catenin mRNA did contain a putative binding site for miR-200a.Meanwhile,it was found that the sequence of this binding site was different from that of human β-catenin mRNA with a deletion of two adjacent nucleotides (U and C).But the results of luciferase targeting assay in HEK 293T cells and the overexpression of miR-200a in rat NRK cells demonstrated that miR-200a did target rat β-catenin mRNA and cause the suppression of its expression.All these results show that miR-200a should be involved in rat epididymal development by targeting β-catenin mRNA of rat and suppressing its expression.

  4. Exposure to sevoflurane anesthesia during development does not impair aspects of attention during adulthood in rats.

    Murphy, Kathy L; McGaughy, Jill; Croxson, Paula L; Baxter, Mark G

    Exposure to general anesthetic agents during development has been associated with neurotoxicity and long-term behavioral impairments in rodents and non-human primates. The phenotype of anesthetic-induced cognitive impairment has a robust learning and memory component, however less is known about other psychological domains. Data from retrospective human patient studies suggest that children undergoing multiple procedures requiring general anesthesia are at increased risk of attention deficit hyperactivity disorder. We therefore assessed whether single or repeated exposures of neonatal rats to general anesthesia caused long-term attentional impairments. Female or male Long-Evans pups were exposed to 2.5% sevoflurane for 2h on postnatal day (P) 7, or for 2h each on P7, P10 and P13. Rats were behaviorally tested in late adolescence on the sustained attention task and on the attentional set shifting task. There was no compelling evidence for anesthetic-induced impairment in attentional processing in adult rats exposed to general anesthesia as neonates. These results suggest that, at least at the developmental stage tested here, the phenotype of anesthetic-induced cognitive impairment does not involve disruptions to attentional processing. Copyright © 2016. Published by Elsevier Inc.

  5. Postnatal development of retrosplenial projections to the parahippocampal region of the rat.

    Sugar, Jørgen; Witter, Menno P


    The rat parahippocampal region (PHR) and retrosplenial cortex (RSC) are cortical areas important for spatial cognition. In PHR, head-direction cells are present before eye-opening, earliest detected in postnatal day (P)11 animals. Border cells have been recorded around eye-opening (P16), while grid cells do not obtain adult-like features until the fourth postnatal week. In view of these developmental time-lines, we aimed to explore when afferents originating in RSC arrive in PHR. To this end, we injected rats aged P0-P28 with anterograde tracers into RSC. First, we characterized the organization of RSC-PHR projections in postnatal rats and compared these results with data obtained in the adult. Second, we described the morphological development of axonal plexus in PHR. We conclude that the first arriving RSC-axons in PHR, present from P1 onwards, already show a topographical organization similar to that seen in adults, although the labeled plexus does not obtain adult-like densities until P12.

  6. Toxicity of bryostatin-1 on the embryo-fetal development of Sprague-Dawley rats.

    Jiangbo, Zhu; Xuying, Wan; Yuping, Zhu; Xili, Ma; Yiwen, Zheng; Tianbao, Zhang


    Bryostatin-1, a highly oxygenated marine macrolide with a unique polyacetate backbone isolated from the marine animal Bugula neritina (Linnaeus), is now being developed as an anti-cancer drug for treating malignancy. In the present study, developmental toxicity of bryostatin-1 was evaluated in Sprague-Dawley rats. Bryostatin-1 was intravenously administered to rats on gestation days 6-15 at 4.0, 8.0, and 16.0 microg/kg on a daily basis. Then the reproductive parameters were determined in animals, and fetuses were examined for external, visceral, and skeletal malformations. The total weight gains were significantly different in animals between the control group and 8.0 and 16.0 microg/kg bryostatin-1 groups during and after treatment. The resorption and death fetus rates were significantly different between the bryostatin-1 group (16 microg/kg) and the control group. The fetal weight and fetal crown-rump length in the bryostatin-1 groups were significantly lower than that in the control group. Our results indicated that maternal toxicity occurred when the dose of bryostatin-1 was at 8.0 microg/kg, embryotoxicity at 16.0 microg/kg, and fetotoxicity at 4.0 microg/kg; but bryostatin-1 showed no teratogenic effect in rats. In light of our findings, bryostatin-1 should be used with caution in pregnant women with cancer, if they would like to continue the pregnancy.

  7. Development of a behavior model of pain induced by experimental tooth movement in rats.

    Yang, Zhi; Luo, Wei; Hou, Jingqiu; Zhao, Zhihe; Jian, Fan; Wamalwa, Peter; Lai, Wenli; Wang, Jing; Wang, Yan; Liao, Zhenyu


    The mechanism of orthodontic pain and discomfort is poorly understood partly because of the limited number of animal behavioral models for pain assessment. This study aimed to develop a behavioral model for assessment of tooth-movement pain in rats using directed face-grooming activity. Male Sprague-Dawley rats weighing 200-300 g were used. They were videotaped on days 1, 3, 5, 7, and 14 after experimental tooth movement and their directed face-grooming behavior was evaluated. In addition, we also evaluated behavioral responses to the application of a progressively higher magnitude force and to multiple applications of an equal magnitude force. Finally, the effects of peripherally and systemically administered morphine and of the N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801, on the behavioral responses were evaluated. The results indicated that time spent on directed face-grooming activity increased dramatically after initiating experimental tooth movement. The change concurred with the initial orthodontic pain response. This behavioral change was reproducible and was related to force magnitude. Application of both systemic and peripheral morphine and MK-801 could exert an analgesic effect on this pain model. These results suggest that directed face-grooming behavior can be a reliable measure for tooth-movement pain in rats, which could be widely used in investigating the orthodontic pain mechanism.

  8. Electroencephalographic studies on the development of tolerance and cross tolerance to mescaline in the rat.

    Colasanti, B; Khazan, N


    Recordings of the electroencephalogram (EEG) and the electromyogram (EMG) were collected continuously from rats equipped with permanent cortical and temporalis muscle electrodes. Automatic injections of mescaline were administered through indwelling i.p. cannulas at an initial dose of 30 mg/kg every 6 hrs for the first 2 days. This dose was then increased to 60 mg/kg 6 hr which was given for the duration of the study. The initial injections of the mescaline induced an