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Sample records for human dentate nucleus

  1. Evidence for a motor and a non-motor domain in the human dentate nucleus--an fMRI study.

    PubMed

    Küper, M; Dimitrova, A; Thürling, M; Maderwald, S; Roths, J; Elles, H G; Gizewski, E R; Ladd, M E; Diedrichsen, J; Timmann, D

    2011-02-14

    Dum and Strick (J. Neurophysiol. 2003; 89, 634-639) proposed a division of the cerebellar dentate nucleus into a "motor" and "non-motor" area based on anatomical data in the monkey. We asked the question whether motor and non-motor domains of the dentate can be found in humans using functional magnetic resonance imaging (fMRI). Therefore dentate activation was compared in motor and cognitive tasks. Young, healthy participants were tested in a 1.5 T MRI scanner. Data from 13 participants were included in the final analysis. A block design was used for the experimental conditions. Finger tapping of different complexities served as motor tasks, while cognitive testing included a verbal working memory and a visuospatial task. To further confirm motor-related dentate activation, a simple finger movement task was tested in a supplementary experiment using ultra-highfield (7 T) fMRI in 23 participants. For image processing, a recently developed region of interest (ROI) driven normalization method of the deep cerebellar nuclei was used. Dorso-rostral dentate nucleus activation was associated with motor function, whereas cognitive tasks led to prominent activation of the caudal nucleus. The visuospatial task evoked activity bilaterally in the caudal dentate nucleus, whereas verbal working memory led to activation predominantly in the right caudal dentate. These findings are consistent with Dum and Strick's anatomical findings in the monkey. PMID:21081171

  2. Morphometric study of dentate nucleus of cerebellum in Bangladeshi cadaver.

    PubMed

    Haque, M A; Khalil, M; Sultana, S Z; Mannan, S; Uddin, M M; Hossain, M; Ara, A; Choudhury, S; Shammi, N J

    2015-01-01

    This cross sectional descriptive study was done by using nonprobability sampling technique and performed by examining 63 (sixty three) cerebellum. Out of them 40 postmortem human cerebellum collected from Bangladeshi cadavers of both sexes (male 25 and female 15) age ranging from 5 to 60 years and 23 cerebellums from caesarian section of intrauterine death cases of both sexes (male 14 and female 9) age ranging from 34 to 41 weeks of gestation. Specimens were collected from dead bodies autopsied on different dates from April' 2009 to September' 2009 at the autopsy laboratory of department of Forensic Medicine and prenatal cases from Gynaecology and Obstetrics Department of Mymensingh Medical College, Mymensingh. The collected specimens were grouped into three age groups like Group A (28 to 42 weeks of gestation), Group B (5 to 30 years) and Group C (31 to 60 years) and, two sex groups (male and female) and two sides (right and left). A transverse section was made at the level of horizontal fissure, and length and breadth of dentate nucleus were measured by divider and scale. The mean (±SD) length and breadth of dentate nucleus was 8.619±2.995mm and 14.770±3.604mm respectively and it was observed that length and breadth of dentate nucleus increased with age upto certain level then slightly decreased in the late age Group C. In this study, differences of the mean length of dentate nucleus on both right and left sides were statistically moderately significant between age Groups A&B. The differences of mean breadth of dentate nucleus on both right and left side were statistically highly significant between age Groups A&B and moderately significant between age Groups A&C on right side and only significant on left side. The differences between male & female were statistically insignificant in length and breadth of dentate nucleus. PMID:25725664

  3. Activation of the dentate nucleus in a verb generation task: A 7T MRI study.

    PubMed

    Thürling, M; Küper, M; Stefanescu, R; Maderwald, S; Gizewski, E R; Ladd, M E; Timmann, D

    2011-08-01

    There is increasing evidence of a topographic organization within the human cerebellar cortex for motor and non-motor functions. Likewise, a subdivision of the dentate nucleus in a more dorsal and rostral motor domain and a more ventral and caudal non-motor domain has been proposed by Dum and Strick (2003) based on anatomical studies in monkey. In humans, however, very little is known about topographic organization within the dentate nucleus. Activation of the dentate nucleus in a verb generation task was examined in young and healthy subjects using ultra-highfield 7T functional magnetic resonance imaging (fMRI) with its increase in signal-to-noise ratio. Data of 17 subjects were included in statistical analysis. Subjects were asked to (i) read words (nouns) aloud presented on a screen, (ii) silently read the same nouns, (iii) silently generate the appropriate verbs to the same nouns and (iv) to silently repeat the names of the months. A block design was used. For image processing, a recently developed region of interest (ROI) driven normalization method of the dentate nuclei was applied. Activation related to motor speech (contrast aloud reading minus silent reading) was strongest in the rostral parts of the dentate nucleus. Dorsorostral activations were present bilaterally. Activation related to verb generation (contrast verb generation minus silent reading) was found in the ventrocaudal parts of the dentate nucleus on the right. The present findings are in good accordance with the anatomical data in monkeys and suggest that the human dentate nucleus can be subdivided into a rostral and more dorsal motor domain and a ventrocaudal non-motor domain. PMID:21640191

  4. Calretinin expression in hilar mossy cells of the hippocampal dentate gyrus of nonhuman primates and humans.

    PubMed

    Seress, László; Abrahám, Hajnalka; Czéh, Boldizsár; Fuchs, Eberhard; Léránth, Csaba

    2008-01-01

    Mossy cells, the major excitatory neurons of the hilus of the dentate gyrus constitutively express calretinin in several rodent species, including mouse and hamster, but not in rats. Several studies suggest that mossy cells of the monkey dentate gyrus are calretinin-positive, but others have reported mossy cells in monkeys to be devoid of detectable calretinin-like immunoreactivity. In the present study, the hilar region was investigated throughout the entire longitudinal extent of the hippocampal dentate gyrus in both Old World and New World monkeys, as well as in humans. In the examined four monkey species, mossy cells were found to be calretinin-positive at the uncal pole and at variable length within the main body of the dentate gyrus but not in the tail part. The associational pathway, formed by axons of mossy cells in the inner dentate molecular layer was calretinin-positive in more caudal sections, suggesting that mossy cell axon terminals may contain calretinin, whereas mossy cell somata may contain calretinin in a concentration too low to be detected by immunocytochemistry. In contrast, human mossy cells appear to be devoid of calretinin immunoreactivity in both their somata and their axon terminals. Taken together, mossy cells of nonhuman primates and humans exhibit different expression pattern for calretinin whereas they show similarities in neurochemical content, such as the cocaine and amphetamine-related transcript peptide. PMID:18189312

  5. High signal intensity in dentate nucleus and globus pallidus on unenhanced T1-weighted MR images in three patients with impaired renal function and vascular calcification.

    PubMed

    Barbieri, Sebastiano; Schroeder, Christophe; Froehlich, Johannes M; Pasch, Andreas; Thoeny, Harriet C

    2016-05-01

    Gadolinium-based contrast agents (primarily those with linear chelates) are associated with a dose-dependent signal hyperintensity in the dentate nucleus and the globus pallidus on unenhanced T1-weighted MRI following administration to selected patients with normal renal function. The accumulation of gadolinium has also been reported in the skin, heart, liver, lung, and kidney of patients with impaired renal function suffering from nephrogenic systemic fibrosis (NSF). Here we report on three patients with impaired renal function and vascular calcification (two with confirmed NSF) whose unenhanced T1-weighted MRIs showed conspicuous high signal intensity in the dentate nucleus and the globus pallidus after they had been exposed to relatively low doses of linear gadolinium-based contrast agents (0.27, 0.45, and 0.68 mmol/kg). Signal ratios between dentate nucleus and pons and between globus pallidus and thalamus were comparable with previously reported measurements in subjects without renal impairment. Of note, all three analysed patients suffered from transient signs of neurological disorders of undetermined cause. In conclusion, the exposure to 0.27-0.68 mmol/kg of linear gadolinium-based contrast agent was associated with probable gadolinium accumulation in the brain of three patients suffering from impaired renal function and vascular calcification. © 2016 The Authors. Contrast Media & Molecular Imaging published by John Wiley & Sons Ltd. PMID:26929131

  6. Gadodiamide and Dentate Nucleus T1 Hyperintensity in Patients With Meningioma Evaluated by Multiple Follow-Up Contrast-Enhanced Magnetic Resonance Examinations With No Systemic Interval Therapy.

    PubMed

    Quattrocchi, Carlo Cosimo; Mallio, Carlo Augusto; Errante, Yuri; Cirimele, Vincenzo; Carideo, Luciano; Ax, Antonella; Zobel, Bruno Beomonte

    2015-07-01

    The dentate nucleus of the cerebellum may appear as hyperintense on unenhanced T1 magnetic resonance images (MRIs) of the brain. Recently, T1 signal hyperintensity has received attention owing to data on the association of this finding with the history of multiple injections of gadolinium-based contrast agents, specifically gadodiamide, in patients with multiple sclerosis and brain metastases. We conducted a retrospective study on patients with a meningioma who had routinely undergone follow-up enhanced MRI scans with gadodiamide. Across a time interval of 18 months (from January 2013 to July 2014), we identified 102 consecutive patients eligible for this study. A significant increase in T1 hyperintensity of the dentate nuclei of the cerebellum on nonenhanced scans was observed between the first and the last MRI in the group of patients with a history of at least 6 enhanced MRI scans (P < 0.01), whereas no differences were observed in the group with 1 to 5 enhanced MRI scans (P = 0.74). Further research is necessary to shed light on the mechanism of the T1 hyperintensity as well as on the histological and microstructural appearance of the dentate nucleus after multiple intravenous injections of gadodiamide. The finding raises the question of substantial dechelation of this agent in patients with normal renal function. PMID:25756685

  7. Dynamic risk control by human nucleus accumbens.

    PubMed

    Nachev, Parashkev; Lopez-Sosa, Fernando; Gonzalez-Rosa, Javier Jesus; Galarza, Ana; Avecillas, Josue; Pineda-Pardo, Jose Angel; Lopez-Ibor, Juan José; Reneses, Blanca; Barcia, Juan Antonio; Strange, Bryan

    2015-12-01

    Real-world decisions about reward often involve a complex counterbalance of risk and value. Although the nucleus accumbens has been implicated in the underlying neural substrate, its criticality to human behaviour remains an open question, best addressed with interventional methodology that probes the behavioural consequences of focal neural modulation. Combining a psychometric index of risky decision-making with transient electrical modulation of the nucleus accumbens, here we reveal profound, highly dynamic alteration of the relation between probability of reward and choice during therapeutic deep brain stimulation in four patients with treatment-resistant psychiatric disease. Short-lived phasic electrical stimulation of the region of the nucleus accumbens dynamically altered risk behaviour, transiently shifting the psychometric function towards more risky decisions only for the duration of stimulation. A critical, on-line role of human nucleus accumbens in dynamic risk control is thereby established. PMID:26428667

  8. Safety of the Gadolinium-Based Contrast Agents for Magnetic Resonance Imaging, Focusing in Part on Their Accumulation in the Brain and Especially the Dentate Nucleus.

    PubMed

    Runge, Val M

    2016-05-01

    The established class of intravenous contrast media for magnetic resonance imaging is the gadolinium chelates, more generally referred to as the gadolinium-based contrast agents (GBCAs). These can be differentiated on the basis of stability in vivo, with safety and tolerability of the GBCAs dependent upon chemical and biologic inertness. This review discusses first the background in terms of development of these agents and safety discussions therein, and second their relative stability based both on in vitro studies and clinical observations before and including the advent of nephrogenic systemic fibrosis. This sets the stage for the subsequent focus of the review, the current knowledge regarding accumulation of gadolinium in the brain and specifically the dentate nucleus after intravenous administration of the GBCAs and differentiation among agents on this basis. The information available to date, from the initial conception of these agents in 1981 to the latest reports concerning safety, demonstrates a significant difference between the macrocyclic and linear chelates. The review concludes with a discussion of the predictable future, which includes, importantly, a reassessment of the use of the linear GBCAs or a subset thereof. PMID:26945278

  9. Inactivation of nucleus incertus impairs passive avoidance learning and long term potentiation of the population spike in the perforant path-dentate gyrus evoked field potentials in rats.

    PubMed

    Nategh, Mohsen; Nikseresht, Sara; Khodagholi, Fariba; Motamedi, Fereshteh

    2016-04-01

    Involvement of brainstem nucleus incertus (NI) in hippocampal theta rhythm suggests that this structure might play a role in hippocampal-dependent learning and memory. In the present study we aimed to address if NI is involved in an avoidance learning task as well as dentate gyrus (DG) short-term and long-term potentiation. Lidocaine was injected into the NI to transiently inactivate the nucleus, and control rats received saline. Role of NI was studied in passive avoidance learning (PAL) in 3 memory phases of acquisition, consolidation and retrieval. Levels of hippocampal phosphorylated p70 were also assessed in rats involved in PAL. Perforant path-DG short-term synaptic plasticity was studied upon NI inactivation before the paired-pulse stimulation, and also before or after tetanic stimulation in freely moving rats. It was found that NI inactivation delayed learning and impaired retention in the PAL task, with decreased levels of phosphorylated p70 in the respective groups. However, short-term plasticity was not affected by NI inactivation. But long term potentiation (LTP) of DG population spike was poorly induced with NI inactivation compared to the saline group, and it had no effect on population excitatory post-synaptic potential. Furthermore, when NI was inactivated after the induction of LTP, there was no difference between the saline and lidocaine groups. These observations suggest that NI has a role in PAL task, and its inactivation does not change the perforant path-DG granule cell synaptic input but decreases the excitability of the DG granule cells. Further studies should elucidate direct and indirect paths through which NI might influence hippocampal activity. PMID:26927304

  10. Dissociated Signals in Human Dentate Gyrus and CA3 Predict Different Facets of Recognition Memory

    PubMed Central

    Reagh, Zachariah M.; Watabe, Joseph; Ly, Maria; Murray, Elizabeth

    2014-01-01

    A wealth of evidence has implicated the hippocampus and surrounding medial temporal lobe cortices in support of recognition memory. However, the roles of the various subfields of the hippocampus are poorly understood. In this study, we concurrently varied stimulus familiarization and repetition to engage different facets of recognition memory. Using high-resolution fMRI (1.5 mm isotropic), we observed distinct familiarity and repetition-related recognition signal profiles in the dentate gyrus (DG)/CA3 subfield in human subjects. The DG/CA3 demonstrated robust response suppression with repetition and familiarity-related facilitation. Both of these discrete responses were predictive of different aspects of behavioral performance. Consistent with previous work, we observed novelty responses in CA1 consistent with “match/mismatch detection,” as well as mixed recognition signaling distributed across medial temporal lobe cortices. Additional analyses indicated that the repetition and familiarity-related signals in the DG/CA3 were strikingly dissociated along the hippocampal longitudinal axis and that activity in the posterior hippocampus was strongly correlated with the retrosplenial cortex. These data provide novel insight into the roles of hippocampal subfields in support of recognition memory and further provide evidence of a functional heterogeneity in the human DG/CA3, particularly along the longitudinal axis. PMID:25274810

  11. Distinct Pattern Separation Related Transfer Functions in Human CA3/Dentate and CA1 Revealed Using High-Resolution fMRI and Variable Mnemonic Similarity

    ERIC Educational Resources Information Center

    Lacy, Joyce W.; Yassa, Michael A.; Stark, Shauna M.; Muftuler, L. Tugan; Stark, Craig E. L.

    2011-01-01

    Producing and maintaining distinct (orthogonal) neural representations for similar events is critical to avoiding interference in long-term memory. Recently, our laboratory provided the first evidence for separation-like signals in the human CA3/dentate. Here, we extended this by parametrically varying the change in input (similarity) while…

  12. Effect of lanosterol on human cataract nucleus

    PubMed Central

    Shanmugam, P Mahesh; Barigali, Aditya; Kadaskar, Jayant; Borgohain, Sandip; Mishra, Divaynsh Kailash Chandra; Ramanjulu, Rajesh; Minija, C K

    2015-01-01

    Aim: To study the effect of lanosterol on age-related cataractous human lens nuclei. Materials and Methods: Forty age-related cataractous nuclei removed during manual small incision cataract surgery were obtained and randomly immersed in 25 mM lanosterol solution or in control solution and stored at room temperature for 6 days. Pre- and post-immersion photographs were graded by two masked observers and collated for the regression or progression of lens opacity. Results: Both lanosterol and control groups showed progression or no change in the lens opacity at the end of 6 days. Conclusion: Lanosterol 25 mM solution did not reverse opacification of human age-related cataractous nuclei. PMID:26862091

  13. Morphometric analysis of the supraoptic nucleus in the human brain.

    PubMed Central

    Hofman, M A; Goudsmit, E; Purba, J S; Swaab, D F

    1990-01-01

    The supraoptic nucleus (SON) in the human hypothalamus is an elongated, densely packed collection of large neurosecretory cells. The size, shape and cellular morphology of the dorsolateral part of the SON was examined in relation to sex and age in adult subjects. In this region, the following parameters were measured: length of the rostrocaudal axis, maximum cross-sectional area, volume, numerical cell density, total cell number and the mean diameter of the cell nuclei. No sexual differences were observed in any of these parameters with the exception that males have a more elongated SON than females. In contrast to absolute size, sex-linked differences were found in the way the morphometric parameters are interrelated. Of the parameters investigated, only the number of cells in the SON showed significant changes with ageing. A striking increase in the total number of cells, by about 30%, was found between 40 and 65 years of age. A further increase in cell number was observed after the age of 65 years, as a result of which the nucleus contained, on average, 1.4 times as many cells in old subjects (65-90 years) as in young individuals (20-40 years). These findings suggest that a substantial proliferation of glial cells takes place in the human supraoptic nucleus with advancing age. Finally, the morphology of the SON was compared with that of other hypothalamic regions--the suprachiasmatic nucleus (SCN) and the paraventricular nucleus (PVN)--using the same material as that used in previous investigations in this series (Hofman et al. 1988; Hofman & Swaab, 1989). PMID:2272907

  14. Attention alters orientation processing in the human lateral geniculate nucleus.

    PubMed

    Ling, Sam; Pratte, Michael S; Tong, Frank

    2015-04-01

    Orientation selectivity is a cornerstone property of vision, commonly believed to emerge in the primary visual cortex. We found that reliable orientation information could be detected even earlier, in the human lateral geniculate nucleus, and that attentional feedback selectively altered these orientation responses. This attentional modulation may allow the visual system to modify incoming feature-specific signals at the earliest possible processing site. PMID:25730671

  15. Attention alters orientation processing in the human lateral geniculate nucleus

    PubMed Central

    Ling, Sam; Pratte, Michael; Tong, Frank

    2015-01-01

    Orientation selectivity is a cornerstone property of vision, commonly believed to emerge in the primary visual cortex (V1). Here, we demonstrate that reliable orientation information can be detected even earlier, in the human lateral geniculate nucleus (LGN), and that attentional feedback selectively alters these orientation responses. This attentional modulation may allow the visual system to modify incoming feature-specific signals at the earliest possible processing site. PMID:25730671

  16. Sensory Deviancy Detection Measured Directly Within the Human Nucleus Accumbens.

    PubMed

    Dürschmid, Stefan; Zaehle, Tino; Hinrichs, Hermann; Heinze, Hans-Jochen; Voges, Jürgen; Garrido, Marta I; Dolan, Raymond J; Knight, Robert T

    2016-03-01

    Rapid changes in the environment evoke a comparison between expectancy and actual outcome to inform optimal subsequent behavior. The nucleus accumbens (NAcc), a key interface between the hippocampus and neocortical regions, is a candidate region for mediating this comparison. Here, we report event-related potentials obtained from the NAcc using direct intracranial recordings in 5 human participants while they listened to trains of auditory stimuli differing in their degree of deviation from repetitive background stimuli. NAcc recordings revealed an early mismatch signal (50-220 ms) in response to all deviants. NAcc activity in this time window was also sensitive to the statistics of stimulus deviancy, with larger amplitudes as a function of the level of deviancy. Importantly, this NAcc mismatch signal also predicted generation of longer latency scalp potentials (300-400 ms). The results provide direct human evidence that the NAcc is a key component of a network engaged in encoding statistics of the sensory environmental. PMID:25576536

  17. Antibodies to human caudate nucleus neurons in Huntington's chorea.

    PubMed Central

    Husby, G; Li, L; Davis, L E; Wedege, E; Kokmen, E; Williams, R C

    1977-01-01

    Antibodies reacting with neuronal cytoplasmic antigens present in normal human caudate and subthalamic nuclei were detected in 37 of 80 probands afflicted with Huntington's disease (HD). IgG antibodies were detected by immunofluorescence using frozen sections of unfixed normal human and rat brain. Specificity of IgG binding was confirmed using pepsin F(ab')2 fragments of IgG isolated from positive sera. In vitro complement fixation of IgG antibody was detected in 22 of 31 sera tested. Neuronal cytoplasmic antigens reacting with positive HD sera were diminished after trypsin or RNAase treatment of tissue sections but were not removed by DNAase, neuraminidase, EDTA, or dithiothreitol treatment. Antibody staining of neurons could be removed after absorption with isolated caudate nucleus neurons or by using perchloroacetic acid extracts of caudate nucleus. Prevalence of antibody reacting with neuronal cytoplasm was 3% in 60 normal controls and 6% among a wide variety of patients with diverse neurological disorders. However, one-third of 33 patients with Parkinson's disease showed presence of antineuronal antibody. Among patients with HD, a significant association was noted between duration of clinical disease greater than 7 yr and titers of antibody of 1:2 or greater (P less than 0.001). When 115 family members of HD probands were tested, 30% of unaffected spouses showed presence of antineuronal antibody. 23.2% of first-degree relatives at risk for developing HD was also positive (P less than 0.001). 10.5% of second-degree relatives showed presence of antineuronal antibody. These data may support an environmental or infectious factor somehow involved in the ultimate expression of HD. Images PMID:140183

  18. Human Disc Nucleus Properties and Vertebral Endplate Permeability

    PubMed Central

    Rodriguez, Azucena G.; Slichter, Chloe K.; Acosta, Frank L.; Rodriguez-Soto, Ana E.; Burghardt, Andrew J.; Majumdar, Sharmila; Lotz, Jeffrey C.

    2010-01-01

    Study of human cadaveric discs quantifying endplate permeability and porosity and correlating these with measures of disc quality: cell density, proteoglycan content, and overall degeneration. Permeability and porosity increased with age and were not correlated with cell density or overall degeneration, suggesting that endplate calcification may not accelerate disc degeneration. Study Design Experimental quantification of relationships between vertebral endplate morphology, permeability, disc cell density, glycosaminoglycan content and degeneration in samples harvested from human cadaveric spines. Objective To test the hypothesis that variation in endplate permeability and porosity contribute to changes in intervertebral disc cell density and overall degeneration. Summary of Background Data Cells within the intervertebral disc are dependent on diffusive exchange with capillaries in the adjacent vertebral bone. Previous findings suggest that blocked routes of transport negatively affect disc quality, yet there are no quantitative relationships between human vertebral endplate permeability, porosity, cell density and disc degeneration. Such relationships would be valuable for clarifying degeneration risk factors, and patient features that may impede efforts at disc tissue engineering. Methods Fifty-one motion segments were harvested from 13 frozen cadaveric human lumbar spines (32 to 85 years) and classified for degeneration using the MRI-based Pfirrmann scale. A cylindrical core was harvested from the center of each motion segment that included vertebral bony and cartilage endplates along with adjacent nucleus tissue. The endplate mobility, a type of permeability, was measured directly using a custom-made permeameter before and after the cartilage endplate was removed. Cell density within the nucleus tissue was estimated using the picogreen method while the nuclear GAG content was quantified using the DMMB technique. Specimens were imaged at 8 μm resolution using

  19. Hyperintense Dentate Nuclei on T1-Weighted MRI: Relation to Repeat Gadolinium Administration

    PubMed Central

    Adin, M.E.; Kleinberg, L.; Vaidya, D.; Zan, E.; Mirbagheri, S.; Yousem, D.M.

    2016-01-01

    BACKGROUND AND PURPOSE A hyperintense appearance of the dentate nucleus on T1-weighted MR images has been related to various clinical conditions, but the etiology remains indeterminate. We aimed to investigate the possible associations between a hyperintense appearance of the dentate nucleus on T1-weighted MR images in patients exposed to radiation and factors including, but not limited to, the cumulative number of contrast-enhanced MR images, amount of gadolinium administration, dosage of ionizing radiation, and patient demographics. MATERIALS AND METHODS The medical records of 706 consecutive patients who were treated with brain irradiation at The Johns Hopkins Medical Institutions between 1995 and 2010 were blindly reviewed by 2 readers. RESULTS One hundred eighty-four subjects were included for dentate nuclei analysis. Among the 184 subjects who cumulatively underwent 2677 MR imaging studies following intravenous gadolinium administration, 103 patients had hyperintense dentate nuclei on precontrast T1-weighted MR images. The average number of gadolinium-enhanced MR imaging studies performed in the group with normal dentate nuclei was significantly lower than that of the group with hyperintense dentate nuclei. The average follow-up time was 62.5 months. No significant difference was observed between hyperintense and normal dentate nuclei groups in terms of exposed radiation dose, serum creatinine and calcium/phosphate levels, patient demographics, history of chemotherapy, and strength of the scanner. No dentate nuclei abnormalities were found on the corresponding CT scans of patients with hyperintense dentate nuclei (n = 44). No dentate nuclei abnormalities were found in 53 healthy volunteers. CONCLUSIONS Repeat performance of gadolinium-enhanced studies likely contributes to a long-standing hyperintense appearance of dentate nuclei on precontrast T1-weighted-MR images. PMID:26294649

  20. Neural Correlates of Decision Thresholds in the Human Subthalamic Nucleus.

    PubMed

    Herz, Damian M; Zavala, Baltazar A; Bogacz, Rafal; Brown, Peter

    2016-04-01

    If humans are faced with difficult choices when making decisions, the ability to slow down responses becomes critical in order to avoid suboptimal choices. Current models of decision making assume that the subthalamic nucleus (STN) mediates this function by elevating decision thresholds, thereby requiring more evidence to be accumulated before responding [1-9]. However, direct electrophysiological evidence for the exact role of STN during adjustment of decision thresholds is lacking. Here, we show that trial-by-trial variations in STN low-frequency oscillatory activity predict adjustments of decision thresholds before subjects make a response. The relationship between STN activity and decision thresholds critically depends on the subjects' level of cautiousness. While increased oscillatory activity of the STN predicts elevated decision thresholds during high levels of cautiousness, it predicts decreased decision thresholds during low levels of cautiousness. This context-dependent relationship may be mediated by increased influence of the medial prefrontal cortex (mPFC)-STN pathway on decision thresholds during high cautiousness. Subjects who exhibit a stronger increase in phase alignment of low-frequency oscillatory activity in mPFC and STN before making a response have higher decision thresholds and commit fewer erroneous responses. Together, our results demonstrate that STN low-frequency oscillatory activity and corresponding mPFC-STN coupling are involved in determining how much evidence subjects accumulate before making a decision. This finding might explain why deep-brain stimulation of the STN can impair subjects' ability to slow down responses and can induce impulsive suboptimal decisions. PMID:26996501

  1. Neural Correlates of Decision Thresholds in the Human Subthalamic Nucleus

    PubMed Central

    Herz, Damian M.; Zavala, Baltazar A.; Bogacz, Rafal; Brown, Peter

    2016-01-01

    Summary If humans are faced with difficult choices when making decisions, the ability to slow down responses becomes critical in order to avoid suboptimal choices. Current models of decision making assume that the subthalamic nucleus (STN) mediates this function by elevating decision thresholds, thereby requiring more evidence to be accumulated before responding [1, 2, 3, 4, 5, 6, 7, 8, 9]. However, direct electrophysiological evidence for the exact role of STN during adjustment of decision thresholds is lacking. Here, we show that trial-by-trial variations in STN low-frequency oscillatory activity predict adjustments of decision thresholds before subjects make a response. The relationship between STN activity and decision thresholds critically depends on the subjects’ level of cautiousness. While increased oscillatory activity of the STN predicts elevated decision thresholds during high levels of cautiousness, it predicts decreased decision thresholds during low levels of cautiousness. This context-dependent relationship may be mediated by increased influence of the medial prefrontal cortex (mPFC)-STN pathway on decision thresholds during high cautiousness. Subjects who exhibit a stronger increase in phase alignment of low-frequency oscillatory activity in mPFC and STN before making a response have higher decision thresholds and commit fewer erroneous responses. Together, our results demonstrate that STN low-frequency oscillatory activity and corresponding mPFC-STN coupling are involved in determining how much evidence subjects accumulate before making a decision. This finding might explain why deep-brain stimulation of the STN can impair subjects’ ability to slow down responses and can induce impulsive suboptimal decisions. PMID:26996501

  2. Red nucleus connectivity as revealed by constrained spherical deconvolution tractography.

    PubMed

    Milardi, Demetrio; Cacciola, Alberto; Cutroneo, Giuseppina; Marino, Silvia; Irrera, Mariangela; Cacciola, Giorgio; Santoro, Giuseppe; Ciolli, Pietro; Anastasi, Giuseppe; Calabrò, Rocco Salvatore; Quartarone, Angelo

    2016-07-28

    Previous Diffusion Tensor Imaging studies have demonstrated that the human red nucleus is widely interconnected with sensory-motor and prefrontal cortices. In this study, we assessed red nucleus connectivity by using a multi-tensor model called non- negative Constrained Spherical Deconvolution (CSD), which is able to resolve more than one fiber orientation per voxel. Connections of the red nuclei of fifteen volunteers were studied at 3T using CSD axonal tracking. We found significant connectivity between RN and the following cortical and subcortical areas: cerebellar cortex, thalamus, paracentral lobule, postcentral gyrus, precentral gyrus, superior frontal gyrus and dentate nucleus. We confirmed that red nucleus is tightly linked with the cerebral cortex and has dense subcortical connections with thalamus and cerebellar cortex. These findings may be useful in a clinical context considering that RN is involved in motor control and it is known to have potential to compensate for injury of the corticospinal tract. PMID:27181514

  3. Understanding the human pedunculopontine nucleus in Parkinson's disease.

    PubMed

    Fytagoridis, Anders; Silburn, Peter A; Coyne, Terry J; Thevathasan, Wesley

    2016-07-01

    This paper presents the Brisbane experience of pedunculopontine nucleus (PPN) deep brain stimulation (DBS) in Parkinson's disease (PD). Clinical outcomes along with studies of the mechanisms and neurophysiology of PPN in PD patients with severe freezing of gait (FoG) and postural imbalance (PI) are summarised and presented. Our results indicate that PPN DBS improves FoG and falls in the relatively uncommon group of PD patients who respond well to medication other than for continuing on time FoG and falls. Our studies indicate that bilateral DBS is more beneficial than unilateral DBS, and that the more caudal region of the PPN seems preferable for stimulation. There is evidence that rapid-release programs for initiation and correction of gait and posture are modulated by the PPN, possibly to some extent independently of the cerebral cortex. These functions were found to be impaired in PD patients with severe FoG/PI, but to some extent corrected by bilateral PPN DBS. PMID:26780720

  4. Rapid feedback processing in human nucleus accumbens and motor thalamus.

    PubMed

    Schüller, Thomas; Gruendler, Theo O J; Jocham, Gerhard; Klein, Tilmann A; Timmermann, Lars; Visser-Vandewalle, Veerle; Kuhn, Jens; Ullsperger, Markus

    2015-04-01

    The nucleus accumbens (NAcc) and thalamus are integral parts in models of feedback processing. Deep brain stimulation (DBS) has been successfully employed to alleviate symptoms of psychiatric conditions including obsessive-compulsive disorder (OCD) and Tourette's syndrome (TS). Common target structures are the NAcc and the ventral anterior and ventro-lateral nuclei (VA/VL) of the thalamus, for OCD and TS, respectively. The feedback related negativity (FRN) is an event-related potential associated with feedback processing reflecting posterior medial frontal cortex (pMFC) activity. Here we report on three cases where we recorded scalp EEG and local field potentials (LFP) from externalized electrodes located in the NAcc or thalamus (VA/VL) while patients engaged in a modified time estimation task, known to engage feedback processing and elicit the FRN. Additionally, scalp EEG were recorded from 29 healthy participants (HP) engaged in the same task. The signal in all structures (pMFC, NAcc, and thalamus) was differently modulated by positive and negative feedback. LFP activity in the NAcc showed a biphasic time course after positive feedback during the FRN time interval. Negative feedback elicited a much weaker and later response. In the thalamus a monophasic modulation was recorded during the FRN time interval. Again, this modulation was more pronounced after positive performance feedback compared to negative feedback. In channels outside the target area no modulation was observed. The surface-FRN was reliably elicited on a group level in HP and showed no significant difference following negative feedback between patients and HP. German Clinical Trial Register: Neurocognitive specification of dysfunctions within basal ganglia-cortex loops and their therapeutic modulation by deep brain stimulation in patients with obsessive compulsive disorder and Tourette syndrome, http://www.drks.de/DRKS00005316. PMID:25726897

  5. Neuroelectric signatures of reward learning and decision-making in the human nucleus accumbens.

    PubMed

    Cohen, Michael X; Axmacher, Nikolai; Lenartz, Doris; Elger, Christian E; Sturm, Volker; Schlaepfer, Thomas E

    2009-06-01

    Learning that certain actions lead to risky rewards is critical for biological, social, and economic survival, but the precise neural mechanisms of such reward-guided learning remain unclear. Here, we show that the human nucleus accumbens plays a key role in learning about risks by representing reward value. We recorded electrophysiological activity directly from the nucleus accumbens of five patients undergoing deep brain stimulation for treatment of refractory major depression. Patients engaged in a simple reward-learning task in which they first learned stimulus-outcome associations (learning task), and then were able to choose from among the learned stimuli (choosing task). During the learning task, nucleus accumbens activity reflected potential and received reward values both during the cue stimulus and during the feedback. During the choosing task, there was no nucleus accumbens activity during the cue stimulus, but feedback-related activity was pronounced and similar to that during the learning task. This pattern of results is inconsistent with a prediction error response. Finally, analyses of cross-correlations between the accumbens and simultaneous recordings of medial frontal cortex suggest a dynamic interaction between these structures. The high spatial and temporal resolution of these recordings provides novel insights into the timing of activity in the human nucleus accumbens, its functions during reward-guided learning and decision-making, and its interactions with medial frontal cortex. PMID:19092783

  6. The central vestibular complex in dolphins and humans: functional implications of Deiters' nucleus.

    PubMed

    Kern, A; Seidel, K; Oelschläger, H H A

    2009-01-01

    Toothed whales (Odontocetes; e.g., dolphins) are well-known for efficient underwater locomotion and for their acrobatic capabilities. Nevertheless, in relation to other mammals including the human and with respect to body size, their vestibular apparatus is reduced, particularly the semicircular canals. Concomitantly, the vestibular nerve and most of the vestibular nuclei are thin and small, respectively, in comparison with those in terrestrial mammals. In contrast, the lateral (Deiters') vestibular nucleus is comparatively well developed in both coastal and pelagic dolphins. In the La Plata dolphin (Pontoporia blainvillei) and the Common dolphin (Delphinus delphis), all of the vestibular nuclei are present and their topographic relations are similar to those in humans. Quantitative analysis, however, revealed that in the dolphin most of the nuclei (superior, medial, descending nucleus) are minute both in absolute and relative terms. Here, the only exception is the lateral vestibular nucleus, which is of comparable size in humans and Pontoporia and decidedly more voluminous in Delphinus. While the small size of the majority of the dolphin's vestibular nuclei correlates well with miniaturization of the semicircular canals, the size of Deiters' nucleus seems to support its relative independence from the vestibular system and a close functional relationship with the cerebellum. In comparison with findings in humans and other terrestrial mammals, both of these aspects seem to be related to the physical conditions of aquatic life and locomotion in three dimensions. PMID:19390175

  7. Effects of aging on nitrergic neurons in human striatum and subthalamic nucleus.

    PubMed

    Santos-Lobato, Bruno Lopes dos; Del-Bel, Elaine Aparecida; Pittella, José Eymard Homem; Tumas, Vitor

    2015-09-01

    Nitric oxide (NO) is a major neurotransmitter associated with motor control in basal ganglia. Movement disorders, as essential tremor and Parkinson's disease, are more prevalent on aged individuals. We investigated the effects of aging on neuronal density and diameter/area of nitrergic neurons in samples of striatum (caudate and putamen) and subthalamic nucleus of 20 human brains from normal subjects, stained by histochemistry for NADPH-diaphorase and immunohistochemistry for neuronal NO synthase. Our data showed aging does not modify the neuronal density and size of nitrergic neurons in striatum and subthalamic nucleus. These findings suggest a lack of association between aging and morphologic changes on nitrergic neurons. PMID:26352497

  8. Cortical drive of low-frequency oscillations in the human nucleus accumbens during action selection

    PubMed Central

    Litvak, Vladimir; Rutledge, Robb B.; Zaehle, Tino; Schmitt, Friedhelm C.; Voges, Jürgen; Heinze, Hans-Jochen; Dolan, Raymond J.

    2015-01-01

    The nucleus accumbens is thought to contribute to action selection by integrating behaviorally relevant information from multiple regions, including prefrontal cortex. Studies in rodents suggest that information flow to the nucleus accumbens may be regulated via task-dependent oscillatory coupling between regions. During instrumental behavior, local field potentials (LFP) in the rat nucleus accumbens and prefrontal cortex are coupled at delta frequencies (Gruber AJ, Hussain RJ, O'Donnell P. PLoS One 4: e5062, 2009), possibly mediating suppression of afferent input from other areas and thereby supporting cortical control (Calhoon GG, O'Donnell P. Neuron 78: 181–190, 2013). In this report, we demonstrate low-frequency cortico-accumbens coupling in humans, both at rest and during a decision-making task. We recorded LFP from the nucleus accumbens in six epilepsy patients who underwent implantation of deep brain stimulation electrodes. All patients showed significant coherence and phase-synchronization between LFP and surface EEG at delta and low theta frequencies. Although the direction of this coupling as indexed by Granger causality varied between subjects in the resting-state data, all patients showed a cortical drive of the nucleus accumbens during action selection in a decision-making task. In three patients this was accompanied by a significant coherence increase over baseline. Our results suggest that low-frequency cortico-accumbens coupling represents a highly conserved regulatory mechanism for action selection. PMID:25878159

  9. Reduction of the immunostainable length of the hippocampal dentate granule cells' primary cilia in 3xAD-transgenic mice producing human A{beta}{sub 1-42} and tau

    SciTech Connect

    Chakravarthy, Balu; Gaudet, Chantal; Menard, Michel; Brown, Leslie; Atkinson, Trevor; LaFerla, Frank M.; Ito, Shingo; Armato, Ubaldo; Dal Pra, Ilaria; Whitfield, James

    2012-10-12

    Highlights: Black-Right-Pointing-Pointer A{beta} and tau-induced neurofibrillary tangles play a key role in Alzheimer's disease. Black-Right-Pointing-Pointer A{beta}{sub 1-42} and mutant tau protein together reduce the primary cilium length. Black-Right-Pointing-Pointer This shortening likely reduces cilium-dependent neurogenesis and memory function. Black-Right-Pointing-Pointer This provides a model of an A{beta}/tau targeting of a neuronal signaling organelle. -- Abstract: The hippocampal dentate gyrus is one of the two sites of continuous neurogenesis in adult rodents and humans. Virtually all dentate granule cells have a single immobile cilium with a microtubule spine or axoneme covered with a specialized cell membrane loaded with receptors such as the somatostatin receptor 3 (SSTR3), and the p75 neurotrophin receptor (p75{sup NTR}). The signals from these receptors have been reported to stimulate neuroprogenitor proliferation and the post-mitotic maturation of newborn granule cells into functioning granule cells. We have found that in 6-24-months-old triple transgenic Alzheimer's disease model mice (3xTg-AD) producing both A{beta}{sub 1-42} and the mutant human tau protein tau{sub P301L,} the dentate granule cells still had immunostainable SSTR3- and p75{sup NTR}-bearing cilia but they were only half the length of the immunostained cilia in the corresponding wild-type mice. However, the immunostainable length of the granule cell cilia was not reduced either in 2xTg-AD mice accumulating large amounts of A{beta}{sub 1-42} or in mice accumulating only a mutant human tau protein. Thus it appears that a combination of A{beta}{sub 1-42} and tau protein accumulation affects the levels of functionally important receptors in 3xTg-AD mice. These observations raise the important possibility that structural and functional changes in granule cell cilia might have a role in AD.

  10. Serial interactome capture of the human cell nucleus

    PubMed Central

    Conrad, Thomas; Albrecht, Anne-Susann; de Melo Costa, Veronica Rodrigues; Sauer, Sascha; Meierhofer, David; Ørom, Ulf Andersson

    2016-01-01

    Novel RNA-guided cellular functions are paralleled by an increasing number of RNA-binding proteins (RBPs). Here we present ‘serial RNA interactome capture' (serIC), a multiple purification procedure of ultraviolet-crosslinked poly(A)–RNA–protein complexes that enables global RBP detection with high specificity. We apply serIC to the nuclei of proliferating K562 cells to obtain the first human nuclear RNA interactome. The domain composition of the 382 identified nuclear RBPs markedly differs from previous IC experiments, including few factors without known RNA-binding domains that are in good agreement with computationally predicted RNA binding. serIC extends the number of DNA–RNA-binding proteins (DRBPs), and reveals a network of RBPs involved in p53 signalling and double-strand break repair. serIC is an effective tool to couple global RBP capture with additional selection or labelling steps for specific detection of highly purified RBPs. PMID:27040163

  11. Yes, there is a medial nucleus of the trapezoid body in humans

    PubMed Central

    Kulesza, Randy J.; Grothe, Benedikt

    2015-01-01

    The medial nucleus of the trapezoid body (MNTB) is a collection of brainstem neurons that function within the ascending auditory pathway. MNTB neurons are associated with a number of anatomical and physiological specializations which make these cells especially well-equipped to provide extremely fast and precise glycinergic inhibition to its target neurons in the superior olivary complex and ventral nucleus of the lateral lemniscus. The inhibitory influence of MNTB neurons plays essentials roles in the localization of sound sources and encoding temporal features of complex sounds. The morphology, afferent and efferent connections and physiological response properties of MNTB neurons have been well-characterized in a number of laboratory rodents and some carnivores. Furthermore, the MNTB has been positively identified in all mammals examined, ranging from opossum and mice to chimpanzees. From the early 1970s through 2009, a number of studies denied the existence of the MNTB in humans and consequentially, the existence of this nucleus in the human brain has been debated for nearly 50 years. The absence of the MNTB from the human brain would negate current principles of sound localization and would require a number of novel adaptations, entirely unique to humans. However, a number of recent studies of human post-mortem tissue have provided evidence supporting the existence of the MNTB in humans. It therefore seems timely to review the structure and function of the MNTB, critically review the literature which led to the denial of the human MNTB and then review recent investigations supporting the existence of the MNTB in the human brain. PMID:25873865

  12. Suppression of beta oscillations in the subthalamic nucleus following cortical stimulation in humans

    PubMed Central

    Doyle Gaynor, L M F; Kühn, A A; Dileone, M; Litvak, V; Eusebio, A; Pogosyan, A; Androulidakis, A G; Tisch, S; Limousin, P; Insola, A; Mazzone, P; Di Lazzaro, V; Brown, P

    2008-01-01

    It is unclear how subthalamic nucleus activity is modulated by the cerebral cortex. Here we investigate the effect of transcranial magnetic stimulation (TMS) of the cortex on oscillatory subthalamic local field potential activity in the 8–35 Hz (alpha/beta) band, as exaggerated synchronization in this band is implicated in the pathophysiology of parkinsonism. We studied nine patients with Parkinson’s disease (PD) to test whether cortical stimulation can modulate synchronized oscillations in the human subthalamic nucleus. With patients at rest, single-pulse TMS was delivered every 5 s over each primary motor area and supplementary motor area at intensities of 85–115% resting motor threshold. Subthalamic local field potentials were recorded from deep brain stimulation electrodes implanted into this nucleus for the treatment of PD. Motor cortical stimulation suppressed beta activity in the subthalamic nucleus from ∼0.2 to 0.6 s after TMS (repeated measures anova; main effect of time, P<0.01; main effect of side, P=0.03), regardless of intensity. TMS over the supplementary motor area also reduced subthalamic beta activity at 95% (P=0.05) and 115% resting motor threshold (P=0.01). The oscillatory activity decreased to 80 ± 26% of baseline (averaged across sites and stimulation intensities). Suppression with subthreshold stimuli confirmed that these changes were centrally driven and not due to peripheral afference. The results may have implications for mechanisms underlying the reported therapeutic benefits of cortical stimulation. PMID:18657185

  13. Effect of vertebroplasty filler materials on viability and gene expression of human nucleus pulposus cells.

    PubMed

    Lazáry, Aron; Speer, Gábor; Varga, Péter Pál; Balla, Bernadett; Bácsi, Krisztián; Kósa, János P; Nagy, Zsolt; Takács, István; Lakatos, Péter

    2008-05-01

    Consequences of intradiscal cement leakage--often occurring after vertebral cement augmentation for the treatment of vertebral compression fractures--are still unknown. In this study, we have investigated the influences of vertebroplasty filler materials (polymethylmethacrylate-, calcium phosphate- and calcium sulfate-based bone cement) on isolated nucleus pulposus cells. Cell viability of cultured human nucleus pulposus cells were measured after treatment with vertebroplasty filler materials. Gene expression profile of selected genes was determined with quantitative real-time PCR. The widely used polymethylmethacrylate and calcium phosphate cement significantly decreased cell number in a dose- and time-dependent manner while calcium sulfate cement affected cell viability less. Expression of genes involved in matrix metabolism of nucleus pulposus--aggrecan, collagens, small proteoglycans--as well as important transcription factors have also significantly changed due to treatment (e.g., 2.5-fold decrease in aggrecan expression was determined in cultures due to polymethylmethacrylate treatment). Our results suggest that vertebroplasty filler materials--depending on the type of applied material--can accelerate the degeneration of nucleus pulposus cells resulting in a less flexible disc in case of intradiscal cement leakage. This process may increase the risk of a subsequent new vertebral fracture, the main complication of vertebral augmentation. PMID:18176942

  14. Sex Steroids and the Dentate Gyrus

    PubMed Central

    Hajszan, Tibor; Leranth, Csaba

    2006-01-01

    In the late 1980s, the finding that the dentate gyrus contains more granule cells in the male than in the female of certain mouse strains provided the first indication that the dentate gyrus is a significant target for the effects of sex steroids during development. Gonadal hormones also play a crucial role in shaping the function and morphology of the adult brain. Besides reproduction-related processes, sex steroids participate in higher brain operations such as cognition and mood, in which the hippocampus is a critical mediator. Being part of the hippocampal formation, the dentate gyrus is naturally involved in these mechanisms and as such, this structure is also a critical target for the activational effects of sex steroids. These activational effects are the results of three major types of steroid-mediated actions. Sex steroids modulate the function of dentate neurons under normal conditions. In addition, recent research suggests that hormone-induced cellular plasticity may play a larger role than previously thought, particularly in the dentate gyrus. Specifically, the regulation of dentate gyrus neurogenesis and synaptic remodeling by sex steroids received increasing attention lately. Finally, the dentate gyrus is influenced by gonadal hormones in the context of cellular injury, and the work in this area demonstrates that gonadal hormones have neuroprotective potential. The expression of estrogen, progestin and androgen receptors in the dentate gyrus suggests that sex steroids, which could be of gonadal origin and/or synthesized locally in the dentate gyrus, may act directly on dentate cells. In addition, gonadal hormones could also influence the dentate gyrus indirectly, by subcortical hormone-sensitive structures such as the cholinergic septohippocampal system. Importantly, these three sex steroid-related themes, functional effects in the normal dentate gyrus, mechanisms involving neurogenesis and synaptic remodeling, as well as neuroprotection, have

  15. Export of Precursor tRNAIle from the Nucleus to the Cytoplasm in Human Cells.

    PubMed

    Wei, Min; Zhao, Xia; Liu, Mi; Niu, Meijuan; Seif, Elias; Kleiman, Lawrence

    2016-01-01

    In the current concept, tRNA maturation in vertebrate cells, including splicing of introns, trimming of 5' leader and 3' trailer, and adding of CCA, is thought to occur exclusively in the nucleus. Here we provide evidence to challenge this concept. Unspliced intron-containing precursor tRNAIle was identified in Human Immunodeficiency Virus type 1 (HIV-1) virions, which are synthesized in the cytoplasm. Northern blot, confocal microscopy and quantitative RT-PCR further verified enrichment of this unspliced tRNAIle within the cytoplasm in human cells. In addition to containing an intron, the cytoplasmic precursor tRNAIle also contains a short incompletely processed 5´ leader and a 3´ trailer, which abundance is around 1000 fold higher than the nuclear precursor tRNAIle with long 5' leader and long 3' trailer. In vitro data also suggest that the cytoplasmic unspliced end-immature precursor tRNAIle could be processed by short isoform of RNase Z, but not long isoform of RNase Z. These data suggest that precursor tRNAs could export from the nucleus to the cytoplasm in human cells, instead of be processed only in the nucleus. PMID:27101286

  16. Export of Precursor tRNAIle from the Nucleus to the Cytoplasm in Human Cells

    PubMed Central

    Wei, Min; Zhao, Xia; Liu, Mi; Niu, Meijuan; Seif, Elias; Kleiman, Lawrence

    2016-01-01

    In the current concept, tRNA maturation in vertebrate cells, including splicing of introns, trimming of 5’ leader and 3’ trailer, and adding of CCA, is thought to occur exclusively in the nucleus. Here we provide evidence to challenge this concept. Unspliced intron-containing precursor tRNAIle was identified in Human Immunodeficiency Virus type 1 (HIV-1) virions, which are synthesized in the cytoplasm. Northern blot, confocal microscopy and quantitative RT-PCR further verified enrichment of this unspliced tRNAIle within the cytoplasm in human cells. In addition to containing an intron, the cytoplasmic precursor tRNAIle also contains a short incompletely processed 5´ leader and a 3´ trailer, which abundance is around 1000 fold higher than the nuclear precursor tRNAIle with long 5’ leader and long 3’ trailer. In vitro data also suggest that the cytoplasmic unspliced end-immature precursor tRNAIle could be processed by short isoform of RNase Z, but not long isoform of RNase Z. These data suggest that precursor tRNAs could export from the nucleus to the cytoplasm in human cells, instead of be processed only in the nucleus. PMID:27101286

  17. Cortical Innervation of the Hypoglossal Nucleus in the Non-Human Primate (Macaca mulatta)

    PubMed Central

    Morecraft, Robert J.; Stilwell-Morecraft, Kimberly S.; Solon-Cline, Kathryn M.; Ge, Jizhi; Darling, Warren G.

    2014-01-01

    The corticobulbar projection to the hypoglossal nucleus was studied from the frontal, parietal, cingulate and insular cortices in the rhesus monkey using high-resolution anterograde tracers and stereology. The hypoglossal nucleus received bilateral input from the face/head region of the primary (M1), ventrolateral pre- (LPMCv), supplementary (M2), rostral cingulate (M3), and caudal cingulate (M4) motor cortices. Additional bilateral corticohypoglossal projections were found from the dorsolateral premotor cortex (LPMCd), ventrolateral proisocortical motor area (ProM), ventrolateral primary somatosensory cortex (S1), rostral insula and pregenual region of the anterior cingulate gyrus (areas 24/32). Dense terminal projections arose from the ventral region of M1, moderate projections from LPMCv and rostral part of M2, with considerably less hypoglossal projections arising from the other cortical regions. These findings demonstrate that extensive regions of the non-human primate cerebral cortex innervate the hypoglossal nucleus. The widespread and bilateral nature of this corticobulbar connection suggests recovery of tongue movement after cortical injury that compromises a subset of these areas, may occur from spared corticohypoglossal projection areas located on the lateral, as well as medial surfaces of both hemispheres. Since functional imaging studies have shown that homologous cortical areas are activated in humans during tongue movement tasks, these corticobulbar projections may exist in the human brain. PMID:24752643

  18. Formation of tRNA granules in the nucleus of heat-induced human cells

    SciTech Connect

    Miyagawa, Ryu; Mizuno, Rie; Watanabe, Kazunori; Ijiri, Kenichi

    2012-02-03

    Highlights: Black-Right-Pointing-Pointer tRNAs are tranlocated into the nucleus in heat-induced HeLa cells. Black-Right-Pointing-Pointer tRNAs form the unique granules in the nucleus. Black-Right-Pointing-Pointer tRNA ganules overlap with nuclear stress granules. -- Abstract: The stress response, which can trigger various physiological phenomena, is important for living organisms. For instance, a number of stress-induced granules such as P-body and stress granule have been identified. These granules are formed in the cytoplasm under stress conditions and are associated with translational inhibition and mRNA decay. In the nucleus, there is a focus named nuclear stress body (nSB) that distinguishes these structures from cytoplasmic stress granules. Many splicing factors and long non-coding RNA species localize in nSBs as a result of stress. Indeed, tRNAs respond to several kinds of stress such as heat, oxidation or starvation. Although nuclear accumulation of tRNAs occurs in starved Saccharomyces cerevisiae, this phenomenon is not found in mammalian cells. We observed that initiator tRNA{sup Met} (Meti) is actively translocated into the nucleus of human cells under heat stress. During this study, we identified unique granules of Meti that overlapped with nSBs. Similarly, elongator tRNA{sup Met} was translocated into the nucleus and formed granules during heat stress. Formation of tRNA granules is closely related to the translocation ratio. Then, all tRNAs may form the specific granules.

  19. Compartmental organization of the peptide network in the human caudate nucleus.

    PubMed

    Manley, M S; Young, S J; Groves, P M

    1994-08-01

    The mammalian striatum may be divided into a striosomal compartment and a surrounding matrix region. We have examined the distribution of leucine enkephalin (LENK) and substance P (SP) immunoreactivity in relation to striosomes defined by calbindin-D (CABD) staining in alternate 70 microns serial sections from the human caudate nucleus. The distribution of LENK immunoreactivity showed a transition from dorsal to ventral striatum: dorsally, LENK-rich patches were present in a lightly stained matrix; mid-ventrally, annular patches of LENK staining with a lighter core were seen. These patches corresponded to striosomal regions defined by CABD-poor zones. In contrast, in the ventral caudate and nucleus accumbens, LENK-poor zones matched CABD-defined striosomes. CABD staining in the matrix was intense in the dorsal caudate, diminishing ventrally. SP-rich zones in dorsal caudate and SP-poor areas in the mid-ventral region overlapped striosomes. In the ventromedial sector, the SP staining pattern was complex and did not consistently correlate with striosomes. Computer-assisted three-dimensional reconstruction of the striosomal system in the human, based on regions of either high LENK or low CABD immunoreactivity, revealed the existence of considerable long-range order. Patches appeared aligned over several millimeters to form long, horizontal structures in the caudate nucleus, with occasional orthogonal interconnecting crossbridges. Our results are in accord with previous work in the human and in other species. These three-dimensional networks are strikingly similar across individuals and may relate to the segregation of and interactions between striatal circuits. PMID:7531455

  20. Perturbation of nucleo-cytoplasmic transport affects size of nucleus and nucleolus in human cells.

    PubMed

    Ganguly, Abira; Bhattacharjee, Chumki; Bhave, Madhura; Kailaje, Vaishali; Jain, Bhawik K; Sengupta, Isha; Rangarajan, Annapoorni; Bhattacharyya, Dibyendu

    2016-03-01

    Size regulation of human cell nucleus and nucleolus are poorly understood subjects. 3D reconstruction of live image shows that the karyoplasmic ratio (KR) increases by 30-80% in transformed cell lines compared to their immortalized counterpart. The attenuation of nucleo-cytoplasmic transport causes the KR value to increase by 30-50% in immortalized cell lines. Nucleolus volumes are significantly increased in transformed cell lines and the attenuation of nucleo-cytoplasmic transport causes a significant increase in the nucleolus volume of immortalized cell lines. A cytosol and nuclear fraction swapping experiment emphasizes the potential role of unknown cytosolic factors in nuclear and nucleolar size regulation. PMID:26813731

  1. The sexually dimorphic nucleus of the preoptic area in the human brain: a comparative morphometric study.

    PubMed Central

    Hofman, M A; Swaab, D F

    1989-01-01

    The sexually dimorphic nucleus of the preoptic area (SDN-POA) in the human hypothalamus is an ovoid, densely packed collection of large cells. The size, shape and cellular morphology of the SDN-POA was examined in relation to sex and age in adult human subjects. In this region the following parameters were measured: length of the rostrocaudal axis, maximum cross-sectional area, volume, numerical cell density, total number of cells, and the diameter of the cell nucleus. The SDN-POA was elongated in females and more spherical in males. The mean volume and total cell number were markedly sexually dimorphic: the volume of the SDN-POA was 2.2 times as large in males as in females and contained 2.1 times as many cells. No sex differences were observed in either cell density or mean diameter of the cell nuclei. Furthermore, multivariate regression analysis revealed that there are also sex-linked differences in the structural organisation of the human SDN-POA, finding expression in the way the morphometric parameters are interrelated. Of the parameters measured, only the volume and cell number of the SDN-POA showed a dramatic decrease with ageing. The reduction in cell number, however, was not constant throughout adulthood but was found to depend upon sex and age. In males, a major reduction in SDN-POA cell number was observed between the age of 50-60 years. In females, cell death was found to be more prominent than in males, especially among old people (t greater than 70 years), dropping to values which were only 10-15% of the cell number found in early childhood. In conclusion, the human SDN-POA has a sex-dependent pattern of ageing. Finally, the morphology of the SDN-POA was compared with that of other hypothalamic regions--the suprachiasmatic nucleus (SCN) and the paraventricular nucleus (PVN)--both in man and in rat. Species-specific differences in the dimensions of these nuclear regions are discussed in the light of their assumed functional significance. PMID:2606795

  2. Behavior modification after inactivation of cerebellar dentate nuclei.

    PubMed

    Peterson, Todd C; Villatoro, Lee; Arneson, Tom; Ahuja, Brittany; Voss, Stephanie; Swain, Rodney A

    2012-08-01

    Effort-based decision making occurs when subjects are given a choice between a reward available at a high response cost and a reward available at a low response cost and is altered in individuals with disorders such as autism or particular patterns of brain injury. The current study explored the relationship between effort-based decision making and reinforcement characteristics in the T maze. This was done using both normal animals and animals with bilateral inactivation of the cerebellar dentate nuclei. Rats chose between alternatives in which one arm contained high-density reinforcement (HR) and the other arm contained low-density reinforcement (LR). During training, the HR arm was obstructed and the point at which the animal no longer worked for reinforcement (breaking point) was determined. The cerebellar dentate nuclei were then transiently inactivated and once again breaking points were assessed. The results indicated that inactivation of the dentate nucleus disrupted effort-based decision making. Additionally, altering both the palatability and the magnitude of the reinforcement were assessed in an attempt to reestablish the original preinactivation breaking point. It was hypothesized that an increase in the strength or magnitude of the reinforcement would promote an increase in the breaking point of the animal even when the cerebellum was inactivated. The results indicated that with both strategies animals effectively reestablished original breaking points. The results of this study will inform the current literature regarding the modification of behavior after brain injury and further the understanding of the behavioral deficits associated with cerebellar dysfunction. PMID:22845704

  3. Insulin receptor substrate 1 translocation to the nucleus by the human JC virus T-antigen.

    PubMed

    Lassak, Adam; Del Valle, Luis; Peruzzi, Francesca; Wang, Jin Ying; Enam, Sahnila; Croul, Sidney; Khalili, Kamel; Reiss, Krzysztof

    2002-05-10

    Insulin receptor substrate 1 (IRS-1) is the major signaling molecule for the insulin and insulin-like growth factor I receptors, which transduces both metabolic and growth-promoting signals, and has transforming properties when overexpressed in the cells. Here we show that IRS-1 is translocated to the nucleus in the presence of the early viral protein-T-antigen of the human polyomavirus JC. Nuclear IRS-1 was detected in T-antigen-positive cell lines and in T-antigen-positive biopsies from patients diagnosed with medulloblastoma. The IRS-1 domain responsible for a direct JC virus T-antigen binding was localized within the N-terminal portion of IRS-1 molecule, and the binding was independent from IRS-1 tyrosine phosphorylation and was strongly inhibited by IRS-1 serine phosphorylation. In addition, competition for the IRS-1-T-antigen binding by a dominant negative mutant of IRS-1 inhibited growth and survival of JC virus T-antigen-transformed cells in anchorage-independent culture conditions. Based on these findings, we propose a novel role for the IRS-1-T-antigen complex in controlling cellular equilibrium during viral infection. It may involve uncoupling of IRS-1 from its surface receptor and translocation of its function to the nucleus. PMID:11877394

  4. Human Cytomegalovirus IE1 Protein Disrupts Interleukin-6 Signaling by Sequestering STAT3 in the Nucleus

    PubMed Central

    Reitsma, Justin M.; Sato, Hiromi; Nevels, Michael

    2013-01-01

    In the canonical STAT3 signaling pathway, binding of agonist to receptors activates Janus kinases that phosphorylate cytoplasmic STAT3 at tyrosine 705 (Y705). Phosphorylated STAT3 dimers accumulate in the nucleus and drive the expression of genes involved in inflammation, angiogenesis, invasion, and proliferation. Here, we demonstrate that human cytomegalovirus (HCMV) infection rapidly promotes nuclear localization of STAT3 in the absence of robust phosphorylation at Y705. Furthermore, infection disrupts interleukin-6 (IL-6)-induced phosphorylation of STAT3 and expression of a subset of IL-6-induced STAT3-regulated genes, including SOCS3. We show that the HCMV 72-kDa immediate-early 1 (IE1) protein associates with STAT3 and is necessary to localize STAT3 to the nucleus during infection. Furthermore, expression of IE1 is sufficient to disrupt IL-6-induced phosphorylation of STAT3, binding of STAT3 to the SOCS3 promoter, and SOCS3 gene expression. Finally, inhibition of STAT3 nuclear localization or STAT3 expression during infection is linked to diminished HCMV genome replication. Viral gene expression is also disrupted, with the greatest impact seen following viral DNA synthesis. Our study identifies IE1 as a new regulator of STAT3 intracellular localization and IL-6 signaling and points to an unanticipated role of STAT3 in HCMV infection. PMID:23903834

  5. Color responses and their adaptation in human superior colliculus and lateral geniculate nucleus.

    PubMed

    Chang, Dorita H F; Hess, Robert F; Mullen, Kathy T

    2016-09-01

    We use an fMRI adaptation paradigm to explore the selectivity of human responses in the lateral geniculate nucleus (LGN) and superior colliculus (SC) to red-green color and achromatic contrast. We measured responses to red-green (RG) and achromatic (ACH) high contrast sinewave counter-phasing rings with and without adaptation, within a block design. The signal for the RG test stimulus was reduced following both RG and ACH adaptation, whereas the signal for the ACH test was unaffected by either adaptor. These results provide compelling evidence that the human LGN and SC have significant capacity for color adaptation. Since in the LGN red-green responses are mediated by P cells, these findings are in contrast to earlier neurophysiological data from non-human primates that have shown weak or no contrast adaptation in the P pathway. Cross-adaptation of the red-green color response by achromatic contrast suggests unselective response adaptation and points to a dual role for P cells in responding to both color and achromatic contrast. We further show that subcortical adaptation is not restricted to the geniculostriate system, but is also present in the superior colliculus (SC), an oculomotor region that until recently, has been thought to be color-blind. Our data show that the human SC not only responds to red-green color contrast, but like the LGN, shows reliable but unselective adaptation. PMID:27150230

  6. Directed Communication between Nucleus Accumbens and Neocortex in Humans Is Differentially Supported by Synchronization in the Theta and Alpha Band

    PubMed Central

    Horschig, Jörn M.; Smolders, Ruud; Bonnefond, Mathilde; Schoffelen, Jan-Mathijs; van den Munckhof, Pepijn; Schuurman, P. Richard; Cools, Roshan; Denys, Damiaan; Jensen, Ole

    2015-01-01

    Here, we report evidence for oscillatory bi-directional interactions between the nucleus accumbens and the neocortex in humans. Six patients performed a demanding covert visual attention task while we simultaneously recorded brain activity from deep-brain electrodes implanted in the nucleus accumbens and the surface electroencephalogram (EEG). Both theta and alpha oscillations were strongly coherent with the frontal and parietal EEG during the task. Theta-band coherence increased during processing of the visual stimuli. Granger causality analysis revealed that the nucleus accumbens was communicating with the neocortex primarily in the theta-band, while the cortex was communicating the nucleus accumbens in the alpha-band. These data are consistent with a model, in which theta- and alpha-band oscillations serve dissociable roles: Prior to stimulus processing, the cortex might suppress ongoing processing in the nucleus accumbens by modulating alpha-band activity. Subsequently, upon stimulus presentation, theta oscillations might facilitate the active exchange of stimulus information from the nucleus accumbens to the cortex. PMID:26394404

  7. Chondroprotective supplementation promotes the mechanical properties of injectable scaffold for human nucleus pulposus tissue engineering.

    PubMed

    Foss, Berit L; Maxwell, Thomas W; Deng, Ying

    2014-01-01

    A result of intervertebral disc (IVD) degeneration, the nucleus pulposus (NP) is no longer able to withstand applied load leading to pain and disability. The objective of this study is to fabricate a tissue-engineered injectable scaffold with chondroprotective supplementation in vitro to improve the mechanical properties of a degenerative NP. Tissue-engineered scaffolds were fabricated using different concentrations of alginate and calcium chloride and mechanically evaluated. Fabrication conditions were based on structural and mechanical resemblance to the native NP. Chondroprotective supplementation, glucosamine (GCSN) and chondroitin sulfate (CS), were added to scaffolds at concentrations of 0:0µg/mL (0:0-S), 125:100µg/mL (125:100-S), 250:200µg/mL (250:200-S), and 500:400µg/mL (500:400-S), GCSN and CS, respectively. Scaffolds were used to fabricate tissue-engineered constructs through encapsulation of human nucleus pulposus cells (HNPCs). The tissue-engineered constructs were collected at days 1, 14, and 28 for biochemical and biomechanical evaluations. Confocal microscopy showed HNPC viability and rounded morphology over the 28 day period. MTT analysis resulted in significant increases in cell proliferation for each group. Collagen type II ELISA quantification and compressive aggregate moduli (HA) showed increasing trends for both 250:200-S and the 500:400-S groups on Day 28 with significantly greater HA compared to 0:0-S group. Glycosaminoglycan and water content decreased for all groups. Results indicate the increased mechanical properties of the 250:200-S and the 500:400-S was due to production of a functional matrix. This study demonstrated potential for a chondroprotective supplemented injectable scaffold to restore biomechanical function of a degenerative disc through the production of a mechanically functional matrix. PMID:24055794

  8. Type 1 IGF receptor translocates to the nucleus of human tumor cells

    PubMed Central

    Aleksic, Tamara; Chitnis, Meenali M.; Perestenko, Olga V.; Gao, Shan; Thomas, Peter H.; Turner, Gareth D.; Protheroe, Andrew S.; Howarth, Mark; Macaulay, Valentine M.

    2010-01-01

    The type 1 insulin-like growth factor receptor (IGF-1R) is a transmembrane glycoprotein comprising two extracellular α subunits and two β subunits with tyrosine kinase activity. The IGF-1R is frequently upregulated in cancers, and signals from the cell surface to promote proliferation and cell survival. Recent attention has focused on the IGF-1R as a target for cancer treatment. Here we report that the nuclei of human tumor cells contain IGF-1R, detectable using multiple antibodies to α- and β- subunit domains. Cell surface IGF-1R translocates to the nucleus following clathrin-mediated endocytosis, regulated by IGF levels. The IGF-1R is unusual among transmembrane receptors that undergo nuclear import, in that both α and β subunits traffic to the nucleus. Nuclear IGF-1R is phosphorylated in response to ligand, and undergoes IGF-induced interaction with chromatin, suggesting direct engagement in transcriptional regulation. The IGF-dependence of these phenomena indicate a requirement for the receptor kinase, and indeed IGF-1R nuclear import and chromatin binding can be blocked by a novel IGF-1R kinase inhibitor. Nuclear IGF-1R is detectable in primary renal cancer cells, formalin-fixed tumors, preinvasive lesions in the breast, and non-malignant tissues characterized by a high proliferation rate. In clear cell renal cancer, nuclear IGF-1R is associated with adverse prognosis. Our findings suggest that IGF-1R nuclear import has biological significance, may contribute directly to IGF-1R function, and may influence the efficacy of IGF-1R inhibitory drugs. PMID:20710042

  9. Measurement of the Nucleus Area and Nucleus/Cytoplasm and Mitochondria/Nucleus Ratios in Human Colon Tissues by Dual-Colour Two-Photon Microscopy Imaging

    PubMed Central

    Su Lim, Chang; Sun Kim, Eun; Yeon Kim, Ji; Taek Hong, Seung; Jai Chun, Hoon; Eun Kang, Dong; Rae Cho, Bong

    2015-01-01

    We developed two-photon (TP) probes for DNA (ABI-Nu), cytoplasm (Pyr-CT), and mitochondria (BF-MT). We found that ABI-Nu binds to AT in the minor groove, while ABI-Nu and BF-MT are effective for tracking in the cytoplasm and mitochondria, respectively. These probes showed very large effective two-photon action cross section values of 2230, 1555, and 790 Göppert-Mayer units (1 GM  =  10−50 cm4 s photon−1molecule−1) at 740 nm with emission maxima at 473, 561, and 560 nm, respectively, in each organelle. Using these probes, we quantitatively estimated the mean nuclear area and the ratios of nuclei to cytoplasm and mitochondria to nuclei in human colon tissues by dual-colour two-photon microscopy imaging within 2  h after biopsy. The mean nuclear area and the nuclei to cytoplasm and mitochondria to cytoplasm ratios increased in the following order: normal colon mucosa

  10. Ultra-High Field MRI Post Mortem Structural Connectivity of the Human Subthalamic Nucleus, Substantia Nigra, and Globus Pallidus

    PubMed Central

    Plantinga, Birgit R.; Roebroeck, Alard; Kemper, Valentin G.; Uludağ, Kâmil; Melse, Maartje; Mai, Jürgen; Kuijf, Mark L.; Herrler, Andreas; Jahanshahi, Ali; ter Haar Romeny, Bart M.; Temel, Yasin

    2016-01-01

    Introduction: The subthalamic nucleus, substantia nigra, and globus pallidus, three nuclei of the human basal ganglia, play an important role in motor, associative, and limbic processing. The network of the basal ganglia is generally characterized by a direct, indirect, and hyperdirect pathway. This study aims to investigate the mesoscopic nature of these connections between the subthalamic nucleus, substantia nigra, and globus pallidus and their surrounding structures. Methods: A human post mortem brain specimen including the substantia nigra, subthalamic nucleus, and globus pallidus was scanned on a 7 T MRI scanner. High resolution diffusion weighted images were used to reconstruct the fibers intersecting the substantia nigra, subthalamic nucleus, and globus pallidus. The course and density of these tracks was analyzed. Results: Most of the commonly established projections of the subthalamic nucleus, substantia nigra, and globus pallidus were successfully reconstructed. However, some of the reconstructed fiber tracks such as the connections of the substantia nigra pars compacta to the other included nuclei and the connections with the anterior commissure have not been shown previously. In addition, the quantitative tractography approach showed a typical degree of connectivity previously not documented. An example is the relatively larger projections of the subthalamic nucleus to the substantia nigra pars reticulata when compared to the projections to the globus pallidus internus. Discussion: This study shows that ultra-high field post mortem tractography allows for detailed 3D reconstruction of the projections of deep brain structures in humans. Although the results should be interpreted carefully, the newly identified connections contribute to our understanding of the basal ganglia. PMID:27378864

  11. Proliferation-dependent positioning of individual centromeres in the interphase nucleus of human lymphoblastoid cell lines

    PubMed Central

    Ollion, Jean; Loll, François; Cochennec, Julien; Boudier, Thomas; Escudé, Christophe

    2015-01-01

    The cell nucleus is a highly organized structure and plays an important role in gene regulation. Understanding the mechanisms that sustain this organization is therefore essential for understanding genome function. Centromeric regions (CRs) of chromosomes have been known for years to adopt specific nuclear positioning patterns, but the significance of this observation is not yet completely understood. Here, using a combination of fluorescence in situ hybridization and immunochemistry on fixed human cells and high-throughput imaging, we directly and quantitatively investigated the nuclear positioning of specific human CRs. We observe differential attraction of individual CRs toward both the nuclear border and the nucleoli, the former being enhanced in nonproliferating cells and the latter being enhanced in proliferating cells. Similar positioning patterns are observed in two different lymphoblastoid cell lines. Moreover, the positioning of CRs differs from that of noncentromeric regions, and CRs display specific orientations within chromosome territories. These results suggest the existence of not-yet-characterized mechanisms that drive the nuclear positioning of CRs and therefore pave the way toward a better understanding of how CRs affect nuclear organization. PMID:25947134

  12. Expression of soluble Fas and soluble FasL in human nucleus pulposus cells.

    PubMed

    Sun, Zhen; Wan, Zhong-Yuan; Liu, Zhi-Heng; Guo, Yun-Shan; Yin, Jun-Bin; Duan, Chun-Guang; Gao, Yang; Li, Tao; Wang, Hai-Qiang; Luo, Zhuo-Jing

    2013-01-01

    The study aimed for addressing the expression of soluble Fas (sFas) and soluble Fas Ligand (sFasL) in human nucleus pulposus (NP) and its attendant relationship with disc degeneration. Human NP samples were collected from patients with disc degeneration and cadavers as degenerate and normal groups, respectively. Subsequently, NP cells were cultured in monolayer. ELISA was performed to identify the expression levels of sFas and sFasL in the supernatant of NP cell cultures in vitro. Quantitative real-time PCR was used to detect the expression of sFas and sFasL in human NP cells in mRNA solution. The study comprised 12 degenerate and 8 normal cadaveric NP samples. The concentration value of sFas in the supernatant was significantly higher from degenerate NP than that from normal NP at each time point. In contrast, sFasL was significantly lower at each time point. Moreover, the expression of sFas and sFasL reached the peak at various early stages of cell cultures and decreased thereafter. Furthermore, the mRNA level of Fas in degenerate NP cells was significantly higher than that in normal cells; whereas FasL showed an opposite pattern. The study is the first addressing the expression of sFas and sFasL in human NP cell cultures. Moreover, the expression of sFas and sFasL varies with culture time in vitro with different levels in degenerate and normal settings. These findings indicate that sFas and sFasL might play a role in intervertebral disc degeneration. PMID:23923075

  13. Injectable hydrogel provides growth-permissive environment for human nucleus pulposus cells.

    PubMed

    Priyadarshani, Priyanka; Li, Yongchao; Yang, ShangYou; Yao, Li

    2016-02-01

    Degeneration of intervertebral discs (IVDs) results in an overall alteration of the biomechanics of the spinal column and becomes a major cause of low back pain. In this study, an injectable hydrogel composite is fabricated and characterized as a potential scaffold for the treatment of degenerated IVDs. Crosslinking of type II collagen-hyaluronic acid (HA) hydrogel with 1-ethyl-3(3-dimethyl aminopropyl) carbodiimide (EDC) increases the gel stability against collagenase digestion and reduces water uptake in comparison with non-crosslinked gel. Cell viability assay exhibits the proliferation of human nucleus pulposus (HNP) cells in hydrogels. The cells in non-crosslinked gel and the gel crosslinked with a low concentration of EDC (0.1 mM) show superior cell viability and morphology compared with cells in gels crosslinked with higher concentration of EDC. Quantitative PCR assay demonstrates the gene expression of extracellular matrix (ECM) by cells cultured in the gels. The expression of ECM genes by HNP cells in the gels demonstrated the phenotypic change of the cells. This study suggests that the type II collagen-HA hydrogel and crosslinked hydrogel (0.1 mM EDC) are permissive matrix for the growth of HNP cells and can be potentially applied in NP repair. PMID:26422588

  14. Mechanical behavior of the human lumbar intervertebral disc with polymeric hydrogel nucleus implant: An experimental and finite element study

    NASA Astrophysics Data System (ADS)

    Joshi, Abhijeet Bhaskar

    The origin of the lower back pain is often the degenerated lumbar intervertebral disc (IVD). We are proposing replacement of the degenerated nucleus by a PVA/PVP polymeric hydrogel implant. We hypothesize that a polymeric hydrogel nucleus implant can restore the normal biomechanics of the denucleated IVD by mimicking the natural load transfer phenomenon as in case of the intact IVD. Lumbar IVDs (n = 15) were harvested from human cadavers. In the first part, specimens were tested in four different conditions for compression: Intact, bone in plug, denucleated and Implanted. Hydrogel nucleus implants were chosen to have line-to-line fit in the created nuclear cavity. In the second part, nucleus implant material (modulus) and geometric (height and diameter) parameters were varied and specimens (n = 9) were tested. Nucleus implants with line-to-line fit significantly restored (88%) the compressive stiffness of the denucleated IVD. The synergistic effect between the implant and the intact annulus resulted in the nonlinear increase in implanted IVD stiffness, where Poisson effect of the hydrogel played major role. Nucleus implant parameters were observed to have a significant effect on the compressive stiffness. All implants with modulus in the tested range restored the compressive stiffness. The undersize implants resulted in incomplete restoration while oversize implants resulted in complete restoration compared to the BI condition. Finite element models (FEM) were developed to simulate the actual test conditions and validated against the experimental results for all conditions. The annulus (defined as hyperelastic, isotropic) mainly determined the nonlinear response of the IVD. Validated FEMs predicted 120--3000 kPa as a feasible range for nucleus implant modulus. FEMs also predicted that overdiameter implant would be more effective than overheight implant in terms of stiffness restoration. Underdiameter implants, initially allowed inward deformation of the annulus and

  15. Subcellular Microanatomy by 3D Deconvolution Brightfield Microscopy: Method and Analysis Using Human Chromatin in the Interphase Nucleus

    PubMed Central

    Tadrous, Paul Joseph

    2012-01-01

    Anatomy has advanced using 3-dimensional (3D) studies at macroscopic (e.g., dissection, injection moulding of vessels, radiology) and microscopic (e.g., serial section reconstruction with light and electron microscopy) levels. This paper presents the first results in human cells of a new method of subcellular 3D brightfield microscopy. Unlike traditional 3D deconvolution and confocal techniques, this method is suitable for general application to brightfield microscopy. Unlike brightfield serial sectioning it has subcellular resolution. Results are presented of the 3D structure of chromatin in the interphase nucleus of two human cell types, hepatocyte and plasma cell. I show how the freedom to examine these structures in 3D allows greater morphological discrimination between and within cell types and the 3D structural basis for the classical “clock-face” motif of the plasma cell nucleus is revealed. Potential for further applications discussed. PMID:22567315

  16. Inflammatory Kinetics and Efficacy of Anti-inflammatory Treatments on Human Nucleus Pulposus Cells

    PubMed Central

    Walter, Benjamin A; Purmessur, Devina; Likhitpanichkul, Morakot; Weinberg, Alan; Cho, Samuel K.; Qureshi, Sheeraz A.; Hecht, Andrew C.; Iatridis, James C.

    2015-01-01

    Study Design Human nucleus pulposus (NP) cell culture study investigating response to tumor necrosis factor-α (TNFα), effectiveness of clinically available anti-inflammatory drugs, and interactions between pro-inflammatory cytokines. Objective To characterize the kinetic response of pro-inflammatory cytokines released by human NP cells to TNFα stimulation and the effectiveness of multiple anti-inflammatories with 3 sub-studies: Timecourse, Same-time blocking, Delayed blocking. Summary of Background Data Chronic inflammation is a key component of painful intervertebral disc (IVD) degeneration. Improved efficacy of anti-inflammatories requires better understanding of how quickly NP cells produce pro-inflammatory cytokines and which pro-inflammatory mediators are most therapeutically advantageous to target. Methods Degenerated human NP cells (n=10) were cultured in alginate with or without TNFα (10ng/mL). Cells were incubated with one of four anti-inflammatories (anti-IL-6 receptor/atlizumab, IL-1 receptor anatagonist, anti-TNFα/infliximab and sodium pentosan polysulfate/PPS) in two blocking-studies designed to determine how intervention timing influences drug efficacy. Cell viability, protein and gene expression for IL-1β, IL-6 & IL-8 were assessed. Results Timecourse: TNFα substantially increased the amount of IL-6, IL-8 & IL-1β, with IL-1β and IL-8 reaching equilibrium within ~72 hours (IL-1β: 111±40pg/mL, IL-8: 8478±957pg/mL), and IL-6 not reaching steady state after 144 hours (1570±435 pg/mL). Anti-TNFα treatment was most effective at reducing the expression of all cytokines measured when added at the same time as TNFα stimulation. Similar trends were observed when drugs were added 72 hours after TNFα stimulation, however, no anti-inflammatories significantly reduced cytokine levels compared to TNF control. Conclusion IL-1β, IL-6 and IL-8 were expressed at different rates and magnitudes suggesting different roles for these cytokines in disease

  17. Subthalamic nucleus long-range synchronization—an independent hallmark of human Parkinson's disease

    PubMed Central

    Moshel, Shay; Shamir, Reuben R.; Raz, Aeyal; de Noriega, Fernando R.; Eitan, Renana; Bergman, Hagai; Israel, Zvi

    2013-01-01

    Beta-band synchronous oscillations in the dorsolateral region of the subthalamic nucleus (STN) of human patients with Parkinson's disease (PD) have been frequently reported. However, the correlation between STN oscillations and synchronization has not been thoroughly explored. The simultaneous recordings of 2390 multi-unit pairs recorded by two parallel microelectrodes (separated by fixed distance of 2 mm, n = 72 trajectories with two electrode tracks >4 mm STN span) in 57 PD patients undergoing STN deep brain stimulation surgery were analyzed. Automatic procedures were utilized to divide the STN into dorsolateral oscillatory and ventromedial non-oscillatory regions, and to quantify the intensity of STN oscillations and synchronicity. Finally, the synchronicity of simultaneously vs. non-simultaneously recorded pairs were compared using a shuffling procedure. Synchronization was observed predominately in the beta range and only between multi-unit pairs in the dorsolateral oscillatory region (n = 615). In paired recordings between sites in the dorsolateral and ventromedial (n = 548) and ventromedial-ventromedial region pairs (n = 1227), no synchronization was observed. Oscillation and synchronicity intensity decline along the STN dorsolateral-ventromedial axis suggesting a fuzzy border between the STN regions. Synchronization strength was significantly correlated to the oscillation power, but synchronization was no longer observed following shuffling. We conclude that STN long-range beta oscillatory synchronization is due to increased neuronal coupling in the Parkinsonian brain and does not merely reflect the outcome of oscillations at similar frequency. The neural synchronization in the dorsolateral (probably the motor domain) STN probably augments the pathological changes in firing rate and patterns of subthalamic neurons in PD patients. PMID:24312018

  18. Confirmation of functional zones within the human subthalamic nucleus: Patterns of connectivity and sub-parcellation using diffusion weighted imaging

    PubMed Central

    Lambert, Christian; Zrinzo, Ludvic; Nagy, Zoltan; Lutti, Antoine; Hariz, Marwan; Foltynie, Thomas; Draganski, Bogdan; Ashburner, John; Frackowiak, Richard

    2012-01-01

    The subthalamic nucleus (STN) is a small, glutamatergic nucleus situated in the diencephalon. A critical component of normal motor function, it has become a key target for deep brain stimulation in the treatment of Parkinson's disease. Animal studies have demonstrated the existence of three functional sub-zones but these have never been shown conclusively in humans. In this work, a data driven method with diffusion weighted imaging demonstrated that three distinct clusters exist within the human STN based on brain connectivity profiles. The STN was successfully sub-parcellated into these regions, demonstrating good correspondence with that described in the animal literature. The local connectivity of each sub-region supported the hypothesis of bilateral limbic, associative and motor regions occupying the anterior, mid and posterior portions of the nucleus respectively. This study is the first to achieve in-vivo, non-invasive anatomical parcellation of the human STN into three anatomical zones within normal diagnostic scan times, which has important future implications for deep brain stimulation surgery. PMID:22173294

  19. Role of Dentate Gyrus in Aligning Internal Spatial Map to External Landmark

    ERIC Educational Resources Information Center

    Lee, Jong Won; Kim, Woon Ryoung; Sun, Woong; Jung, Min Whan

    2009-01-01

    Humans and animals form internal representations of external space based on their own body movement (dead reckoning) as well as external landmarks. It is poorly understood, however, how different types of information are integrated to form a unified representation of external space. To examine the role of dentate gyrus (DG) in this process, we…

  20. Good Vibrations: Cross-Frequency Coupling in the Human Nucleus Accumbens during Reward Processing

    ERIC Educational Resources Information Center

    Cohen, Michael X.; Axmacher, Nikolai; Lenartz, Doris; Elger, Christian E.; Sturm, Volker; Schlaepfer, Thomas E.

    2009-01-01

    The nucleus accumbens is critical for reward-guided learning and decision-making. It is thought to "gate" the flow of a diverse range of information (e.g., rewarding, aversive, and novel events) from limbic afferents to basal ganglia outputs. Gating and information encoding may be achieved via cross-frequency coupling, in which bursts of…

  1. miR-21 promotes human nucleus pulposus cell proliferation through PTEN/AKT signaling.

    PubMed

    Liu, Hongzhe; Huang, Xiangwang; Liu, Xiangyang; Xiao, Sheng; Zhang, Yi; Xiang, Tiecheng; Shen, Xiongjie; Wang, Guoping; Sheng, Bin

    2014-01-01

    The precise role of nucleus pulposus cell proliferation in the pathogenesis of intervertebral disc degeneration remains to be elucidated. Recent findings have revealed that microRNAs, a class of small noncoding RNAs, may regulate cell proliferation in many pathological conditions. Here, we showed that miR-21 was significantly upregulated in degenerative nucleus pulposus tissues when compared with nucleus pulposus tissues that were isolated from patients with idiopathic scoliosis and that miR-10b levels were associated with disc degeneration grade. Moreover, bioinformatics target prediction identified PTEN as a putative target of miR-21. miR-21 inhibited PTEN expression by directly targeting the 3'UTR, and this inhibition was abolished through miR-21 binding site mutations. miR-21 overexpression stimulated cell proliferation and AKT signaling pathway activation, which led to cyclin D1 translation. Additionally, the increase in proliferation and cyclin D1 expression induced by miR-21 overexpression was almost completely blocked by Ly294002, an AKT inhibitor. Taken together, aberrant miR-21 upregulation in intervertebral disc degeneration could target PTEN, which would contribute to abnormal nucleus pulposus cell proliferation through derepressing the Akt pathway. Our study also underscores the potential of miR-21 and the PTEN/Akt pathway as novel therapeutic targets in intervertebral disc degeneration. PMID:24603539

  2. miR-21 Promotes Human Nucleus Pulposus Cell Proliferation through PTEN/AKT Signaling

    PubMed Central

    Liu, Hongzhe; Huang, Xiangwang; Liu, Xiangyang; Xiao, Sheng; Zhang, Yi; Xiang, Tiecheng; Shen, Xiongjie; Wang, Guoping; Sheng, Bin

    2014-01-01

    The precise role of nucleus pulposus cell proliferation in the pathogenesis of intervertebral disc degeneration remains to be elucidated. Recent findings have revealed that microRNAs, a class of small noncoding RNAs, may regulate cell proliferation in many pathological conditions. Here, we showed that miR-21 was significantly upregulated in degenerative nucleus pulposus tissues when compared with nucleus pulposus tissues that were isolated from patients with idiopathic scoliosis and that miR-10b levels were associated with disc degeneration grade. Moreover, bioinformatics target prediction identified PTEN as a putative target of miR-21. miR-21 inhibited PTEN expression by directly targeting the 3′UTR, and this inhibition was abolished through miR-21 binding site mutations. miR-21 overexpression stimulated cell proliferation and AKT signaling pathway activation, which led to cyclin D1 translation. Additionally, the increase in proliferation and cyclin D1 expression induced by miR-21 overexpression was almost completely blocked by Ly294002, an AKT inhibitor. Taken together, aberrant miR-21 upregulation in intervertebral disc degeneration could target PTEN, which would contribute to abnormal nucleus pulposus cell proliferation through derepressing the Akt pathway. Our study also underscores the potential of miR-21 and the PTEN/Akt pathway as novel therapeutic targets in intervertebral disc degeneration. PMID:24603539

  3. Cocaine-induced alterations in nucleus accumbens ionotropic glutamate receptor subunits in human and non-human primates.

    PubMed

    Hemby, Scott E; Tang, Wenxue; Muly, Emil C; Kuhar, Michael J; Howell, Leonard; Mash, Deborah C

    2005-12-01

    Chronic cocaine and withdrawal induce significant alterations in nucleus accumbens (NAc) glutamatergic function in humans and rodent models of cocaine addiction. Dysregulation of glutamatergic function of the prefrontal cortical-NAc pathway has been proposed as a critical substrate for unmanageable drug seeking. Previously, we demonstrated significant up-regulation of NMDA, (+/-)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptor subunit mRNAs and protein levels in the ventral tegmental area (VTA), but not the substantia nigra, of cocaine overdose victims (COD). The present study was undertaken to examine the extent of altered ionotropic glutamate receptor (iGluR) subunit expression in the NAc and the putamen in cocaine overdose victims. Results revealed statistically significant increases in the NAc, but not in the putamen, of NMDA receptor subunit (NR)1 and glutamate receptor subunit (GluR)2/3 wit trends in GluR1 and GluR5 in COD. These results extend our previous finding and indicate pathway-specific alterations in iGluRs in COD. In order to determine that changes were related to cocaine intake and not to other factors in the COD victims, we examined the effects of cocaine intravenous self-administration in rhesus monkeys for 18 months (unit dose of 0.1 mg/kg/injection and daily drug intake of 0.5 mg/kg/session). Total drug intake for the group of four monkeys was 37.9 +/- 4.6 mg/kg. Statistically significant elevations were observed for NR1, GluR1, GluR2/3 and GluR5 (p < 0.05) and a trend towards increased NR1 phosphorylated at serine 896 (p = 0.07) in the NAc but not putamen of monkeys self-administering cocaine compared with controls. These results extend previous results by demonstrating an up-regulation of NR1, GluR2/3 and GluR5 in the NAc and suggest these alterations are pathway specific. Furthermore, these changes may mediate persistent drug intake and craving in the human cocaine abuser. PMID:16363995

  4. Cocaine-induced alterations in nucleus accumbens ionotropic glutamate receptor subunits in human and non-human primates

    PubMed Central

    Hemby, Scott E.; Tang, Wenxue; Muly, Emil C.; Kuhar, Michael J.; Howell, Leonard; Mash, Deborah C.

    2013-01-01

    Chronic cocaine and withdrawal induce significant alterations in nucleus accumbens (NAc) glutamatergic function in humans and rodent models of cocaine addiction. Dysregulation of glutamatergic function of the prefrontal cortical–NAc pathway has been proposed as a critical substrate for unmanageable drug seeking. Previously, we demonstrated significant up-regulation of NMDA, (±)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptor subunit mRNAs and protein levels in the ventral tegmental area (VTA), but not the substantia nigra, of cocaine overdose victims (COD). The present study was undertaken to examine the extent of altered ionotropic glutamate receptor (iGluR) subunit expression in the NAc and the putamen in cocaine overdose victims. Results revealed statistically significant increases in the NAc, but not in the putamen, of NMDA receptor subunit (NR)1 and glutamate receptor subunit (GluR)2/3 wit trends in GluR1 and GluR5 in COD. These results extend our previous finding and indicate pathway-specific alterations in iGluRs in COD. In order to determine that changes were related to cocaine intake and not to other factors in the COD victims, we examined the effects of cocaine intravenous self-administration in rhesus monkeys for 18 months (unit dose of 0.1 mg/kg/injection and daily drug intake of 0.5 mg/kg/session). Total drug intake for the group of four monkeys was 37.9 ± 4.6 mg/kg. Statistically significant elevations were observed for NR1, GluR1, GluR2/3 and GluR5 (p < 0.05) and a trend towards increased NR1 phosphorylated at serine 896 (p = 0.07) in the NAc but not putamen of monkeys self-administering cocaine compared with controls. These results extend previous results by demonstrating an up-regulation of NR1, GluR2/3 and GluR5 in the NAc and suggest these alterations are pathway specific. Furthermore, these changes may mediate persistent drug intake and craving in the human cocaine abuser. PMID:16363995

  5. In vivo evaluation of the dentate gate theory in epilepsy

    PubMed Central

    Krook-Magnuson, Esther; Armstrong, Caren; Bui, Anh; Lew, Sean; Oijala, Mikko; Soltesz, Ivan

    2015-01-01

    The dentate gyrus is a region subject to intense study in epilepsy because of its posited role as a ‘gate’, acting to inhibit overexcitation in the hippocampal circuitry through its unique synaptic, cellular and network properties that result in relatively low excitability. Numerous changes predicted to produce dentate hyperexcitability are seen in epileptic patients and animal models. However, recent findings question whether changes are causative or reactive, as well as the pathophysiological relevance of the dentate in epilepsy. Critically, direct in vivo modulation of dentate ‘gate’ function during spontaneous seizure activity has not been explored. Therefore, using a mouse model of temporal lobe epilepsy with hippocampal sclerosis, a closed-loop system and selective optogenetic manipulation of granule cells during seizures, we directly tested the dentate ‘gate’ hypothesis in vivo. Consistent with the dentate gate theory, optogenetic gate restoration through granule cell hyperpolarization efficiently stopped spontaneous seizures. By contrast, optogenetic activation of granule cells exacerbated spontaneous seizures. Furthermore, activating granule cells in non-epileptic animals evoked acute seizures of increasing severity. These data indicate that the dentate gyrus is a critical node in the temporal lobe seizure network, and provide the first in vivo support for the dentate ‘gate’ hypothesis. Key points A key mechanistic concept in epilepsy is the dentate gate hypothesis, which argues that the dentate gyrus protects hippocampal circuits from overexcitation and that a breakdown of this gate leads to epilepsy. Direct in vivo evidence for the dentate gate hypothesis is lacking and it is therefore unclear whether interventions selectively targeting the dentate gyrus would inhibit seizures. We demonstrate that on-demand optogenetic restoration of the dentate gate through selective inhibition of granule cells is sufficient to inhibit spontaneous

  6. Impaired Survival of Neural Progenitor Cells in Dentate Gyrus of Adult Mice Lacking FMRP

    PubMed Central

    Lazarov, Orly; Demars, Michael P.; Zhao, Kai Da Tommy; Ali, Haroon M.; Grauzas, Vanessa; Kney, Adam; Larson, John

    2011-01-01

    Fragile X syndrome (FXS) is the most common form of inherited intellectual disability in humans. Individuals affected with the disorder exhibit a deficiency of the fragile X mental retardation protein (FMRP), due to transcriptional silencing of the Fmr1 gene. It is widely accepted that learning deficits in FXS result from impaired synaptic function and/or plasticity in the brain. Interestingly, recent evidence suggests that conditional knockout of Fmr1 in neural progenitor cells in mice impairs hippocampal neurogenesis, which in turn contributes to learning impairments. To examine the nature of the neurogenic impairments and determine whether they impact the morphology of the dentate gyrus, we assessed the extent of neural progenitor cell proliferation, survival, and differentiation in older adult Fmr1 knockout mice. Here we show that the number of fast- proliferating cells in the subgranule layer of the dentate gyrus, as well as the subsequent survival of these cells, are dramatically reduced in Fmr1 knockout mice. In addition, the number of mature neurons in the granule layer of the dentate gyrus of these mice is significantly smaller than in WT littermate controls, suggesting that impaired proliferation and survival of neural progenitor cells compromises the structure of the dentate gyrus. Impaired adult neurogenesis may underlie, at least in part, the learning deficits that characterize fragile X syndrome. PMID:22128095

  7. Stable association of RNAi machinery is conserved between the cytoplasm and nucleus of human cells.

    PubMed

    Kalantari, Roya; Hicks, Jessica A; Li, Liande; Gagnon, Keith T; Sridhara, Viswanadham; Lemoff, Andrew; Mirzaei, Hamid; Corey, David R

    2016-07-01

    Argonaute 2 (AGO2), the catalytic engine of RNAi, is typically associated with inhibition of translation in the cytoplasm. AGO2 has also been implicated in nuclear processes including transcription and splicing. There has been little insight into AGO2's nuclear interactions or how they might differ relative to cytoplasm. Here we investigate the interactions of cytoplasmic and nuclear AGO2 using semi-quantitative mass spectrometry. Mass spectrometry often reveals long lists of candidate proteins, complicating efforts to rigorously discriminate true interacting partners from artifacts. We prioritized candidates using orthogonal analytical strategies that compare replicate mass spectra of proteins associated with Flag-tagged and endogenous AGO2. Interactions with TRNC6A, TRNC6B, TNRC6C, and AGO3 are conserved between nuclei and cytoplasm. TAR binding protein interacted stably with cytoplasmic AGO2 but not nuclear AGO2, consistent with strand loading in the cytoplasm. Our data suggest that interactions between functionally important components of RNAi machinery are conserved between the nucleus and cytoplasm but that accessory proteins differ. Orthogonal analysis of mass spectra is a powerful approach to streamlining identification of protein partners. PMID:27198507

  8. Deep Brain Stimulation of the Pedunculopontine Tegmental Nucleus (PPN) Influences Visual Contrast Sensitivity in Human Observers

    PubMed Central

    Strumpf, Hendrik; Noesselt, Toemme; Schoenfeld, Mircea Ariel; Voges, Jürgen; Panther, Patricia; Kaufmann, Joern; Heinze, Hans-Jochen; Hopf, Jens-Max

    2016-01-01

    The parapontine nucleus of the thalamus (PPN) is a neuromodulatory midbrain structure with widespread connectivity to cortical and subcortical motor structures, as well as the spinal cord. The PPN also projects to the thalamus, including visual relay nuclei like the LGN and the pulvinar. Moreover, there is intense connectivity with sensory structures of the tegmentum in particular with the superior colliculus (SC). Given the existence and abundance of projections to visual sensory structures, it is likely that activity in the PPN has some modulatory influence on visual sensory selection. Here we address this possibility by measuring the visual discrimination performance (luminance contrast thresholds) in a group of patients with Parkinson’s Disease (PD) treated with deep-brain stimulation (DBS) of the PPN to control gait and postural motor deficits. In each patient we measured the luminance-contrast threshold of being able to discriminate an orientation-target (Gabor-grating) as a function of stimulation frequency (high 60Hz, low 8/10, no stimulation). Thresholds were determined using a standard staircase-protocol that is based on parameter estimation by sequential testing (PEST). We observed that under low frequency stimulation thresholds increased relative to no and high frequency stimulation in five out of six patients, suggesting that DBS of the PPN has a frequency-dependent impact on visual selection processes at a rather elementary perceptual level. PMID:27167979

  9. Stable association of RNAi machinery is conserved between the cytoplasm and nucleus of human cells

    PubMed Central

    Kalantari, Roya; Hicks, Jessica A.; Li, Liande; Gagnon, Keith T.; Sridhara, Viswanadham; Lemoff, Andrew; Mirzaei, Hamid; Corey, David R.

    2016-01-01

    Argonaute 2 (AGO2), the catalytic engine of RNAi, is typically associated with inhibition of translation in the cytoplasm. AGO2 has also been implicated in nuclear processes including transcription and splicing. There has been little insight into AGO2's nuclear interactions or how they might differ relative to cytoplasm. Here we investigate the interactions of cytoplasmic and nuclear AGO2 using semi-quantitative mass spectrometry. Mass spectrometry often reveals long lists of candidate proteins, complicating efforts to rigorously discriminate true interacting partners from artifacts. We prioritized candidates using orthogonal analytical strategies that compare replicate mass spectra of proteins associated with Flag-tagged and endogenous AGO2. Interactions with TRNC6A, TRNC6B, TNRC6C, and AGO3 are conserved between nuclei and cytoplasm. TAR binding protein interacted stably with cytoplasmic AGO2 but not nuclear AGO2, consistent with strand loading in the cytoplasm. Our data suggest that interactions between functionally important components of RNAi machinery are conserved between the nucleus and cytoplasm but that accessory proteins differ. Orthogonal analysis of mass spectra is a powerful approach to streamlining identification of protein partners. PMID:27198507

  10. Most Human Proteins Made in Both Nucleus and Cytoplasm Turn Over within Minutes

    PubMed Central

    Baboo, Sabyasachi; Bhushan, Bhaskar; Jiang, Haibo; Grovenor, Chris R. M.; Pierre, Philippe; Davis, Benjamin G.; Cook, Peter R.

    2014-01-01

    In bacteria, protein synthesis can be coupled to transcription, but in eukaryotes it is believed to occur solely in the cytoplasm. Using pulses as short as 5 s, we find that three analogues – L-azidohomoalanine, puromycin (detected after attaching fluors using ‘click’ chemistry or immuno-labeling), and amino acids tagged with ‘heavy’ 15N and 13C (detected using secondary ion mass spectrometry) – are incorporated into the nucleus and cytoplasm in a process sensitive to translational inhibitors. The nuclear incorporation represents a significant fraction of the total, and labels in both compartments have half-lives of less than a minute; results are consistent with most newly-made peptides being destroyed soon after they are made. As nascent RNA bearing a premature termination codon (detected by fluorescence in situ hybridization) is also eliminated by a mechanism sensitive to a translational inhibitor, the nuclear turnover of peptides is probably a by-product of proof-reading the RNA for stop codons (a process known as nonsense-mediated decay). We speculate that the apparently-wasteful turnover of this previously-hidden (‘dark-matter’) world of peptide is involved in regulating protein production. PMID:24911415

  11. Thymosin Beta-4 Recombinant Adeno-associated Virus Enhances Human Nucleus Pulposus Cell Proliferation and Reduces Cell Apoptosis and Senescence

    PubMed Central

    Wang, Yuan-Yi; Zhu, Qing-San; Wang, Yi-Wei; Yin, Ruo-Feng

    2015-01-01

    Background: Thymosin beta-4 (TB-4) is considered key roles in tissue development, maintenance and pathological processes. The study aimed to prove TB-4 positive biological function on nucleus pulposus (NP) cell apoptosis and slowing the process of cell aging while increasing the cell proliferation. Methods: TB-4 recombinant adeno-associated virus (AAV) was constructed and induced to human NP cells. Cell of same group were cultured without gene modification as controlled group. Proliferation capacity and cell apoptosis were observed during 6 passages of the cells. Morphology and expression of the TB-4 gene were documented as parameter of cell activity during cell passage. Results: NP cells with TB-4 transfection has normal TB-4 expression and exocytosis. NP cells with TB-4 transfection performed significantly higher cell activity than that at the control group in each generation. TB-4 recombinant AAV-transfected human NP cells also show slower cell aging, lower cell apoptosis and higher cell proliferation than control group. Conclusions: TB-4 can prevent NP cell apoptosis, slow NP cell aging and promote NP cell proliferation. AAV transfection technique was able to highly and stably express TB-4 in human NP cells, which may provide a new pathway for innovation in the treatment of intervertebral disc degenerative diseases. PMID:26021512

  12. Regenerative and Immunogenic Characteristics of Cultured Nucleus Pulposus Cells from Human Cervical Intervertebral Discs

    PubMed Central

    Stich, Stefan; Stolk, Meaghan; Girod, Pierre Pascal; Thomé, Claudius; Sittinger, Michael; Ringe, Jochen; Seifert, Martina; Hegewald, Aldemar Andres

    2015-01-01

    Cell-based regenerative approaches have been suggested as primary or adjuvant procedures for the treatment of degenerated intervertebral disc (IVD) diseases. Our aim was to evaluate the regenerative and immunogenic properties of mildly and severely degenerated cervical nucleus pulposus (NP) cells with regard to cell isolation, proliferation and differentiation, as well as to cell surface markers and co-cultures with autologous or allogeneic peripheral blood mononuclear cells (PBMC) including changes in their immunogenic properties after 3-dimensional (3D)-culture. Tissue from the NP compartment of 10 patients with mild or severe grades of IVD degeneration was collected. Cells were isolated, expanded with and without basic fibroblast growth factor and cultured in 3D fibrin/poly (lactic-co-glycolic) acid transplants for 21 days. Real-time reverse-transcription polymerase chain reaction (RT-PCR) showed the expression of characteristic NP markers ACAN, COL1A1 and COL2A1 in 2D- and 3D-culture with degeneration- and culture-dependent differences. In a 5,6-carboxyfluorescein diacetate N-succinimidyl ester-based proliferation assay, NP cells in monolayer, regardless of their grade of degeneration, did not provoke a significant proliferation response in T cells, natural killer (NK) cells or B cells, not only with donor PBMC, but also with allogeneic PBMC. In conjunction with low inflammatory cytokine expression, analyzed by Cytometric Bead Array and fluorescence-activated cell sorting (FACS), a low immunogenicity can be assumed, facilitating possible therapeutic approaches. In 3D-culture, however, we found elevated immune cell proliferation levels, and there was a general trend to higher responses for NP cells from severely degenerated IVD tissue. This emphasizes the importance of considering the specific immunological alterations when including biomaterials in a therapeutic concept. The overall expression of Fas receptor, found on cultured NP cells, could have

  13. Endogenous interleukin 1 alpha must be transported to the nucleus to exert its activity in human endothelial cells.

    PubMed Central

    Maier, J A; Statuto, M; Ragnotti, G

    1994-01-01

    We have previously shown that the signal peptideless cytokine interleukin 1 alpha (IL-1 alpha) may play a role as an intracellular regulator of human endothelial cell senescence (J. A. M. Maier, P. Voulalas, D. Roeder, and T. Maciag, Science 249:1570-1574, 1990). To investigate the potential intracellular function of IL-1 alpha, transformed endothelial cells were transfected with the human cDNAs that code for the two forms of IL-1 alpha, the precursor molecule IL-1(1-271) and the mature protein IL-1(113-271). The subcellular localization of the two different polypeptides was investigated directly or by using chimeric genes constructed by fusion of different fragments of the IL-1 alpha gene and the beta-galactosidase open reading frames. The IL-1(113-271) protein was cytoplasmic, while IL-1(1-271) was nuclear. The basic cluster at the NH2 terminus of IL-1, KVLKKRR, has been shown to mediate IL-1 alpha nuclear targeting. Moreover, nuclear localization of IL-1 alpha correlates with impaired cell growth and expression of some IL-1 alpha-inducible genes. These results suggest that transport of endogenous IL-1(1-271) into the nucleus is required for it to modulate endothelial cell function. Images PMID:8114717

  14. Phase-amplitude cross-frequency coupling in the human nucleus accumbens tracks action monitoring during cognitive control

    PubMed Central

    Dürschmid, Stefan; Zaehle, Tino; Kopitzki, Klaus; Voges, Jürgen; Schmitt, Friedhelm C.; Heinze, Hans-Jochen; Knight, Robert T.; Hinrichs, Hermann

    2013-01-01

    The Nucleus Accumbens (NAcc) is an important structure for the transfer of information between cortical and subcortical structures, especially the prefrontal cortex and the hippocampus. However, the mechanism that allows the NAcc to achieve this integration is not well understood. Phase-amplitude cross-frequency coupling (PAC) of oscillations in different frequency bands has been proposed as an effective mechanism to form functional networks to optimize transfer and integration of information. Here we assess PAC between theta and high gamma oscillations as a potential mechanism that facilitates motor adaptation. To address this issue we recorded intracranial field potentials directly from the bilateral human NAcc in three patients while they performed a motor learning task that varied in the level of cognitive control needed to perform the task. As in rodents, PAC was observable in the human NAcc, transiently occurring contralateral to a movement following the motor response. Importantly, PAC correlated with the level of cognitive control needed to monitor the action performed. This functional relation indicates that the NAcc is engaged in action monitoring and supports the evaluation of motor programs during adaptive behavior by means of PAC. PMID:24109448

  15. Neuronal subtypes and diversity revealed by single-nucleus RNA sequencing of the human brain.

    PubMed

    Lake, Blue B; Ai, Rizi; Kaeser, Gwendolyn E; Salathia, Neeraj S; Yung, Yun C; Liu, Rui; Wildberg, Andre; Gao, Derek; Fung, Ho-Lim; Chen, Song; Vijayaraghavan, Raakhee; Wong, Julian; Chen, Allison; Sheng, Xiaoyan; Kaper, Fiona; Shen, Richard; Ronaghi, Mostafa; Fan, Jian-Bing; Wang, Wei; Chun, Jerold; Zhang, Kun

    2016-06-24

    The human brain has enormously complex cellular diversity and connectivities fundamental to our neural functions, yet difficulties in interrogating individual neurons has impeded understanding of the underlying transcriptional landscape. We developed a scalable approach to sequence and quantify RNA molecules in isolated neuronal nuclei from a postmortem brain, generating 3227 sets of single-neuron data from six distinct regions of the cerebral cortex. Using an iterative clustering and classification approach, we identified 16 neuronal subtypes that were further annotated on the basis of known markers and cortical cytoarchitecture. These data demonstrate a robust and scalable method for identifying and categorizing single nuclear transcriptomes, revealing shared genes sufficient to distinguish previously unknown and orthologous neuronal subtypes as well as regional identity and transcriptomic heterogeneity within the human brain. PMID:27339989

  16. Microelastic mapping of the rat dentate gyrus

    PubMed Central

    Luque, Tomás; Schaffer, David V.; Kumar, Sanjay

    2016-01-01

    The lineage commitment of many cultured stem cells, including adult neural stem cells (NSCs), is strongly sensitive to the stiffness of the underlying extracellular matrix. However, it remains unclear how well the stiffness ranges explored in culture align with the microscale stiffness values stem cells actually encounter within their endogenous tissue niches. To address this question in the context of hippocampal NSCs, we used atomic force microscopy to spatially map the microscale elastic modulus (E) of specific anatomical substructures within living slices of rat dentate gyrus in which NSCs reside during lineage commitment in vivo. We measured depth-dependent apparent E-values at locations across the hilus (H), subgranular zone (SGZ) and granule cell layer (GCL) and found a two- to threefold increase in stiffness at 500 nm indentation from the H (49 ± 7 Pa) and SGZ (58 ± 8 Pa) to the GCL (115 ± 18 Pa), a fold change in stiffness we have previously found functionally relevant in culture. Additionally, E exhibits nonlinearity with depth, increasing significantly for indentations larger than 1 µm and most pronounced in the GCL. The methodological advances implemented for these measurements allow the quantification of the elastic properties of hippocampal NSC niche at unprecedented spatial resolution. PMID:27152213

  17. Differential expression of extracellular-signal-regulated kinase 5 (ERK5) in normal and degenerated human nucleus pulposus tissues and cells

    SciTech Connect

    Liang, Weiguo; Fang, Dejian; Ye, Dongping; Zou, Longqiang; Shen, Yan; Dai, Libing; Xu, Jiake

    2014-07-11

    Highlights: • ERK5 involved in NP cells. • ERK5 involved in NP tissue. • It was important modulator. - Abstract: Extracellular-signal-regulated kinase 5 (ERK5) is a member of the mitogen-activated protein kinase (MAPK) family and regulates a wide variety of cellular processes such as proliferation, differentiation, necrosis, apoptosis and degeneration. However, the expression of ERK5 and its role in degenerated human nucleus pulposus (NP) is hitherto unknown. In this study, we observed the differential expression of ERK5 in normal and degenerated human nucleus pulposus tissues by using immunohistochemical staining and Western blot. Treatment of NP cells with Pro-inflammatory cytokine, TNF-α decreased ERK5 gene expression as well as NP marker gene expression; including the type II collagen and aggrecan. Suppression of ERK5 gene expression in NP cells by ERK5 siRNA resulted in decreased gene expression of type II collagen and aggrecan. Furthermore, inhibition of ERK5 activation by BIX02188 (5 μM) decreased the gene expression of type II collagen and aggrecan in NP cells. Our results document the expression of ERK5 in degenerated nucleus pulposus tissues, and suggest a potential involvement of ERK5 in human degenerated nucleus pulposus.

  18. SDF-1/CXCR4 axis induces apoptosis of human degenerative nucleus pulposus cells via the NF-κB pathway

    PubMed Central

    LIU, ZONGCHAO; MA, CHUAN; SHEN, JIELIANG; WANG, DAWU; HAO, JIE; HU, ZHENMING

    2016-01-01

    Intervertebral disc degeneration (IVDD) is a major cause of lower back pain, and increased cell apoptosis is a key characteristic of IVDD. The present study aimed to investigate the effects and mechanism of the stromal cell-derived factor-1 (SDF-1)/C-X-C motif chemokine receptor 4 (CXCR4) axis on apoptosis in human degenerative nucleus pulposus cells (NPCs). The expression levels of SDF-1 and CXCR4 in human intervertebral discs (IVD) were determined using immunohistochemistry and western blot analysis. Apoptosis of primary cultured NPCs was quantified by Annexin V/propidium iodide staining following stimulation with SDF-1 and knockdown of CXCR4 using small interfering RNA (siRNA). The association with the nuclear factor-κB (NF-κB) signaling pathway was investigated using CXCR4-siRNA and NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC), treatment. The results demonstrated that SDF-1 and its receptor, CXCR4, were upregulated in degenerative IVD samples compared with normal samples. Stimulation with SDF-1 increased the level of apoptosis in cultured NPCs, and conversely, the apoptosis level was suppressed post-transfection with CXCR4 siRNA compared with SDF-1 stimulation alone. Furthermore, SDF-1 treatment increased the level of phosphorylated NF-κB subunit P65, which was downregulated following CXCR4 siRNA and PDTC treatment. In addition, CXCR4 siRNA and PDTC inhibited the nuclear translocation of P65, which was induced by SDF-1. Taken together, SDF-1-mediated apoptosis was suppressed by NF-κB inhibition using PDTC. In conclusion, the SDF-1/CXCR4 axis promoted cell apoptosis in human degenerative NPCs via the NF-κB pathway, thus suggesting that SDF-1/CXCR signaling may be a therapeutic target for the treatment of degenerative IVD diseases. PMID:27220474

  19. SDF‑1/CXCR4 axis induces apoptosis of human degenerative nucleus pulposus cells via the NF‑κB pathway.

    PubMed

    Liu, Zongchao; Ma, Chuan; Shen, Jieliang; Wang, Dawu; Hao, Jie; Hu, Zhenming

    2016-07-01

    Intervertebral disc degeneration (IVDD) is a major cause of lower back pain, and increased cell apoptosis is a key characteristic of IVDD. The present study aimed to investigate the effects and mechanism of the stromal cell‑derived factor‑1 (SDF‑1)/C‑X‑C motif chemokine receptor 4 (CXCR4) axis on apoptosis in human degenerative nucleus pulposus cells (NPCs). The expression levels of SDF‑1 and CXCR4 in human intervertebral discs (IVD) were determined using immunohistochemistry and western blot analysis. Apoptosis of primary cultured NPCs was quantified by Annexin V/propidium iodide staining following stimulation with SDF‑1 and knockdown of CXCR4 using small interfering RNA (siRNA). The association with the nuclear factor‑κB (NF‑κB) signaling pathway was investigated using CXCR4‑siRNA and NF‑κB inhibitor, pyrrolidine dithiocarbamate (PDTC), treatment. The results demonstrated that SDF‑1 and its receptor, CXCR4, were upregulated in degenerative IVD samples compared with normal samples. Stimulation with SDF‑1 increased the level of apoptosis in cultured NPCs, and conversely, the apoptosis level was suppressed post‑transfection with CXCR4 siRNA compared with SDF‑1 stimulation alone. Furthermore, SDF‑1 treatment increased the level of phosphorylated NF‑κB subunit P65, which was downregulated following CXCR4 siRNA and PDTC treatment. In addition, CXCR4 siRNA and PDTC inhibited the nuclear translocation of P65, which was induced by SDF‑1. Taken together, SDF‑1‑mediated apoptosis was suppressed by NF‑κB inhibition using PDTC. In conclusion, the SDF‑1/CXCR4 axis promoted cell apoptosis in human degenerative NPCs via the NF‑κB pathway, thus suggesting that SDF‑1/CXCR signaling may be a therapeutic target for the treatment of degenerative IVD diseases. PMID:27220474

  20. No unified reward prediction error in local field potentials from the human nucleus accumbens: evidence from epilepsy patients

    PubMed Central

    Rutledge, Robb B.; Zaehle, Tino; Schmitt, Friedhelm C.; Kopitzki, Klaus; Kowski, Alexander B.; Voges, Jürgen; Heinze, Hans-Jochen; Dolan, Raymond J.

    2015-01-01

    Functional magnetic resonance imaging (fMRI), cyclic voltammetry, and single-unit electrophysiology studies suggest that signals measured in the nucleus accumbens (Nacc) during value-based decision making represent reward prediction errors (RPEs), the difference between actual and predicted rewards. Here, we studied the precise temporal and spectral pattern of reward-related signals in the human Nacc. We recorded local field potentials (LFPs) from the Nacc of six epilepsy patients during an economic decision-making task. On each trial, patients decided whether to accept or reject a gamble with equal probabilities of a monetary gain or loss. The behavior of four patients was consistent with choices being guided by value expectations. Expected value signals before outcome onset were observed in three of those patients, at varying latencies and with nonoverlapping spectral patterns. Signals after outcome onset were correlated with RPE regressors in all subjects. However, further analysis revealed that these signals were better explained as outcome valence rather than RPE signals, with gamble gains and losses differing in the power of beta oscillations and in evoked response amplitudes. Taken together, our results do not support the idea that postsynaptic potentials in the Nacc represent a RPE that unifies outcome magnitude and prior value expectation. We discuss the generalizability of our findings to healthy individuals and the relation of our results to measurements of RPE signals obtained from the Nacc with other methods. PMID:26019312

  1. No unified reward prediction error in local field potentials from the human nucleus accumbens: evidence from epilepsy patients.

    PubMed

    Stenner, Max-Philipp; Rutledge, Robb B; Zaehle, Tino; Schmitt, Friedhelm C; Kopitzki, Klaus; Kowski, Alexander B; Voges, Jürgen; Heinze, Hans-Jochen; Dolan, Raymond J

    2015-08-01

    Functional magnetic resonance imaging (fMRI), cyclic voltammetry, and single-unit electrophysiology studies suggest that signals measured in the nucleus accumbens (Nacc) during value-based decision making represent reward prediction errors (RPEs), the difference between actual and predicted rewards. Here, we studied the precise temporal and spectral pattern of reward-related signals in the human Nacc. We recorded local field potentials (LFPs) from the Nacc of six epilepsy patients during an economic decision-making task. On each trial, patients decided whether to accept or reject a gamble with equal probabilities of a monetary gain or loss. The behavior of four patients was consistent with choices being guided by value expectations. Expected value signals before outcome onset were observed in three of those patients, at varying latencies and with nonoverlapping spectral patterns. Signals after outcome onset were correlated with RPE regressors in all subjects. However, further analysis revealed that these signals were better explained as outcome valence rather than RPE signals, with gamble gains and losses differing in the power of beta oscillations and in evoked response amplitudes. Taken together, our results do not support the idea that postsynaptic potentials in the Nacc represent a RPE that unifies outcome magnitude and prior value expectation. We discuss the generalizability of our findings to healthy individuals and the relation of our results to measurements of RPE signals obtained from the Nacc with other methods. PMID:26019312

  2. Afferent projections to the deep mesencephalic nucleus in the rat

    SciTech Connect

    Veazey, R.B.; Severin, C.M.

    1982-01-10

    Afferent projections to the deep mesencephalic nucleus (DMN) of the rat were demonstrated with axonal transport techniques. Potential sources for projections to the DMN were first identified by injecting the nucleus with HRP and examining the cervical spinal cord, brain stem, and cortex for retrogradely labeled neurons. Areas consistently labeled were then injected with a tritiated radioisotope, the tissue processed for autoradiography, and the DMN examined for anterograde labeling. Afferent projections to the medial and/or lateral parts of the DMN were found to originate from a number of spinal, bulbar, and cortical centers. Rostral brain centers projecting to both medial and lateral parts of the DMN include the ipsilateral motor and somatosensory cortex, the entopeduncular nucleus, and zona incerta. at the level of the midbrain, the ipsilateral substantia nigra and contralateral DMN likewise project to the DMN. Furthermore, the ipsilateral superior colliculus projects to the DMN, involving mainly the lateral part of the nucleus. Afferents from caudal centers include bilateral projections from the sensory nucleus of the trigeminal complex and the nucleus medulla oblongata centralis, as well as from the contralateral dentate nucleus. The projections from the trigeminal complex and nucleus medullae oblongatae centralis terminate in the intermediate and medial parts of the DMN, whereas projections from the contralateral dentate nucleus terminate mainly in its lateral part. In general, the afferent connections of the DMN arise from diverse areas of the brain. Although most of these projections distribute throughout the entire extent of the DMN, some of them project mainly to either medial or lateral parts of the nucleus, thus suggesting that the organization of the DMN is comparable, at least in part, to that of the reticular formation of the pons and medulla, a region in which hodological differences between medial and lateral subdivisions are known to exist.

  3. Evolution of the mammalian dentate gyrus.

    PubMed

    Hevner, Robert F

    2016-02-15

    The dentate gyrus (DG), a part of the hippocampal formation, has important functions in learning, memory, and adult neurogenesis. Compared with homologous areas in sauropsids (birds and reptiles), the mammalian DG is larger and exhibits qualitatively different phenotypes: 1) folded (C- or V-shaped) granule neuron layer, concave toward the hilus and delimited by a hippocampal fissure; 2) nonperiventricular adult neurogenesis; and 3) prolonged ontogeny, involving extensive abventricular (basal) migration and proliferation of neural stem and progenitor cells (NSPCs). Although gaps remain, available data indicate that these DG traits are present in all orders of mammals, including monotremes and marsupials. The exception is Cetacea (whales, dolphins, and porpoises), in which DG size, convolution, and adult neurogenesis have undergone evolutionary regression. Parsimony suggests that increased growth and convolution of the DG arose in stem mammals concurrently with nonperiventricular adult hippocampal neurogenesis and basal migration of NSPCs during development. These traits could all result from an evolutionary change that enhanced radial migration of NSPCs out of the periventricular zones, possibly by epithelial-mesenchymal transition, to colonize and maintain nonperiventricular proliferative niches. In turn, increased NSPC migration and clonal expansion might be a consequence of growth in the cortical hem (medial patterning center), which produces morphogens such as Wnt3a, generates Cajal-Retzius neurons, and is regulated by Lhx2. Finally, correlations between DG convolution and neocortical gyrification (or capacity for gyrification) suggest that enhanced abventricular migration and proliferation of NSPCs played a transformative role in growth and folding of neocortex as well as archicortex. PMID:26179319

  4. Hypertrophy of the Inferior Olivary Nucleus Impacts Perception of Gravity

    PubMed Central

    Tarnutzer, Alexander A.; Palla, Antonella; Marti, Sarah; Schuknecht, Bernhard; Straumann, Dominik

    2012-01-01

    Interruption of the dentato-olivary projections, interconnecting the dentate nucleus (DN) and the contralateral inferior olivary nucleus (ION), is predicted to interfere with the DN’ role in estimating direction of gravity. In a patient with pendular nystagmus due to hypertrophy of the ION secondary to predominantly right-sided ponto-mesencephalic hemorrhage, perceived vertical shifted from clockwise to counter-clockwise deviations within 4 months. We hypothesize that synchronized oscillations of ION neurons induce a loss of inhibitory control, leading to hyperactivity of the contralateral DN and, as a result, to perceived vertical roll–tilt to the side of the over-active DN. PMID:22593754

  5. The chemical morphology of age-related changes in human intervertebral disc glycosaminoglycans from cervical, thoracic and lumbar nucleus pulposus and annulus fibrosus.

    PubMed Central

    Scott, J E; Bosworth, T R; Cribb, A M; Taylor, J R

    1994-01-01

    Hyaluronan (HA), chondroitin and keratan sulphates (CS, KS), collagen and dry weights were measured in the annulus fibrosus and nucleus pulposus of human cervical, thoracic and lumbar intervertebral discs aged 36-79 y. Alcian blue-critical electrolyte concentration (CEC) staining of sections extended the results. The collagen, total polyanion, HA, CS and KS contents of the nucleus pulposus and annulus fibrosus were plotted for all 3 regions against age. Regional differences and age-related trends were found. For regional differences, the collagen content of the nucleus pulposus was highest in cervical discs and lowest in lumbar discs. In contrast, the total polyanion content of the nucleus pulposus was highest in lumbar discs and lowest in cervical discs. These differences were seen in fetal and adult discs. With respect to age-related trends, the collagen content of the annulus fibrosus was higher in adults and children than in neonates and infants. The collagen content of the nucleus pulposus increased with age in thoracic and lumbar discs, but it was consistently high in cervical discs. There was generally a downward trend of total polyanion and CS with increase in age. This was quite consistent for the annulus fibrosus in all regions and there were dramatic decreases in the lumbar nucleus pulposus in all adults compared with infants and children. These trends were least evident in the cervical nucleus pulposus where infant values were low. CS changes correlated with water content. HA and KS increased in all discs with increasing maturity. Oversulphated KS, absent from fetal discs, reached mature levels by 10 y. Many of the changes occurred before maturity. Glycosaminoglycan (GAG) levels correlated with increasing compressive loads. Higher collagen levels in the cervical nucleus pulposus correlated with greater ranges of torsional and shearing strains in cervical discs. High GAG levels in cervical annulus fibrosus probably facilitate lamellar movements during

  6. The enigmatic mossy cell of the dentate gyrus.

    PubMed

    Scharfman, Helen E

    2016-09-01

    Mossy cells comprise a large fraction of the cells in the hippocampal dentate gyrus, suggesting that their function in this region is important. They are vulnerable to ischaemia, traumatic brain injury and seizures, and their loss could contribute to dentate gyrus dysfunction in such conditions. Mossy cell function has been unclear because these cells innervate both glutamatergic and GABAergic neurons within the dentate gyrus, contributing to a complex circuitry. It has also been difficult to directly and selectively manipulate mossy cells to study their function. In light of the new data generated using methods to preferentially eliminate or activate mossy cells in mice, it is timely to ask whether mossy cells have become any less enigmatic than they were in the past. PMID:27466143

  7. Secondhand tobacco smoke exposure differentially alters nucleus tractus solitarius neurons at two different ages in developing non-human primates

    SciTech Connect

    Sekizawa, Shin-ichi; Joad, Jesse P.; Pinkerton, Kent E.; Bonham, Ann C.

    2010-01-15

    Exposing children to secondhand tobacco smoke (SHS) is associated with increased risk for asthma, bronchiolitis and SIDS. The role for changes in the developing CNS contributing to these problems has not been fully explored. We used rhesus macaques to test the hypothesis that SHS exposure during development triggers neuroplastic changes in the nucleus tractus solitarius (NTS), where lung sensory information related to changes in airway and lung function is first integrated. Pregnant monkeys were exposed to filtered air (FA) or SHS for 6 h/day, 5 days/week starting at 50-day gestational age. Mother/infant pairs continued the exposures postnatally to age 3 or 13 months, which may be equivalent to approximately 1 or 4 years of human age, respectively. Whole-cell recordings were made of second-order NTS neurons in transverse brainstem slices. To target the consequences of SHS exposure based on neuronal subgroups, we classified NTS neurons into two phenotypes, rapid-onset spiking (RS) and delayed-onset spiking (DS), and then evaluated intrinsic and synaptic excitabilities in FA-exposed animals. RS neurons showed greater cell excitability especially at age of 3 months while DS neurons received greater amplitudes of excitatory postsynaptic currents (EPSCs). Developmental neuroplasticity such as increases in intrinsic and synaptic excitabilities were detected especially in DS neurons. In 3 month olds, SHS exposure effects were limited to excitatory changes in RS neurons, specifically increases in evoked EPSC amplitudes and increased spiking responses accompanied by shortened action potential width. By 13 months, the continued SHS exposure inhibited DS neuronal activity; decreases in evoked EPSC amplitudes and blunted spiking responses accompanied by prolonged action potential width. The influence of SHS exposure on age-related and phenotype specific changes may be associated with age-specific respiratory problems, for which SHS exposure can increase the risk, such as SIDS

  8. Microtubule-associated Proteins 1 (MAP1) Promote Human Immunodeficiency Virus Type I (HIV-1) Intracytoplasmic Routing to the Nucleus

    PubMed Central

    Fernandez, Juliette; Portilho, Débora M.; Danckaert, Anne; Munier, Sandie; Becker, Andreas; Roux, Pascal; Zambo, Anaba; Shorte, Spencer; Jacob, Yves; Vidalain, Pierre-Olivier; Charneau, Pierre; Clavel, François; Arhel, Nathalie J.

    2015-01-01

    After cell entry, HIV undergoes rapid transport toward the nucleus using microtubules and microfilaments. Neither the cellular cytoplasmic components nor the viral proteins that interact to mediate transport have yet been identified. Using a yeast two-hybrid screen, we identified four cytoskeletal components as putative interaction partners for HIV-1 p24 capsid protein: MAP1A, MAP1S, CKAP1, and WIRE. Depletion of MAP1A/MAP1S in indicator cell lines and primary human macrophages led to a profound reduction in HIV-1 infectivity as a result of impaired retrograde trafficking, demonstrated by a characteristic accumulation of capsids away from the nuclear membrane, and an overall defect in nuclear import. MAP1A/MAP1S did not impact microtubule network integrity or cell morphology but contributed to microtubule stabilization, which was shown previously to facilitate infection. In addition, we found that MAP1 proteins interact with HIV-1 cores both in vitro and in infected cells and that interaction involves MAP1 light chain LC2. Depletion of MAP1 proteins reduced the association of HIV-1 capsids with both dynamic and stable microtubules, suggesting that MAP1 proteins help tether incoming viral capsids to the microtubular network, thus promoting cytoplasmic trafficking. This work shows for the first time that following entry into target cells, HIV-1 interacts with the cytoskeleton via its p24 capsid protein. Moreover, our results support a role for MAP1 proteins in promoting efficient retrograde trafficking of HIV-1 by stimulating the formation of stable microtubules and mediating the association of HIV-1 cores with microtubules. PMID:25505242

  9. Treatment and maintenance of a dentate patient with 'radiation caries'.

    PubMed

    Craddock, H L

    2008-11-01

    Patients with xerostomia are presenting dental practitioners with challenges in caries control, long-term restoration and prosthodontic difficulties. In many cases, extraction may be the best option, but for younger, dentate patients, this may be inappropriate. This paper describes the management of a young partially dentate patient with severe xerostomia following irradiation of the salivary glands. Preventive and restorative management are discussed, together with treatment and healing of peri-radicular pathology. The case report demonstrates that long-term stabilization and management of caries and peri-radicular lesions are possible over a seven-year period for a patient with severe radiation caries. PMID:19322963

  10. Effect of microRNA-21 on the proliferation of human degenerated nucleus pulposus by targeting programmed cell death 4

    PubMed Central

    Chen, B.; Huang, S.G.; Ju, L.; Li, M.; Nie, F.F.; Zhang, Y.; Zhang, Y.H.; Chen, X.; Gao, F.

    2016-01-01

    This study aims to explore the effect of microRNA-21 (miR-21) on the proliferation of human degenerated nucleus pulposus (NP) by targeting programmed cell death 4 (PDCD4) tumor suppressor. NP tissues were collected from 20 intervertebral disc degeneration (IDD) patients, and from 5 patients with traumatic spine fracture. MiR-21 expressions were tested. NP cells from IDD patients were collected and divided into blank control group, negative control group (transfected with miR-21 negative sequences), miR-21 inhibitor group (transfected with miR-21 inhibitors), miR-21 mimics group (transfected with miR-21 mimics) and PDCD4 siRNA group (transfected with PDCD4 siRNAs). Cell growth was estimated by Cell Counting Kit-8; PDCD4, MMP-2,MMP-9 mRNA expressions were evaluated by qRT-PCR; PDCD4, c-Jun and p-c-Jun expressions were tested using western blot. In IDD patients, the expressions of miR-21 and PDCD4 mRNA were respectively elevated and decreased (both P<0.05). The miR-21 expressions were positively correlated with Pfirrmann grades, but negatively correlated with PDCD4 mRNA (both P<0.001). In miR-21 inhibitor group, cell growth, MMP-2 and MMP-9 mRNA expressions, and p-c-Jun protein expressions were significantly lower, while PDCD4 mRNA and protein expressions were higher than the other groups (all P<0.05). These expressions in the PDCD4 siRNA and miR-21 mimics groups was inverted compared to that in the miR-21 inhibitor group (all P<0.05). MiR-21 could promote the proliferation of human degenerated NP cells by targeting PDCD4, increasing phosphorylation of c-Jun protein, and activating AP-1-dependent transcription of MMPs, indicating that miR-21 may be a crucial biomarker in the pathogenesis of IDD. PMID:27240294

  11. Effect of microRNA-21 on the proliferation of human degenerated nucleus pulposus by targeting programmed cell death 4.

    PubMed

    Chen, B; Huang, S G; Ju, L; Li, M; Nie, F F; Zhang, Y; Zhang, Y H; Chen, X; Gao, F

    2016-05-24

    This study aims to explore the effect of microRNA-21 (miR-21) on the proliferation of human degenerated nucleus pulposus (NP) by targeting programmed cell death 4 (PDCD4) tumor suppressor. NP tissues were collected from 20 intervertebral disc degeneration (IDD) patients, and from 5 patients with traumatic spine fracture. MiR-21 expressions were tested. NP cells from IDD patients were collected and divided into blank control group, negative control group (transfected with miR-21 negative sequences), miR-21 inhibitor group (transfected with miR-21 inhibitors), miR-21 mimics group (transfected with miR-21 mimics) and PDCD4 siRNA group (transfected with PDCD4 siRNAs). Cell growth was estimated by Cell Counting Kit-8; PDCD4, MMP-2,MMP-9 mRNA expressions were evaluated by qRT-PCR; PDCD4, c-Jun and p-c-Jun expressions were tested using western blot. In IDD patients, the expressions of miR-21 and PDCD4 mRNA were respectively elevated and decreased (both P<0.05). The miR-21 expressions were positively correlated with Pfirrmann grades, but negatively correlated with PDCD4 mRNA (both P<0.001). In miR-21 inhibitor group, cell growth, MMP-2 and MMP-9 mRNA expressions, and p-c-Jun protein expressions were significantly lower, while PDCD4 mRNA and protein expressions were higher than the other groups (all P<0.05). These expressions in the PDCD4 siRNA and miR-21 mimics groups was inverted compared to that in the miR-21 inhibitor group (all P<0.05). MiR-21 could promote the proliferation of human degenerated NP cells by targeting PDCD4, increasing phosphorylation of c-Jun protein, and activating AP-1-dependent transcription of MMPs, indicating that miR-21 may be a crucial biomarker in the pathogenesis of IDD. PMID:27240294

  12. Notochordal conditioned media from tissue increases proteoglycan accumulation and promotes a healthy nucleus pulposus phenotype in human mesenchymal stem cells

    PubMed Central

    2011-01-01

    Introduction Notochordal cells (NCs) are influential in development of the intervertebral disc (IVD) and species that retain NCs do not degenerate. IVD repair using bone marrow derived mesenchymal stem cells (MSCs) is an attractive approach and the harsh microenvironment of the IVD suggests pre-differentiation is a necessary first step. The goal of this study was to use soluble factors from NCs in alginate and NCs in their native tissue to differentiate human MSCs to a young nucleus pulposus (NP) phenotype. Methods Human MSCs (cultured under micromass conditions for 21 days in hypoxia) were differentiated with conditioned medium derived from porcine notochordal cells in native tissue (NCT) or in alginate beads (NCA), and compared with chondrogenic (TGFβ-3) or basal medium. A PCR array of 42 genes was utilized to screen a large number of genes known to be associated with the healthy NP phenotype and pellet cultures were also evaluated for glycosaminoglycan content, histology and viability. Proteomic analysis was used to assess candidate soluble factors in NCA and NCT. Results Notochordal cell conditioned media had diverse effects on MSC phenotype. NCT resulted in the highest levels of glycosaminoglycan (GAG), as well as up-regulation of SOX9 and Collagen II gene expression. NCA demonstrated effects that were catabolic yet also anti-fibrotic and minimally hypertrophic with down-regulation of Collagens I and III and low levels of Collagen X, respectively. Micromass culture and hypoxic conditions were sufficient to promote chondrogenesis demonstrating that both basal and chondrogenic media produced similar phenotypes. Candidate matricellular proteins, clusterin and tenascin were identified by proteomics in the NCA group. Conclusions NCs secreted important soluble factors capable of differentiating MSCs to a NP phenotype synthesizing high levels of proteoglycan while also resisting collagen fiber expression and hypertrophy, yet results were sensitive to the conditions

  13. a-Band Oscillations in Intracellular Membrane Potentials of Dentate Gyrus Neurons in Awake Rodents

    ERIC Educational Resources Information Center

    Anderson, Ross W.; Strowbridge, Ben W.

    2014-01-01

    The hippocampus and dentate gyrus play critical roles in processing declarative memories and spatial information. Dentate granule cells, the first relay in the trisynaptic circuit through the hippocampus, exhibit low spontaneous firing rates even during locomotion. Using intracellular recordings from dentate neurons in awake mice operating a…

  14. Adult Neurogenesis in the Mammalian Hippocampus: Why the Dentate Gyrus?

    ERIC Educational Resources Information Center

    Drew, Liam J.; Fusi, Stefano; Hen, René

    2013-01-01

    In the adult mammalian brain, newly generated neurons are continuously incorporated into two networks: interneurons born in the subventricular zone migrate to the olfactory bulb, whereas the dentate gyrus (DG) of the hippocampus integrates locally born principal neurons. That the rest of the mammalian brain loses significant neurogenic capacity…

  15. A possible role of transglutaminase 2 in the nucleus of INS-1E and of cells of human pancreatic islets

    PubMed Central

    Sileno, Sara; D'Oria, Valentina; Stucchi, Riccardo; Alessio, Massimo; Petrini, Stefania; Bonetto, Valentina; Maechler, Pierre; Bertuzzi, Federico; Grasso, Valeria; Paolella, Katia; Barbetti, Fabrizio; Massa, Ornella

    2014-01-01

    Transglutaminase 2 (TG2) is a multifunctional protein with Ca2 +-dependent transamidating and G protein activity. Previously we reported that the role of TG2 in insulin secretion may involve cytoplasmic actin remodeling and a regulative action on other proteins during granule movement. The aim of this study was to gain a better insight into the role of TG2 transamidating activity in mitochondria and in the nucleus of INS-1E rat insulinoma cell line (INS-1E) during insulin secretion. To this end we labeled INS-1E with an artificial donor (biotinylated peptide), in basal condition and after stimulus with glucose for 2, 5, and 8 min. Biotinylated proteins of the nuclear/mitochondrial-enriched fraction were analyzed using two-dimensional electrophoresis and mass spectrometry. Many mitochondrial proteins involved in Ca2 + homeostasis (e.g. voltage-dependent anion-selective channel protein, prohibitin and different ATP synthase subunits) and many nuclear proteins involved in gene regulation (e.g. histone H3, barrier to autointegration factor and various heterogeneous nuclear ribonucleoprotein) were identified among a number of transamidating substrates of TG2 in INS-1E. The combined results provide evidence that a temporal link exists between glucose-stimulation, first phase insulin secretion and the action of TG on histone H3 both in INS-1E and human pancreatic islets. Biological significance Research into the role of transglutaminase 2 during insulin secretion in INS-1E rat insulinoma cellular model is depicting a complex role for this enzyme. Transglutaminase 2 acts in the different INS-1E compartments in the same way: catalyzing a post-translational modification event of its substrates. In this work we identify some mitochondrial and nuclear substrates of INS-1E during first phase insulin secretion. The finding that TG2 interacts with nuclear proteins that include BAF and histone H3 immediately after (2–5 min) glucose stimulus of INS-1E suggests that TG2 may be

  16. Low-intensity pulsed ultrasound stimulates cell proliferation, proteoglycan synthesis and expression of growth factor-related genes in human nucleus pulposus cell line.

    PubMed

    Kobayashi, Y; Sakai, D; Iwashina, T; Iwabuchi, S; Mochida, J

    2009-01-01

    Low-intensity pulsed ultrasound (LIPUS) stimulation has been shown to effect differentiation and activation of human chondrocytes. A study involving stimulation of rabbit disc cells with LIPUS revealed upregulation of cell proliferation and proteoglycan (PG) synthesis. However, the effect of LIPUS on human nucleus pulposus cells has not been investigated. In the present study, therefore, we investigated whether LIPUS stimulation of a human nucleus pulposus cell line (HNPSV-1) exerted a positive effect on cellular activity. HNPSV-1 cells were encapsulated in 1.2% sodium alginate solution at 1x10(5) cells/ml and cultured at 10 beads/well in 6-well plates. The cells were stimulated for 20 min each day using a LIPUS generator, and the effects of LIPUS were evaluated by measuring DNA and PG synthesis. Furthermore, mRNA expression was analyzed by cDNA microarray using total RNA extracted from the cultured cells. Our study revealed no significant difference in cell proliferation between the control and the ultrasound treated groups. However, PG production was significantly upregulated in HNPSV cells stimulated at intensities of 15, 30, 60, and 120 mW/cm(2) compared with the control. The results of cDNA array showed that LIPUS significantly stimulated the gene expression of growth factors and their receptors (BMP2, FGF7, TGFbetaR1 EGFRF1, VEGF). These findings suggest that LIPUS stimulation upregulates PG production in human nucleus pulposus cells by the enhancement of several matrix-related genes including growth factor-related genes. Safe and non-invasive stimulation using LIPUS may be a useful treatment for delaying the progression of disc degeneration. PMID:19598131

  17. Functional interactions between dentate gyrus, striatum and anterior thalamic nuclei on spatial memory retrieval.

    PubMed

    Méndez-Couz, M; Conejo, N M; González-Pardo, H; Arias, J L

    2015-04-24

    The standard model of memory system consolidation supports the temporal reorganization of brain circuits underlying long-term memory storage, including interactions between the dorsal hippocampus and extra-hippocampal structures. In addition, several brain regions have been suggested to be involved in the retrieval of spatial memory. In particular, several authors reported a possible role of the ventral portion of the hippocampus together with the thalamus or the striatum in the persistence of this type of memory. Accordingly, the present study aimed to evaluate the contribution of different cortical and subcortical brain regions, and neural networks involved in spatial memory retrieval. For this purpose, we used cytochrome c oxidase quantitative histochemistry as a reliable method to measure brain oxidative metabolism. Animals were trained in a hidden platform task and tested for memory retention immediately after the last training session; one week after completing the task, they were also tested in a memory retrieval probe. Results showed that retrieval of the previously learned task was associated with increased levels of oxidative metabolism in the prefrontal cortex, the dorsal and ventral striatum, the anterodorsal thalamic nucleus and the dentate gyrus of the dorsal and ventral hippocampus. The analysis of functional interactions between brain regions suggest that the dorsal and ventral dentate gyrus could be involved in spatial memory retrieval. In addition, the results highlight the key role of the extended hippocampal system, thalamus and striatum in this process. Our study agrees with previous ones reporting interactions between the dorsal hippocampus and the prefrontal cortex during spatial memory retrieval. Furthermore, novel activation patterns of brain networks involving the aforementioned regions were found. These functional brain networks could underlie spatial memory retrieval evaluated in the Morris water maze task. PMID:25680583

  18. Effects of developmental hyperserotonemia on the morphology of rat dentate nuclear neurons.

    PubMed

    Hough, L H; Segal, S

    2016-05-13

    Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social cognition, disordered communication, restricted interests and repetitive behaviors. Furthermore, abnormalities in basic motor control, skilled motor gestures, and motor learning, are common in ASD. These characteristics have been attributed to a possible defect in the pre- and postnatal development of specific neural networks including the dentate-thalamo-cortical pathway, which is involved in motor learning, automaticity of movements, and higher cognitive functions. The current study utilized custom diolistic labeling and unbiased stereology to characterize morphological alterations in neurons of the dentate nucleus of the cerebellum in developing rat pups exposed to abnormally high levels of the serotonergic agonist 5-methyloxytryptamine (5-MT) pre-and postnatally. Occurring in as many as 30% of autistic subjects, developmental hyperserotonemia (DHS) is the most consistent neurochemical finding reported in autism and has been implicated in the pathophysiology of ASD. This exposure produced dramatic changes in dendritic architecture and synaptic features. We observed changes in the dendritic branching morphology which did not lead to significant differences (p>0.5) in total dendritic length. Instead, DHS groups presented with dendritic trees that display changes in arborescence, that appear to be short reaching with elaborately branched segments, presenting with significantly fewer (p>0.001) dendritic spines and a decrease in numeric density when compared to age-matched controls. These negative changes may be implicated in the neuropathological and functional/behavioral changes observed in ASD, such as delays in motor learning, difficulties in automaticity of movements, and deficits in higher cognitive functions. PMID:26892293

  19. Running rewires the neuronal network of adult-born dentate granule cells.

    PubMed

    Vivar, Carmen; Peterson, Benjamin D; van Praag, Henriette

    2016-05-01

    Exercise improves cognition in humans and animals. Running increases neurogenesis in the dentate gyrus of the hippocampus, a brain area important for learning and memory. It is unclear how running modifies the circuitry of new dentate gyrus neurons to support their role in memory function. Here we combine retroviral labeling with rabies virus mediated trans-synaptic retrograde tracing to define and quantify new neuron afferent inputs in young adult male C57Bl/6 mice, housed with or without a running wheel for one month. Exercise resulted in a shift in new neuron networks that may promote sparse encoding and pattern separation. Neurogenesis increased in the dorsal, but not the ventral, dentate gyrus by three-fold, whereas afferent traced cell labeling doubled in number. Regional analysis indicated that running differentially affected specific inputs. Within the hippocampus the ratio of innervation from inhibitory interneurons and glutamatergic mossy cells to new neurons was reduced. Distal traced cells were located in sub-cortical and cortical regions, including perirhinal, entorhinal and sensory cortices. Innervation from entorhinal cortex (EC) was augmented, in proportion to the running-induced enhancement of adult neurogenesis. Within EC afferent input and short-term synaptic plasticity from lateral entorhinal cortex, considered to convey contextual information to the hippocampus was increased. Furthermore, running upregulated innervation from regions important for spatial memory and theta rhythm generation, including caudo-medial entorhinal cortex and subcortical medial septum, supra- and medial mammillary nuclei. Altogether, running may facilitate contextual, spatial and temporal information encoding by increasing adult hippocampal neurogenesis and by reorganization of new neuron circuitry. PMID:26589333

  20. The human subthalamic nucleus encodes the subjective value of reward and the cost of effort during decision-making.

    PubMed

    Zénon, Alexandre; Duclos, Yann; Carron, Romain; Witjas, Tatiana; Baunez, Christelle; Régis, Jean; Azulay, Jean-Philippe; Brown, Peter; Eusebio, Alexandre

    2016-06-01

    Adaptive behaviour entails the capacity to select actions as a function of their energy cost and expected value and the disruption of this faculty is now viewed as a possible cause of the symptoms of Parkinson's disease. Indirect evidence points to the involvement of the subthalamic nucleus-the most common target for deep brain stimulation in Parkinson's disease-in cost-benefit computation. However, this putative function appears at odds with the current view that the subthalamic nucleus is important for adjusting behaviour to conflict. Here we tested these contrasting hypotheses by recording the neuronal activity of the subthalamic nucleus of patients with Parkinson's disease during an effort-based decision task. Local field potentials were recorded from the subthalamic nucleus of 12 patients with advanced Parkinson's disease (mean age 63.8 years ± 6.8; mean disease duration 9.4 years ± 2.5) both OFF and ON levodopa while they had to decide whether to engage in an effort task based on the level of effort required and the value of the reward promised in return. The data were analysed using generalized linear mixed models and cluster-based permutation methods. Behaviourally, the probability of trial acceptance increased with the reward value and decreased with the required effort level. Dopamine replacement therapy increased the rate of acceptance for efforts associated with low rewards. When recording the subthalamic nucleus activity, we found a clear neural response to both reward and effort cues in the 1-10 Hz range. In addition these responses were informative of the subjective value of reward and level of effort rather than their actual quantities, such that they were predictive of the participant's decisions. OFF levodopa, this link with acceptance was weakened. Finally, we found that these responses did not index conflict, as they did not vary as a function of the distance from indifference in the acceptance decision. These findings show that low

  1. Stereotactic localization of the human pedunculopontine nucleus: atlas-based coordinates and validation of a magnetic resonance imaging protocol for direct localization.

    PubMed

    Zrinzo, Ludvic; Zrinzo, Laurence V; Tisch, Stephen; Limousin, Patricia Dowsey; Yousry, Tarek A; Afshar, Farhad; Hariz, Marwan I

    2008-06-01

    The pedunculopontine nucleus (PPN) is a promising new target for deep brain stimulation (DBS) in parkinsonian patients with gait disturbance and postural instability refractory to other treatment modalities. This region of the brain is unfamiliar territory to most functional neurosurgeons. This paper reviews the anatomy of the human PPN and describes novel, clinically relevant methods for the atlas-based and MRI-based localization of the nucleus. These two methods of PPN localization are evaluated and compared on stereotactic MRI data acquired from a diverse group of 12 patients undergoing implantation of deep brain electrodes at sites other than the PPN. Atlas-based coordinates of the rostral and caudal PPN poles in relation to fourth ventricular landmarks were established by amalgamating information sourced from two published human brain atlases. These landmarks were identified on acquired T1 images and atlas-derived coordinates used to plot the predicted PPN location on all 24 sides. Images acquired using a specifically modified, proton-density MRI protocol were available for each patient and were spatially fused to the T1 images. This widely available and rapid protocol provided excellent definition between gray and white matter within the region of interest. Together with an understanding of the regional anatomy, direct localization of the PPN was possible on all 24 sides. The coordinates for each directly localized nucleus were measured in relation to third and fourth ventricular landmarks. The mean (SD) of the directly localized PPN midpoints was 6.4 mm (0.5) lateral, 3.5 mm (1.0) posterior and 11.4 mm (1.2) caudal to the posterior commissure in the anterior commissure-posterior commissure plane. For the directly localized nucleus, there was similar concordance for the rostral pole of the PPN in relation to third and fourth ventricular landmarks (P>0.05). For the caudal PPN pole, fourth ventricular landmarks provided greater concordance with reference to the

  2. The human subthalamic nucleus encodes the subjective value of reward and the cost of effort during decision-making

    PubMed Central

    Zénon, Alexandre; Duclos, Yann; Carron, Romain; Witjas, Tatiana; Baunez, Christelle; Régis, Jean; Azulay, Jean-Philippe; Brown, Peter; Eusebio, Alexandre

    2016-01-01

    Adaptive behaviour entails the capacity to select actions as a function of their energy cost and expected value and the disruption of this faculty is now viewed as a possible cause of the symptoms of Parkinson’s disease. Indirect evidence points to the involvement of the subthalamic nucleus—the most common target for deep brain stimulation in Parkinson’s disease—in cost-benefit computation. However, this putative function appears at odds with the current view that the subthalamic nucleus is important for adjusting behaviour to conflict. Here we tested these contrasting hypotheses by recording the neuronal activity of the subthalamic nucleus of patients with Parkinson’s disease during an effort-based decision task. Local field potentials were recorded from the subthalamic nucleus of 12 patients with advanced Parkinson’s disease (mean age 63.8 years ± 6.8; mean disease duration 9.4 years ± 2.5) both OFF and ON levodopa while they had to decide whether to engage in an effort task based on the level of effort required and the value of the reward promised in return. The data were analysed using generalized linear mixed models and cluster-based permutation methods. Behaviourally, the probability of trial acceptance increased with the reward value and decreased with the required effort level. Dopamine replacement therapy increased the rate of acceptance for efforts associated with low rewards. When recording the subthalamic nucleus activity, we found a clear neural response to both reward and effort cues in the 1–10 Hz range. In addition these responses were informative of the subjective value of reward and level of effort rather than their actual quantities, such that they were predictive of the participant’s decisions. OFF levodopa, this link with acceptance was weakened. Finally, we found that these responses did not index conflict, as they did not vary as a function of the distance from indifference in the acceptance decision. These findings show

  3. Relationship between Initial Telomere Length, Initial Telomerase Activity, Age, and Replicative Capacity of Nucleus Pulposus Chondrocytes in Human Intervertebral Discs: What Is a Predictor of Replicative Potential?

    PubMed Central

    Lee, Jun-Seok; Jeong, Seo-Won; Cho, Sung-Wook; Juhn, Joon-Pyo; Kim, Ki-Won

    2015-01-01

    There is evidence that telomere length (TL), telomerase activity (TA), and age are related to the replicative potential of human nucleus pulposus chondrocytes (NPCs). However, it has not yet been established if any of these factors can serve as predictors of the replicative potential of NPCs. To establish predictors of the replicative potential of NPCs, we evaluated potential relationships between replicative capacity of NPCs, initial TL (telomere length at the first passage), initial TA (telomerase activity at the first passage), and age. Nucleus pulposus specimens were obtained from 14 patients of various ages undergoing discectomy. NPCs were serially cultivated until the end of their replicative lifespans. Relationships among cumulative population doubling level (PDL), initial TL, initial TA, and age were analyzed. Initial TA was negatively correlated with age (r = -0.674, P = 0.008). However, no correlation between initial TL and age was observed. Cumulative PDL was also negatively correlated with age (r = -0.585, P = 0.028). Although the cumulative PDL appeared to increase with initial TL or initial TA, this trend was not statistically significant. In conclusion, age is the sole predictor of the replicative potential of human NPCs, and replicative potential decreases with age. Initial TL and initial TA are not predictors of replicative potential, and can serve only as reference values. PMID:26633809

  4. Increased dentate neurogenesis after grafting of glial restricted progenitors or neural stem cells in the aging hippocampus.

    PubMed

    Hattiangady, Bharathi; Shuai, Bing; Cai, Jingli; Coksaygan, Turhan; Rao, Mahendra S; Shetty, Ashok K

    2007-08-01

    Neurogenesis in the dentate gyrus (DG) declines severely by middle age, potentially because of age-related changes in the DG microenvironment. We hypothesize that providing fresh glial restricted progenitors (GRPs) or neural stem cells (NSCs) to the aging hippocampus via grafting enriches the DG microenvironment and thereby stimulates the production of new granule cells from endogenous NSCs. The GRPs isolated from the spinal cords of embryonic day 13.5 transgenic F344 rats expressing human alkaline phosphatase gene and NSCs isolated from embryonic day 9 caudal neural tubes of Sox-2:EGFP transgenic mice were expanded in vitro and grafted into the hippocampi of middle-aged (12 months old) F344 rats. Both types of grafts survived well, and grafted NSCs in addition migrated to all layers of the hippocampus. Phenotypic characterization revealed that both GRPs and NSCs differentiated predominantly into astrocytes and oligodendrocytic progenitors. Neuronal differentiation of graft-derived cells was mostly absent except in the dentate subgranular zone (SGZ), where some of the migrated NSCs but not GRPs differentiated into neurons. Analyses of the numbers of newly born neurons in the DG using 5'-bromodeoxyuridine and/or doublecortin assays, however, demonstrated considerably increased dentate neurogenesis in animals receiving grafts of GRPs or NSCs in comparison with both naïve controls and animals receiving sham-grafting surgery. Thus, both GRPs and NSCs survive well, differentiate predominantly into glia, and stimulate the endogenous NSCs in the SGZ to produce more new dentate granule cells following grafting into the aging hippocampus. Grafting of GRPs or NSCs therefore provides an attractive approach for improving neurogenesis in the aging hippocampus. Disclosure of potential conflicts of interest is found at the end of this article. PMID:17510219

  5. 5-Lipoxygenase is located in the euchromatin of the nucleus in resting human alveolar macrophages and translocates to the nuclear envelope upon cell activation.

    PubMed Central

    Woods, J W; Coffey, M J; Brock, T G; Singer, I I; Peters-Golden, M

    1995-01-01

    5-Lipoxygenase (5-LO) and 5-lipoxygenase-activating protein (FLAP) are two key proteins involved in the synthesis of leukotrienes (LT) from arachidonic acid. Although both alveolar macrophages (AM) and peripheral blood leukocytes (PBL) produce large amounts of LT after activation, 5-LO translocates from a soluble pool to a particulate fraction upon activation of PBL, but is contained in the particulate fraction in AM irrespective of activation. We have therefore examined the subcellular localization of 5-LO in autologous human AM and PBL collected from normal donors. While immunogold electron microscopy demonstrated little 5-LO in resting PBL, resting AM exhibited abundant 5-LO epitopes in the euchromatin region of the nucleus. The presence of substantial quantities of 5-LO in the nucleus of resting AM was verified by cell fractionation and immunoblot analysis and by indirect immunofluorescence microscopy. In both AM and PBL activated by A23187, all of the observable 5-LO immunogold labeling was found associated with the nuclear envelope. In resting cells of both types, FLAP was predominantly associated with the nuclear envelope, and its localization was not affected by activation with A23187. The effects of MK-886, which binds to FLAP, were examined in ionophore-stimulated AM and PBL. Although MK-886 inhibited LT synthesis in both cell types, it failed to prevent the translocation of 5-LO to the nuclear envelope. These results indicate that the nuclear envelope is the site at which 5-LO interacts with FLAP and arachidonic acid to catalyze LT synthesis in activated AM as well as PBL, and that in resting AM the euchromatin region of the nucleus is the predominant source of the translocated enzyme. In addition, LT synthesis is a two-step process consisting of FLAP-independent translocation of 5-LO to the nuclear envelope followed by the FLAP-dependent activation of the enzyme. Images PMID:7738170

  6. Sustained transcription of the immediate early gene Arc in the dentate gyrus after spatial exploration.

    PubMed

    Ramirez-Amaya, Victor; Angulo-Perkins, Arafat; Chawla, Monica K; Barnes, Carol A; Rosi, Susanna

    2013-01-23

    After spatial exploration in rats, Arc mRNA is expressed in ∼2% of dentate gyrus (DG) granule cells, and this proportion of Arc-positive neurons remains stable for ∼8 h. This long-term presence of Arc mRNA following behavior is not observed in hippocampal CA1 pyramidal cells. We report here that in rats ∼50% of granule cells with cytoplasmic Arc mRNA, induced some hours previously during exploration, also show Arc expression in the nucleus. This suggests that recent transcription can occur long after the exploration behavior that elicited it. To confirm that the delayed nuclear Arc expression was indeed recent transcription, Actinomycin D was administered immediately after exploration. This treatment resulted in inhibition of recent Arc expression both when evaluated shortly after exploratory behavior as well as after longer time intervals. Together, these data demonstrate a unique kinetic profile for Arc transcription in hippocampal granule neurons following behavior that is not observed in other cell types. Among a number of possibilities, this sustained transcription may provide a mechanism that ensures that the synaptic connection weights in the sparse population of granule cells recruited during a given behavioral event are able to be modified. PMID:23345235

  7. Expression of acid-sensing ion channels in nucleus pulposus cells of the human intervertebral disk is regulated by non-steroid anti-inflammatory drugs.

    PubMed

    Sun, Xue; Jin, Jun; Zhang, Ji-Gang; Qi, Lin; Braun, Frank Karl; Zhang, Xing-Ding; Xu, Feng

    2014-09-01

    Non-steroid anti-inflammatory drugs (NSAIDs) are generally used in the treatment of inflammation and pain through cyclooxygenase (COX) inhibition. Mounting evidence has indicated additional COX-independent targets for NSAIDs including acid-sensing ion channels (ASICs) 1a and 3. However, detailed function and mechanism of ASICs still remain largely elusive. In this study, the impact of NSAIDs on ASICs in nucleus pulposus cells of the human intervertebral disk was investigated. Nucleus pulposus cells were isolated and cultured from protruded disk tissues of 40 patients. It was shown that ASIC1a and ASIC3 were expressed and functional in these cells by analyzing proton-gated currents after ASIC inhibition. We further investigated the neuroprotective capacity of ibuprofen (a COX inhibitor), psalmotoxin-1 (PcTX1, a tarantula toxin specific for homomeric ASIC1a), and amiloride (a classic inhibitor of the epithelial sodium channel ENaC/DEG family to which ASICs belong). PcTX1-containing venom has been shown to be comparable with amiloride in its neuroprotective features in rodent models of ischemia. Taken together, our data showed that amiloride, PcTX1, and ibuprofen decreased ASIC protein expression and thereby exerted protective effects from ASIC inhibition-mediated cell damage. PMID:25079679

  8. Expression of acid-sensing ion channels in nucleus pulposus cells of the human intervertebral disk is regulated by non-steroid anti-inflammatory drugs

    PubMed Central

    Sun, Xue; Jin, Jun; Zhang, Ji-Gang; Qi, Lin; Braun, Frank Karl; Zhang, Xing-Ding; Xu, Feng

    2014-01-01

    Non-steroid anti-inflammatory drugs (NSAIDs) are generally used in the treatment of inflammation and pain through cyclooxygenase (COX) inhibition. Mounting evidence has indicated additional COX-independent targets for NSAIDs including acid-sensing ion channels (ASICs) 1a and 3. However, detailed function and mechanism of ASICs still remain largely elusive. In this study, the impact of NSAIDs on ASICs in nucleus pulposus cells of the human intervertebral disk was investigated. Nucleus pulposus cells were isolated and cultured from protruded disk tissues of 40 patients. It was shown that ASIC1a and ASIC3 were expressed and functional in these cells by analyzing proton-gated currents after ASIC inhibition. We further investigated the neuroprotective capacity of ibuprofen (a COX inhibitor), psalmotoxin-1 (PcTX1, a tarantula toxin specific for homomeric ASIC1a), and amiloride (a classic inhibitor of the epithelial sodium channel ENaC/DEG family to which ASICs belong). PcTX1-containing venom has been shown to be comparable with amiloride in its neuroprotective features in rodent models of ischemia. Taken together, our data showed that amiloride, PcTX1, and ibuprofen decreased ASIC protein expression and thereby exerted protective effects from ASIC inhibition-mediated cell damage. PMID:25079679

  9. FasL Expression on Human Nucleus Pulposus Cells Contributes to the Immune Privilege of Intervertebral Disc by Interacting with Immunocytes

    PubMed Central

    Liu, Zhi-Heng; Sun, Zhen; Wang, Hai-Qiang; Ge, Jun; Jiang, Ting-Shuai; Chen, Yu-Fei; Ma, Ying; Wang, Chen; Hu, Sheng; Samartzis, Dino; Luo, Zhuo-Jing

    2013-01-01

    The mechanisms of immune privilege in human nucleus pulposus (NP) remain unclear. Accumulating evidence indicates that Fas ligand (FasL) might play an important role in the immune privilege of the disc. We aimed for addressing the role of FasL expression in human intervertebral disc degeneration (IDD) and immune privilege in terms of the interaction between NP cells and immunocytes via the FasL-Fas machinery. We collected NP specimens from 20 patients with IDD as degenerative group and 8 normal cadaveric donors as control. FasL expression was detected by qRT-PCR, western blotting and flow cytometry (FCM). We also collected macrophages and CD8+ T cells from the peripheral blood of patients with IDD for co-cultures with NP cells. And macrophages and CD8+ T cells were harvested for apoptosis analysis by FCM after 2 days of co-cultures. We found that FasL expression in mRNA, protein and cellular resolutions demonstrated a significant decrease in degenerative group compared with normal control (p<0.05). FCM analysis found that human NP cells with increased FasL expression resulted in significantly increased apoptosis ratio of macrophages and CD8+ T cells. Our study demonstrated that FasL expression tends to decrease in degenerated discs and FasL plays an important role in human disc immune privilege, which might provide a novel target for the treatment strategies for IDD. PMID:23801893

  10. In vivo imaging of dendritic pruning in dentate granule cells.

    PubMed

    Gonçalves, J Tiago; Bloyd, Cooper W; Shtrahman, Matthew; Johnston, Stephen T; Schafer, Simon T; Parylak, Sarah L; Tran, Thanh; Chang, Tina; Gage, Fred H

    2016-06-01

    We longitudinally imaged the developing dendrites of adult-born mouse dentate granule cells (DGCs) in vivo and found that they underwent over-branching and pruning. Exposure to an enriched environment and constraint of dendritic growth by disrupting Wnt signaling led to increased branch addition and accelerated growth, which were, however, counteracted by earlier and more extensive pruning. Our results indicate that pruning is regulated in a homeostatic fashion to oppose excessive branching and promote a similar dendrite structure in DGCs. PMID:27135217

  11. Functioning methionine sulfoxide reductases A and B are present in human epidermal melanocytes in the cytosol and in the nucleus

    SciTech Connect

    Schallreuter, Karin U.; Chavan, Bhaven; Gillbro, Johanna M.

    2006-03-31

    Oxidation of methionine residues by reactive oxygen (ROS) in protein structures leads to the formation of methionine sulfoxide which can consequently lead to a plethora of impaired functionality. The generation of methionine sulfoxide yields ultimately a diastereomeric mixture of the S and R sulfoxides. So far two distinct enzyme families have been identified. MSRA reduces methionine S-sulfoxide, while MSRB reduces the R-diastereomer. It has been shown that these enzymes are involved in regulation of protein function and in elimination of ROS via reversible methionine formation besides protein repair. Importantly, both enzymes require coupling to the NADPH/thioredoxin reductase/thioredoxin electron donor system. In this report, we show for First time the expression and function of both sulfoxide reductases together with thioredoxin reductase in the cytosol as well as in the nucleus of epidermal melanocytes which are especially sensitive to ROS. Since this cell resides in the basal layer of the epidermis and its numbers and functions are reduced upon ageing and for instance also in depigmentation processes, we believe that this discovery adds an intricate repair mechanism to melanocyte homeostasis and survival.

  12. Mesenchymal stem cells regulate mechanical properties of human degenerated nucleus pulposus cells through SDF-1/CXCR4/AKT axis.

    PubMed

    Liu, Ming-Han; Bian, Bai-Shi-Jiao; Cui, Xiang; Liu, Lan-Tao; Liu, Huan; Huang, Bo; Cui, You-Hong; Bian, Xiu-Wu; Zhou, Yue

    2016-08-01

    Transplantation of mesenchymal stem cells (MSCs) into the degenerated intervertebral disc (IVD) has shown promise for decelerating or arresting IVD degeneration. Cellular mechanical properties play crucial roles in regulating cell-matrix interactions, potentially reflecting specific changes that occur based on cellular phenotype and behavior. However, the effect of co-culturing of MSCs with nucleus pulposus cells (NPCs) on the mechanical properties of NPCs remains unknown. In our study, we demonstrated that co-culture of degenerated NPCs with MSCs resulted in significantly decreased mechanical moduli (elastic modulus, relaxed modulus, and instantaneous modulus) and increased biological activity (proliferation and expression of matrix genes) in degenerated NPCs, but not normal NPCs. SDF-1, CXCR4 ligand, was highly expressed in MSCs when co-cultured with degenerated NPCs. Inhibition of SDF-1 using CXCR4 antagonist AMD3100 or knocking-down CXCR4 in degenerated NPCs abolished the MSCs-induced decrease in the mechanical moduli and increased biological activity of degenerated NPCs, suggesting a crucial role for SDF-1/CXCR4 signaling. AKT and FAK inhibition attenuated the MSCs- or SDF-1-induced decrease in the mechanical moduli of degenerated NPCs. In conclusion, it was demonstrated in vitro that MSCs regulate the mechanical properties of degenerated NPCs through SDF-1/CXCR4/AKT signaling. These findings highlight a possible mechanical mechanism for MSCs-induced modulation with degenerated NPCs, which may be applicable to MSCs-based therapy for disc degeneration. PMID:27163878

  13. Resting state functional connectivity of the basal nucleus of Meynert in humans: in comparison to the ventral striatum and the effects of age

    PubMed Central

    Li, Chiang-shan R.; Ide, Jaime S.; Zhang, Sheng; Hu, Sien; Chao, Herta H.; Zaborszky, Laszlo

    2014-01-01

    The basal nucleus of Meynert (BNM) provides the primary cholinergic inputs to the cerebral cortex. Loss of neurons in the BNM is linked to cognitive deficits in Alzheimer’s disease and other degenerative conditions. Numerous animal studies described cholinergic and non-cholinergic neuronal responses in the BNM; however, work in humans has been hampered by the difficulty of defining the BNM anatomically. Here, on the basis of a previous study that delineated the BNM of post-mortem human brains in a standard stereotaxic space, we sought to examine functional connectivity of the BNM, as compared to the nucleus accumbens (or ventral striatum, VS), in a large resting state functional magnetic resonance imaging data set. The BNM and VS shared but also showed a distinct pattern of cortical and subcortical connectivity. Compared to the VS, the BNM showed stronger positive connectivity with the putamen, pallidum, thalamus, amygdala and midbrain, as well as the anterior cingulate cortex, supplementary motor area and pre-supplementary motor area, a network of brain regions that respond to salient stimuli and orchestrate motor behavior. In contrast, compared to the BNM, the VS showed stronger positive connectivity with the ventral caudate and medial orbitofrontal cortex, areas implicated in reward processing and motivated behavior. Furthermore, the BNM and VS each showed extensive negative connectivity with visual and lateral prefrontal cortices. Together, the distinct cerebral functional connectivities support the role of the BNM in arousal, saliency responses and cognitive motor control and the VS in reward related behavior. Considering the importance of BNM in age-related cognitive decline, we explored the effects of age on BNM and VS connectivities. BNM connectivity to the visual and somatomotor cortices decreases while connectivity to subcortical structures including the midbrain, thalamus, and pallidum increases with age. These findings of age-related changes of

  14. A highly efficient method for generation of therapeutic quality human pluripotent stem cells by using naive induced pluripotent stem cells nucleus for nuclear transfer.

    PubMed

    Sanal, Madhusudana Girija

    2014-01-01

    Even after several years since the discovery of human embryonic stem cells and induced pluripotent stem cells (iPSC), we are still unable to make any significant therapeutic benefits out of them such as cell therapy or generation of organs for transplantation. Recent success in somatic cell nuclear transfer (SCNT) made it possible to generate diploid embryonic stem cells, which opens up the way to make high-quality pluripotent stem cells. However, the process is highly inefficient and hence expensive compared to the generation of iPSC. Even with the latest SCNT technology, we are not sure whether one can make therapeutic quality pluripotent stem cell from any patient's somatic cells or by using oocytes from any donor. Combining iPSC technology with SCNT, that is, by using the nucleus of the candidate somatic cell which got reprogrammed to pluripotent state instead that of the unmodified nucleus of the candidate somatic cell, would boost the efficiency of the technique, and we would be able to generate therapeutic quality pluripotent stem cells. Induced pluripotent stem cell nuclear transfer (iPSCNT) combines the efficiency of iPSC generation with the speed and natural reprogramming environment of SCNT. The new technique may be called iPSCNT. This technique could prove to have very revolutionary benefits for humankind. This could be useful in generating organs for transplantation for patients and for reproductive cloning, especially for childless men and women who cannot have children by any other techniques. When combined with advanced gene editing techniques (such as CRISPR-Cas system) this technique might also prove useful to those who want to have healthy children but suffer from inherited diseases. The current code of ethics may be against reproductive cloning. However, this will change with time as it happened with most of the revolutionary scientific breakthroughs. After all, it is the right of every human to have healthy offspring and it is the question of

  15. Transient and state modulation of beta power in human subthalamic nucleus during speech production and finger movement.

    PubMed

    Hebb, A O; Darvas, F; Miller, K J

    2012-01-27

    Signs of Parkinson's disease (PD) are augmented by speech and repetitive motor tasks. The neurophysiological basis for this phenomenon is unknown, but may involve augmentation of β (13-30 Hz) oscillations within the subthalamic nucleus (STN). We hypothesized that speech and motor tasks increase β power in STN and propose a mechanism for clinical observations of worsening motor state during such behaviors. Subjects undergoing deep brain stimulation (DBS) surgery performed tasks while STN local field potential (LFP) data were collected. Power in the β frequency range was analyzed across the entire recording to observe slow shifts related to block design and during time epochs synchronized to behavior to evaluate immediate fluctuations related to task execution. Bilaterally symmetric β event related desynchronization was observed in analysis time-locked to subject motor and speech tasks. We also observed slow shifts of β power associated with blocks of tasks. Repetitive combined speech and motor, and isolated motor blocks were associated with the highest bilateral β power state. Overt speech alone and imagined speech were associated with a low bilateral β power state. Thus, changing behavioral tasks is associated with bilateral switching of β power states. This offers a potential neurophysiologic correlate of worsened PD motor signs experienced during clinical examination with provocative tasks: switching into a high β power state may be responsible for worsening motor states in PD patients when performing unilateral repetitive motor tasks and combined speech and motor tasks. Beta state changes could be chronically measured and potentially used to control closed loop neuromodulatory devices in the future. PMID:22173017

  16. Human subthalamic nucleus-medial frontal cortex theta phase coherence is involved in conflict and error related cortical monitoring.

    PubMed

    Zavala, Baltazar; Tan, Huiling; Ashkan, Keyoumars; Foltynie, Thomas; Limousin, Patricia; Zrinzo, Ludvic; Zaghloul, Kareem; Brown, Peter

    2016-08-15

    The medial prefrontal cortex (mPFC) is thought to control the shift from automatic to controlled action selection when conflict is present or when mistakes have been recently committed. Growing evidence suggests that this process involves frequency specific communication in the theta (4-8Hz) band between the mPFC and the subthalamic nucleus (STN), which is the main target of deep brain stimulation (DBS) for Parkinson's disease. Key in this hypothesis is the finding that DBS can lead to impulsivity by disrupting the correlation between higher mPFC oscillations and slower reaction times during conflict. In order to test whether theta band coherence between the mPFC and the STN underlies adjustments to conflict and to errors, we simultaneously recorded mPFC and STN electrophysiological activity while DBS patients performed an arrowed flanker task. These recordings revealed higher theta phase coherence between the two sites during the high conflict trials relative to the low conflict trials. These differences were observed soon after conflicting arrows were displayed, but before a response was executed. Furthermore, trials that occurred after an error was committed showed higher phase coherence relative to trials that followed a correct trial, suggesting that mPFC-STN connectivity may also play a role in error related adjustments in behavior. Interestingly, the phase coherence we observed occurred before increases in theta power, implying that the theta phase and power may influence behavior at separate times during cortical monitoring. Finally, we showed that pre-stimulus differences in STN theta power were related to the reaction time on a given trial, which may help adjust behavior based on the probability of observing conflict during a task. PMID:27181763

  17. Stress decreases, while central nucleus amygdala lesions increase, IL-8 and MIP-1alpha gene expression during tissue healing in non-human primates.

    PubMed

    Kalin, Ned H; Shelton, Steven E; Engeland, Christopher G; Haraldsson, H Magnus; Marucha, Phillip T

    2006-11-01

    Stress impairs healing and in part this effect is thought to be mediated by glucocorticoids. However, the brain systems that underlie the effects of stress on healing remain to be determined. Since the central nucleus of the amygdala (CeA) plays a role in mediating an individual's behavioral and physiological reactivity to stress, we investigated, in rhesus monkeys, whether selective lesions of the CeA altered the gene expression of chemokines (IL-8 and MIP-1alpha) that are associated with early dermal healing. We used rhesus monkeys because they provide an excellent animal model to investigate brain mechanisms relevant to human stress, anxiety, and psychopathology. Hypothalamic-pituitary-adrenal (HPA) activity was assessed in the monkeys prior to the wound healing experiment demonstrating that the CeA lesions reduce HPA activity. In the healing experiment, stress decreased IL-8 and MIP-1alpha gene expression in both CeA lesioned and non-lesioned animals. Conversely, the CeA lesions increased the tissue expression of IL-8 and MIP-1alpha mRNA prior to and after stress exposure. These results demonstrate that in primates the CeA is a key brain region involved in the regulation of processes associated with wound healing. Because of brain and behavioral similarities between rhesus monkeys and humans, these results are particularly relevant to understanding brain mechanisms that influence healing in humans. PMID:16574374

  18. Microglia engulf viable newborn cells in the epileptic dentate gyrus.

    PubMed

    Luo, Cong; Koyama, Ryuta; Ikegaya, Yuji

    2016-09-01

    Microglia, which are the brain's resident immune cells, engulf dead neural progenitor cells during adult neurogenesis in the subgranular zone (SGZ) of the dentate gyrus (DG). The number of newborn cells in the SGZ increases significantly after status epilepticus (SE), but whether and how microglia regulate the number of newborn cells after SE remain unclear. Here, we show that microglia rapidly eliminate newborn cells after SE by primary phagocytosis, a process by which viable cells are engulfed, thereby regulating the number of newborn cells that are incorporated into the DG. The number of newborn cells in the DG was increased at 5 days after SE in the adult mouse brain but rapidly decreased to the control levels within a week. During this period, microglia in the DG were highly active and engulfed newborn cells. We found that the majority of engulfed newborn cells were caspase-negative viable cells. Finally, inactivation of microglia with minocycline maintained the increase in the number of newborn cells after SE. Furthermore, minocycline treatment after SE induced the emergence of hilar ectopic granule cells. Thus, our findings suggest that microglia may contribute to homeostasis of the dentate neurogenic niche by eliminating excess newborn cells after SE via primary phagocytosis. GLIA 2016;64:1508-1517. PMID:27301702

  19. A practical approach to diseases affecting dentate nuclei.

    PubMed

    Khadilkar, S; Jaggi, S; Patel, B; Yadav, R; Hanagandi, P; Faria do Amaral, L L

    2016-01-01

    A wide variety of diseases affect the dentate nuclei. When faced with the radiological demonstration of signal changes in the dentate nuclei, radiologists and clinical neurologists have to sieve through the many possibilities, which they do not encounter on a regular basis. This task can be challenging, and therefore, developing a clinical, radiological, and laboratory approach is important. Information on the topic is scattered and the subject has not yet been reviewed. In this review, a combined clinicoradiological approach is presented. The signal changes in T1, T2, fluid-attenuated inversion recovery (FLAIR), diffusion, susceptibility weighted, and gadolinium-enhanced images can give specific or highly suggestive patterns, which are illustrated. The role of computed tomography (CT) in the diagnostic process is discussed. Specific radiological patterns do not exist in a significant proportion of patients where the clinical and laboratory analysis becomes important. In this review, we group the clinical constellations to narrow down the differential diagnosis and highlight the diagnostic clinical signs, such as tendon xanthomas and Kayser-Fleischer rings. As will be seen, a number of these conditions are potentially reversible, and hence, their early diagnosis is desirable. Finally, key diagnostic tests and available therapies are outlined. The practical approach thus begins with the radiologist and winds its way through the clinician, towards carefully selected diagnostic tests defining the therapy options. PMID:26577296

  20. Early postischemic /sup 45/Ca accumulation in rat dentate hilus

    SciTech Connect

    Benveniste, H.; Diemer, N.H.

    1988-10-01

    Several studies have found postischemic regional accumulation of calcium to be time-dependent and coincident with the progression of ischemic cell change. In the most vulnerable cells in the hippocampus one would therefore expect to find a primary and specific early uptake of calcium after ischemia. Autoradiograms of /sup 45/Ca and /sup 3/H-inulin distribution were investigated before and 1 h after 20 min ischemia in the rat hippocampus. Two different methodological approaches were used for administration of /sup 45/Ca: (a) administration via microdialysis probes, (b) intraventricular injection. During control conditions the /sup 45/Ca autoradiograms showed variations in distribution volume in accordance with /sup 3/H-inulin determination of extracellular space size. One hour after ischemia a massive accumulation of /sup 45/Ca was found in the dentate hilus. No change in the distribution pattern of /sup 3/H-inulin could be demonstrated 1 h after ischemia. We suggest that /sup 45/Ca accumulation in dentate hilus 1 h after ischemia is a result of increased Ca/sup 2 +/ uptake before irreversible cell damage occurs and is not due to passive influx of calcium across a leaky plasma membrane.

  1. Organization of Multisynaptic Inputs to the Dorsal and Ventral Dentate Gyrus: Retrograde Trans-Synaptic Tracing with Rabies Virus Vector in the Rat

    PubMed Central

    Ohara, Shinya; Sato, Sho; Tsutsui, Ken-Ichiro; Witter, Menno P.; Iijima, Toshio

    2013-01-01

    Behavioral, anatomical, and gene expression studies have shown functional dissociations between the dorsal and ventral hippocampus with regard to their involvement in spatial cognition, emotion, and stress. In this study we examined the difference of the multisynaptic inputs to the dorsal and ventral dentate gyrus (DG) in the rat by using retrograde trans-synaptic tracing of recombinant rabies virus vectors. Three days after the vectors were injected into the dorsal or ventral DG, monosynaptic neuronal labeling was present in the entorhinal cortex, medial septum, diagonal band, and supramammillary nucleus, each of which is known to project to the DG directly. As in previous tracing studies, topographical patterns related to the dorsal and ventral DG were seen in these regions. Five days after infection, more of the neurons in these regions were labeled and labeled neurons were also seen in cortical and subcortical regions, including the piriform and medial prefrontal cortices, the endopiriform nucleus, the claustrum, the cortical amygdala, the medial raphe nucleus, the medial habenular nucleus, the interpeduncular nucleus, and the lateral septum. As in the monosynaptically labeled regions, a topographical distribution of labeled neurons was evident in most of these disynaptically labeled regions. These data indicate that the cortical and subcortical inputs to the dorsal and ventral DG are conveyed through parallel disynaptic pathways. This second-order input difference in the dorsal and ventral DG is likely to contribute to the functional differentiation of the hippocampus along the dorsoventral axis. PMID:24223172

  2. High energy nucleus-nucleus collisions

    NASA Technical Reports Server (NTRS)

    Wosiek, B.

    1986-01-01

    Experimental results on high energy nucleus-nucleus interactions are presented. The data are discussed within the framework of standard super-position models and from the point-of-view of the possible formation of new states of matter in heavy ion collisions.

  3. Seizure-Induced Motility of Differentiated Dentate Granule Cells Is Prevented by the Central Reelin Fragment.

    PubMed

    Orcinha, Catarina; Münzner, Gert; Gerlach, Johannes; Kilias, Antje; Follo, Marie; Egert, Ulrich; Haas, Carola A

    2016-01-01

    Granule cell dispersion (GCD) represents a pathological widening of the granule cell layer in the dentate gyrus and it is frequently observed in patients with mesial temporal lobe epilepsy (MTLE). Recent studies in human MTLE specimens and in animal epilepsy models have shown that a decreased expression and functional inactivation of the extracellular matrix protein Reelin correlates with GCD formation, but causal evidence is still lacking. Here, we used unilateral kainate (KA) injection into the mouse hippocampus, an established MTLE animal model, to precisely map the loss of reelin mRNA-synthesizing neurons in relation to GCD along the septotemporal axis of the epileptic hippocampus. We show that reelin mRNA-producing neurons are mainly lost in the hilus and that this loss precisely correlates with the occurrence of GCD. To monitor GCD formation in real time, we used organotypic hippocampal slice cultures (OHSCs) prepared from mice which express enhanced green fluorescent protein (eGFP) primarily in differentiated dentate granule cells. Using life cell microscopy we observed that increasing doses of KA resulted in an enhanced motility of eGFP-positive granule cells. Moreover, KA treatment of OHSC resulted in a rapid loss of Reelin-producing interneurons mainly in the hilus, as observed in vivo. A detailed analysis of the migration behavior of individual eGFP-positive granule cells revealed that the majority of these neurons actively migrate toward the hilar region, where Reelin-producing neurons are lost. Treatment with KA and subsequent addition of the recombinant R3-6 Reelin fragment significantly prevented the movement of eGFP-positive granule cells. Together, these findings suggest that GCD formation is indeed triggered by a loss of Reelin in hilar interneurons. PMID:27516734

  4. Seizure-Induced Motility of Differentiated Dentate Granule Cells Is Prevented by the Central Reelin Fragment

    PubMed Central

    Orcinha, Catarina; Münzner, Gert; Gerlach, Johannes; Kilias, Antje; Follo, Marie; Egert, Ulrich; Haas, Carola A.

    2016-01-01

    Granule cell dispersion (GCD) represents a pathological widening of the granule cell layer in the dentate gyrus and it is frequently observed in patients with mesial temporal lobe epilepsy (MTLE). Recent studies in human MTLE specimens and in animal epilepsy models have shown that a decreased expression and functional inactivation of the extracellular matrix protein Reelin correlates with GCD formation, but causal evidence is still lacking. Here, we used unilateral kainate (KA) injection into the mouse hippocampus, an established MTLE animal model, to precisely map the loss of reelin mRNA-synthesizing neurons in relation to GCD along the septotemporal axis of the epileptic hippocampus. We show that reelin mRNA-producing neurons are mainly lost in the hilus and that this loss precisely correlates with the occurrence of GCD. To monitor GCD formation in real time, we used organotypic hippocampal slice cultures (OHSCs) prepared from mice which express enhanced green fluorescent protein (eGFP) primarily in differentiated dentate granule cells. Using life cell microscopy we observed that increasing doses of KA resulted in an enhanced motility of eGFP-positive granule cells. Moreover, KA treatment of OHSC resulted in a rapid loss of Reelin-producing interneurons mainly in the hilus, as observed in vivo. A detailed analysis of the migration behavior of individual eGFP-positive granule cells revealed that the majority of these neurons actively migrate toward the hilar region, where Reelin-producing neurons are lost. Treatment with KA and subsequent addition of the recombinant R3–6 Reelin fragment significantly prevented the movement of eGFP-positive granule cells. Together, these findings suggest that GCD formation is indeed triggered by a loss of Reelin in hilar interneurons. PMID:27516734

  5. Disruption of the brain-derived neurotrophic factor (BDNF) immunoreactivity in the human Kölliker-Fuse nucleus in victims of unexplained fetal and infant death

    PubMed Central

    Lavezzi, Anna M.; Corna, Melissa F.; Matturri, Luigi

    2014-01-01

    Experimental studies have demonstrated that the neurotrophin brain-derived neutrophic factor (BDNF) is required for the appropriate development of the central respiratory network, a neuronal complex in the brainstem of vital importance to sustaining life. The pontine Kölliker-Fuse nucleus (KFN) is a fundamental component of this circuitry with strong implications in the pre- and postnatal breathing control. This study provides detailed account for the cytoarchitecture, the physiology and the BDNF behavior of the human KFN in perinatal age. We applied immunohistochemistry in formalin-fixed and paraffin-embedded brainstem samples (from 45 fetuses and newborns died of both known and unknown causes), to analyze BDNF, gliosis and apoptosis patterns of manifestation. The KFN showed clear signs of developmental immaturity, prevalently associated to BDNF altered expression, in high percentages of sudden intrauterine unexplained death syndrome (SIUDS) and sudden infant death syndrome (SIDS) victims. Our results indicate that BDNF pathway dysfunctions can derange the normal KFN development so preventing the breathing control in the sudden perinatal death. The data presented here are also relevant to a better understanding of how the BDNF expression in the KFN can be involved in several human respiratory pathologies such as the Rett's and the congenital central hypoventilation syndromes. PMID:25237300

  6. Effects of age, replicative lifespan and growth rate of human nucleus pulposus cells on selecting age range for cell-based biological therapies for degenerative disc diseases.

    PubMed

    Lee, J S; Lee, S M; Jeong, S W; Sung, Y G; Lee, J H; Kim, K W

    2016-07-01

    Autologous disc cell implantation, growth factors and gene therapy appear to be promising therapies for disc regeneration. Unfortunately, the replicative lifespan and growth kinetics of human nucleus pulposus (NP) cells related to host age are unclear. We investigated the potential relations among age, replicative lifespan and growth rate of NP cells, and determined the age range that is suitable for cell-based biological therapies for degenerative disc diseases. We used NP tissues classified by decade into five age groups: 30s, 40s, 50s, 60s and 70s. The mean cumulative population doubling level (PDL) and population doubling rate (PDR) of NP cells were assessed by decade. We also investigated correlations between cumulative PDL and age, and between PDR and age. The mean cumulative PDL and PDR decreased significantly in patients in their 60s. The mean cumulative PDL and PDR in the younger groups (30s, 40s and 50s) were significantly higher than those in the older groups (60s and 70s). There also were significant negative correlations between cumulative PDL and age, and between PDR and age. We found that the replicative lifespan and growth rate of human NP cells decreased with age. The replicative potential of NP cells decreased significantly in patients 60 years old and older. Young individuals less than 60 years old may be suitable candidates for NP cell-based biological therapies for treating degenerative disc diseases. PMID:27149303

  7. A highly efficient method for generation of therapeutic quality human pluripotent stem cells by using naive induced pluripotent stem cells nucleus for nuclear transfer

    PubMed Central

    2014-01-01

    Even after several years since the discovery of human embryonic stem cells and induced pluripotent stem cells (iPSC), we are still unable to make any significant therapeutic benefits out of them such as cell therapy or generation of organs for transplantation. Recent success in somatic cell nuclear transfer (SCNT) made it possible to generate diploid embryonic stem cells, which opens up the way to make high-quality pluripotent stem cells. However, the process is highly inefficient and hence expensive compared to the generation of iPSC. Even with the latest SCNT technology, we are not sure whether one can make therapeutic quality pluripotent stem cell from any patient’s somatic cells or by using oocytes from any donor. Combining iPSC technology with SCNT, that is, by using the nucleus of the candidate somatic cell which got reprogrammed to pluripotent state instead that of the unmodified nucleus of the candidate somatic cell, would boost the efficiency of the technique, and we would be able to generate therapeutic quality pluripotent stem cells. Induced pluripotent stem cell nuclear transfer (iPSCNT) combines the efficiency of iPSC generation with the speed and natural reprogramming environment of SCNT. The new technique may be called iPSCNT. This technique could prove to have very revolutionary benefits for humankind. This could be useful in generating organs for transplantation for patients and for reproductive cloning, especially for childless men and women who cannot have children by any other techniques. When combined with advanced gene editing techniques (such as CRISPR-Cas system) this technique might also prove useful to those who want to have healthy children but suffer from inherited diseases. The current code of ethics may be against reproductive cloning. However, this will change with time as it happened with most of the revolutionary scientific breakthroughs. After all, it is the right of every human to have healthy offspring and it is the question of

  8. Usp9x-deficiency disrupts the morphological development of the postnatal hippocampal dentate gyrus.

    PubMed

    Oishi, Sabrina; Premarathne, Susitha; Harvey, Tracey J; Iyer, Swati; Dixon, Chantelle; Alexander, Suzanne; Burne, Thomas H J; Wood, Stephen A; Piper, Michael

    2016-01-01

    Within the adult mammalian brain, neurogenesis persists within two main discrete locations, the subventricular zone lining the lateral ventricles, and the hippocampal dentate gyrus. Neurogenesis within the adult dentate gyrus contributes to learning and memory, and deficiencies in neurogenesis have been linked to cognitive decline. Neural stem cells within the adult dentate gyrus reside within the subgranular zone (SGZ), and proteins intrinsic to stem cells, and factors within the niche microenvironment, are critical determinants for development and maintenance of this structure. Our understanding of the repertoire of these factors, however, remains limited. The deubiquitylating enzyme USP9X has recently emerged as a mediator of neural stem cell identity. Furthermore, mice lacking Usp9x exhibit a striking reduction in the overall size of the adult dentate gyrus. Here we reveal that the development of the postnatal SGZ is abnormal in mice lacking Usp9x. Usp9x conditional knockout mice exhibit a smaller hippocampus and shortened dentate gyrus blades from as early as P7. Moreover, the analysis of cellular populations within the dentate gyrus revealed reduced stem cell, neuroblast and neuronal numbers and abnormal neuroblast morphology. Collectively, these findings highlight the critical role played by USP9X in the normal morphological development of the postnatal dentate gyrus. PMID:27181636

  9. Usp9x-deficiency disrupts the morphological development of the postnatal hippocampal dentate gyrus

    PubMed Central

    Oishi, Sabrina; Premarathne, Susitha; Harvey, Tracey J.; Iyer, Swati; Dixon, Chantelle; Alexander, Suzanne; Burne, Thomas H. J.; Wood, Stephen A.; Piper, Michael

    2016-01-01

    Within the adult mammalian brain, neurogenesis persists within two main discrete locations, the subventricular zone lining the lateral ventricles, and the hippocampal dentate gyrus. Neurogenesis within the adult dentate gyrus contributes to learning and memory, and deficiencies in neurogenesis have been linked to cognitive decline. Neural stem cells within the adult dentate gyrus reside within the subgranular zone (SGZ), and proteins intrinsic to stem cells, and factors within the niche microenvironment, are critical determinants for development and maintenance of this structure. Our understanding of the repertoire of these factors, however, remains limited. The deubiquitylating enzyme USP9X has recently emerged as a mediator of neural stem cell identity. Furthermore, mice lacking Usp9x exhibit a striking reduction in the overall size of the adult dentate gyrus. Here we reveal that the development of the postnatal SGZ is abnormal in mice lacking Usp9x. Usp9x conditional knockout mice exhibit a smaller hippocampus and shortened dentate gyrus blades from as early as P7. Moreover, the analysis of cellular populations within the dentate gyrus revealed reduced stem cell, neuroblast and neuronal numbers and abnormal neuroblast morphology. Collectively, these findings highlight the critical role played by USP9X in the normal morphological development of the postnatal dentate gyrus. PMID:27181636

  10. Neurons of the Dentate Molecular Layer in the Rabbit Hippocampus

    PubMed Central

    Sancho-Bielsa, Francisco J.; Navarro-López, Juan D.; Alonso-Llosa, Gregori; Molowny, Asunción; Ponsoda, Xavier; Yajeya, Javier; López-García, Carlos

    2012-01-01

    The molecular layer of the dentate gyrus appears as the main entrance gate for information into the hippocampus, i.e., where the perforant path axons from the entorhinal cortex synapse onto the spines and dendrites of granule cells. A few dispersed neuronal somata appear intermingled in between and probably control the flow of information in this area. In rabbits, the number of neurons in the molecular layer increases in the first week of postnatal life and then stabilizes to appear permanent and heterogeneous over the individuals’ life span, including old animals. By means of Golgi impregnations, NADPH histochemistry, immunocytochemical stainings and intracellular labelings (lucifer yellow and biocytin injections), eight neuronal morphological types have been detected in the molecular layer of developing adult and old rabbits. Six of them appear as interneurons displaying smooth dendrites and GABA immunoreactivity: those here called as globoid, vertical, small horizontal, large horizontal, inverted pyramidal and polymorphic. Additionally there are two GABA negative types: the sarmentous and ectopic granular neurons. The distribution of the somata and dendritic trees of these neurons shows preferences for a definite sublayer of the molecular layer: small horizontal, sarmentous and inverted pyramidal neurons are preferably found in the outer third of the molecular layer; vertical, globoid and polymorph neurons locate the intermediate third, while large horizontal and ectopic granular neurons occupy the inner third or the juxtagranular molecular layer. Our results reveal substantial differences in the morphology and electrophysiological behaviour between each neuronal archetype in the dentate molecular layer, allowing us to propose a new classification for this neural population. PMID:23144890

  11. Nucleus-nucleus scattering at high energies

    NASA Technical Reports Server (NTRS)

    Franco, V.; Varma, G. K.

    1977-01-01

    Nucleus-nucleus scattering is treated in the Glauber approximation. The usual optical limit result, generally thought to improve as the number of nucleons in the colliding nuclei increases, is found to be the first term of a series which diverges for large nuclei. Corrections to the optical limit are obtained which provide a means of performing realistic calculations for collisions involving light nuclei. Total cross section predictions agree well with recent measurements.

  12. Transplantation of human retinal pigment epithelial cells in the nucleus accumbens of cocaine self-administering rats provides protection from seeking.

    PubMed

    Venkiteswaran, Kala; Alexander, Danielle N; Puhl, Matthew D; Rao, Anand; Piquet, Amanda L; Nyland, Jennifer E; Subramanian, Megha P; Iyer, Puja; Boisvert, Matthew M; Handly, Erin; Subramanian, Thyagarajan; Grigson, Patricia Sue

    2016-05-01

    Chronic exposure to drugs and alcohol leads to damage to dopaminergic neurons and their projections in the 'reward pathway' that originate in the ventral tegmental area (VTA) and terminate in the nucleus accumbens (NAc). This damage is thought to contribute to the signature symptom of addiction: chronic relapse. In this study we show that bilateral transplants of human retinal pigment epithelial cells (RPECs), a cell mediated dopaminergic and trophic neuromodulator, into the medial shell of the NAc, rescue rats with a history of high rates of cocaine self-administration from drug-seeking when returned, after 2 weeks of abstinence, to the drug-associated chamber under extinction conditions (i.e., with no drug available). Excellent survival was noted for the transplant of RPECs in the shell and/or the core of the NAc bilaterally in all rats that showed behavioral recovery from cocaine seeking. Design based unbiased stereology of tyrosine hydroxylase (TH) positive cell bodies in the VTA showed better preservation (p<0.035) in transplanted animals compared to control animals. This experiment shows that the RPEC graft provides beneficial effects to prevent drug seeking in drug addiction via its effects directly on the NAc and its neural network with the VTA. PMID:26562520

  13. Inhibition of U4 snRNA in human cells causes the stable retention of polyadenylated pre-mRNA in the nucleus.

    PubMed

    Hett, Anne; West, Steven

    2014-01-01

    Most human pre-mRNAs contain introns that are removed by splicing. Such a complex process needs strict control and regulation in order to prevent the expression of aberrant or unprocessed transcripts. To analyse the fate of pre-mRNAs that cannot be spliced, we inhibited splicing using an anti-sense morpholino (AMO) against U4 snRNA. As a consequence, splicing of several selected transcripts was strongly inhibited. This was accompanied by the formation of enlarged nuclear speckles containing polyadenylated RNA, splicing factors and the nuclear poly(A) binding protein. Consistently, more polyadenylated pre-mRNA could be isolated from nucleoplasmic as well as chromatin-associated RNA fractions following U4 inhibition. Further analysis demonstrated that accumulated pre-mRNAs were stable in the nucleus and that nuclear RNA degradation factors did not re-localise to nuclear speckles following splicing inhibition. The accumulation of pre-mRNA and the formation of enlarged speckles were sensitive to depletion of the 3' end processing factor, CPSF73, suggesting a requirement for poly(A) site processing in this mechanism. Finally, we provide evidence that the pre-mRNAs produced following U4 snRNA inhibition remain competent for splicing, perhaps providing a biological explanation for their stability. These data further characterise processes ensuring the nuclear retention of pre-mRNA that cannot be spliced and suggest that, in some cases, unspliced transcripts can complete splicing sometime after their initial synthesis. PMID:24796696

  14. Inositol hexaphosphate represses telomerase activity and translocates TERT from the nucleus in mouse and human prostate cancer cells via the deactivation of Akt and PKC{alpha}

    SciTech Connect

    Jagadeesh, Shankar; Banerjee, Partha P. . E-mail: ppb@georgetown.edu

    2006-11-03

    Inositol hexaphosphate (IP6) has anti-proliferative effects on a variety of cancer cells, including prostate cancer. However, the molecular mechanism of anti-proliferative effects of IP6 is not entirely understood. Since the activation of telomerase is crucial for cells to gain immortality and proliferation ability, we examined the role of IP6 in the regulation of telomerase activity in prostate cancer cells. Here, we show that IP6 represses telomerase activity in mouse and human prostate cancer cells dose-dependently. In addition, IP6 prevents the translocation of TERT to the nucleus. Since phosphorylation of TERT by Akt and/or PKC{alpha} is necessary for nuclear translocation, we examined phosphorylation of Akt and PKC{alpha} after IP6 treatments. Our results show that IP6 inhibits phosphorylation of Akt and PKC{alpha}. These results show for the first time that IP6 represses telomerase activity in prostate cancer cells by posttranslational modification of TERT via the deactivation of Akt and PKC{alpha}.

  15. HUHS1015 induces necroptosis and caspase-independent apoptosis of MKN28 human gastric cancer cells in association with AMID accumulation in the nucleus.

    PubMed

    Kaku, Yoshiko; Tsuchiya, Ayako; Kanno, Takeshi; Nishizaki, Tomoyuki

    2015-01-01

    The newly synthesized naftopidil analogue HUHS1015 reduced viability of MKN28 and MKN45 human gastric cancer cells in a concentration (0.3-100 μM)-dependent manner, with the potential greater than that for naftopidil. In the cell cycle analysis, HUHS1015 significantly increased the proportion at the subG1 phase of cell cycling in MKN28 cells. In the flow cytometry using propidium iodide (PI) and annexin V, HUHS1015 significantly increased the populations of PI-positive/annexin V-negative and PI-positive/annexin V-positive MKN28 cells, corresponding to primary necrosis and late apoptosis/secondary necrosis, respectively. HUHS1015-induced MKN28 cell death was attenuated by the necroptosis inhibitor Nec-1. In the enzymatic caspase assay, caspase-3, -4, -8, and -9 were not sufficiently activated by HUHS1015. HUHS1015 increased nuclear localization of apoptosis-inducing factor-homologous mitochondrion-associated inducer of death (AMID), without affecting expression of the AMID mRNA and protein in MKN28 cells. HUHS1015 caused nuclear fragmentation and condensation in MKN28 cells treated with HUHS1015. Taken together, these results of the present study indicate that HUHS1015 induces both necroptosis and caspase-independent apoptosis of MKN28 cells, possibly the latter effect being due to AMID accumulation in the nucleus. PMID:25244912

  16. Neuronal responses to tactile stimuli and tactile sensations evoked by microstimulation in the human thalamic principal somatic sensory nucleus (ventral caudal).

    PubMed

    Schmid, Anne-Christine; Chien, Jui-Hong; Greenspan, Joel D; Garonzik, Ira; Weiss, Nirit; Ohara, Shinji; Lenz, Frederick Arthur

    2016-06-01

    The normal organization and plasticity of the cutaneous core of the thalamic principal somatosensory nucleus (ventral caudal, Vc) have been studied by single-neuron recordings and microstimulation in patients undergoing awake stereotactic operations for essential tremor (ET) without apparent somatic sensory abnormality and in patients with dystonia or chronic pain secondary to major nervous system injury. In patients with ET, most Vc neurons responded to one of the four stimuli, each of which optimally activates one mechanoreceptor type. Sensations evoked by microstimulation were similar to those evoked by the optimal stimulus only among rapidly adapting neurons. In patients with ET, Vc was highly segmented somatotopically, and vibration, movement, pressure, and sharp sensations were usually evoked by microstimulation at separate sites in Vc. In patients with conditions including spinal cord transection, amputation, or dystonia, RFs were mismatched with projected fields more commonly than in patients with ET. The representation of the border of the anesthetic area (e.g., stump) or of the dystonic limb was much larger than that of the same part of the body in patients with ET. This review describes the organization and reorganization of human Vc neuronal activity in nervous system injury and dystonia and then proposes basic mechanisms. PMID:26864759

  17. Degenerative Grade Affects the Responses of Human Nucleus Pulposus Cells to Link-N, CTGF, and TGFβ3

    PubMed Central

    Abbott, Rosalyn D.; Purmessur, Devina; Monsey, Robert D.; Brigstock, David R.; Laudier, Damien M.; Iatridis, James C.

    2012-01-01

    Study Design Cells isolated from moderately and severely degenerated human intervertebral discs (IVDs) cultured in an alginate scaffold. Objective To compare the regenerative potential of moderately vs. severely degenerated cells using three pro-anabolic stimulants. Summary of Background Data Injection of soluble cell signaling factors has potential to slow the progression of IVD degeneration. While degenerative grade is thought to be an important factor in targeting therapeutic interventions it remains unknown whether cells in severely degenerated IVDs have impaired metabolic functions compared to lesser degenerative levels or if they are primarily influenced by the altered microenvironment. Methods NP cells were cultured in alginate for 21 days and treated with three different pro-anabolic stimulants: a growth factor/anti-inflammatory combination of TGFβ3+Dex, or matricellular proteins CTGF or Link-N. They were assayed for metabolic activity, DNA content, glycosaminoglycan (GAG), and qRT-PCR gene profiling. Results Moderately degenerated cells responded to stimulation with increased proliferation, decreased IL-1β, MMP9 and COL1A1 expression, and upregulated HAS1 as compared to severely degenerated cells. TGFβR1 (ALK5) receptors were expressed at greater levels in moderately than severely degenerated cells. TGFβ3+Dex had a notable stimulatory effect on moderately degenerated NP cells with increased anabolic gene expression, and decreased COL1A1 and ADAMTS5 gene expression. Link-N and CTGF had similar responses in all assays, and both treatments up-regulated IL-1β expression and had a more catabolic response than TGFβ3+Dex, particularly in the more severely degenerated group. All groups, including different degenerative grades, produced similar amounts of GAG. Conclusion Pro-anabolic stimulants alone had limited capacity to overcome the catabolic and pro-inflammatory cytokine expression of severely degenerated NP cells and likely require additional anti

  18. TGF-β1 and GDF5 Act Synergistically to Drive the Differentiation of Human Adipose Stromal Cells toward Nucleus Pulposus-like Cells.

    PubMed

    Colombier, Pauline; Clouet, Johann; Boyer, Cécile; Ruel, Maëva; Bonin, Gaëlle; Lesoeur, Julie; Moreau, Anne; Fellah, Borhane-Hakim; Weiss, Pierre; Lescaudron, Laurent; Camus, Anne; Guicheux, Jérôme

    2016-03-01

    Degenerative disc disease (DDD) primarily affects the central part of the intervertebral disc namely the nucleus pulposus (NP). DDD explains about 40% of low back pain and is characterized by massive cellular alterations that ultimately result in the disappearance of resident NP cells. Thus, repopulating the NP with regenerative cells is a promising therapeutic approach and remains a great challenge. The objectives of this study were to evaluate the potential of growth factor-driven protocols to commit human adipose stromal cells (hASCs) toward NP-like cell phenotype and the involvement of Smad proteins in this differentiation process. Here, we demonstrate that the transforming growth factor-β1 and the growth differentiation factor 5 synergistically drive the nucleopulpogenic differentiation process. The commitment of the hASCs was robust and highly specific as attested by the expression of NP-related genes characteristic of young healthy human NP cells. In addition, the engineered NP-like cells secreted an abundant aggrecan and type II collagen rich extracellular matrix comparable with that of native NP. Furthermore, we demonstrate that these in vitro engineered cells survived, maintained their specialized phenotype and secretory activity after in vivo transplantation in nude mice subcutis. Finally, we provide evidence suggesting that the Smad 2/3 pathway mainly governed the acquisition of the NP cell molecular identity while the Smad1/5/8 pathway controlled the NP cell morphology. This study offers valuable insights for the development of biologically-inspired treatments for DDD by generating adapted and exhaustively characterized autologous regenerative cells. Stem Cells 2016;34:653-667. PMID:26661057

  19. EARLY EFFECTS OF TRIMETHYLTIN ON THE DENTATE GYRUS BASKET CELLS: A MORPHOLOGICAL STUDY

    EPA Science Inventory

    Electrophysiological evidence for reduction of recurrent inhibition in the dentate gyrus in animals exposed to trimethyltin (TMT) suggested alterations in the inhibitory neurons (basket cells) by TMT. The present study was designed to investigate the morphology of basket cells af...

  20. Insulin-Like Growth Factor (IGF) Binding Protein-3 (IGFBP-3) is Closely Associated with the Chondrocyte Nucleus in Human Articular Cartilage

    PubMed Central

    EB, Hunziker; E, Kapfinger; J, Martin; J, Buckwalter; TI, Morales

    2008-01-01

    Objective The Insulin-like Growth Factor-I (IGF-I) is critically involved in the control of cartilage matrix metabolism. It is well known that its binding protein-3 (IGFBP-3) is increased during osteoarthritis (OA), but its function(s) is not known. In other cells, IGFBP-3 can regulate IGF-I action in the extracellular environment and can also act independently inside the cell; this includes transcriptional gene control in the nucleus. These studies were undertaken to localize IGFBP-3 in human articular cartilage, particularly within cells. Design Cartilage was dissected from human femoral heads derived from arthroplasty for OA, and OA grade assessed by histology. Tissue slices were further characterized by extraction and assay of IGFBPs by IGF Ligand blot (LB) and by ELISA. Immunohistochemistry (IHC) for IGF-I and IGFBP-3 was performed on cartilage from donors with mild, moderate and severe OA. Indirect fluorescence and immunogold labeling IHC studies were included. Results LBs of chondrocyte lysates showed a strong signal for IGFBP-3. IHC of femoral cartilage sections at all OA stages showed IGF-I and IGFBP-3 matrix stain particularly in the top zones, and closely associated with most cells. A prominent perinuclear/nuclear IGFBP-3 signal was seen. Controls using non-immune sera or antigen-blocked antibody showed negative or strongly reduced stain. In frozen sections of human ankle cartilage, immunofluorescent IGFBP-3 stain co-localized with the nuclear DAPI stain in greater than 90% of the cells. Immunogold IHC of thin sections and TEM immunogold microscopy of ultra-thin sections showed distinct intra-nuclear staining. Conclusions IGFBP-3 in human cartilage is located in the matrix and within chondrocytes in the cytoplasm and nuclei. This new data indicates that the range of IGFBP-3 actions in articular cartilage is likely to include IGF independent roles and opens the door to studies of its nuclear actions, including the possible regulation of hormone receptors

  1. Unique Features of the Human Brainstem and Cerebellum

    PubMed Central

    Baizer, Joan S.

    2014-01-01

    The cerebral cortex is greatly expanded in the human brain. There is a parallel expansion of the cerebellum, which is interconnected with the cerebral cortex. We have asked if there are accompanying changes in the organization of pre-cerebellar brainstem structures. We have examined the cytoarchitectonic and neurochemical organization of the human medulla and pons. We studied human cases from the Witelson Normal Brain Collection, analyzing Nissl sections and sections processed for immunohistochemistry for multiple markers including the calcium-binding proteins calbindin, calretinin, and parvalbumin, non-phosphorylated neurofilament protein, and the synthetic enzyme for nitric oxide, nitric oxide synthase. We have also compared the neurochemical organization of the human brainstem to that of several other species including the chimpanzee, macaque and squirrel monkey, cat, and rodent, again using Nissl staining and immunohistochemistry. We found that there are major differences in the human brainstem, ranging from relatively subtle differences in the neurochemical organization of structures found in each of the species studied to the emergence of altogether new structures in the human brainstem. Two aspects of human cortical organization, individual differences and left–right asymmetry, are also seen in the brainstem (principal nucleus of the inferior olive) and the cerebellum (the dentate nucleus). We suggest that uniquely human motor and cognitive abilities derive from changes at all levels of the central nervous system, including the cerebellum and brainstem, and not just the cerebral cortex. PMID:24778611

  2. Extensive Direct Subcortical Cerebellum-Basal Ganglia Connections in Human Brain as Revealed by Constrained Spherical Deconvolution Tractography

    PubMed Central

    Milardi, Demetrio; Arrigo, Alessandro; Anastasi, Giuseppe; Cacciola, Alberto; Marino, Silvia; Mormina, Enricomaria; Calamuneri, Alessandro; Bruschetta, Daniele; Cutroneo, Giuseppina; Trimarchi, Fabio; Quartarone, Angelo

    2016-01-01

    The connections between the cerebellum and basal ganglia were assumed to occur at the level of neocortex. However evidences from animal data have challenged this old perspective showing extensive subcortical pathways linking the cerebellum with the basal ganglia. Here we tested the hypothesis if these connections also exist between the cerebellum and basal ganglia in the human brain by using diffusion magnetic resonance imaging and tractography. Fifteen healthy subjects were analyzed by using constrained spherical deconvolution technique obtained with a 3T magnetic resonance imaging scanner. We found extensive connections running between the subthalamic nucleus and cerebellar cortex and, as novel result, we demonstrated a direct route linking the dentate nucleus to the internal globus pallidus as well as to the substantia nigra. These findings may open a new scenario on the interpretation of basal ganglia disorders. PMID:27047348

  3. Extensive Direct Subcortical Cerebellum-Basal Ganglia Connections in Human Brain as Revealed by Constrained Spherical Deconvolution Tractography.

    PubMed

    Milardi, Demetrio; Arrigo, Alessandro; Anastasi, Giuseppe; Cacciola, Alberto; Marino, Silvia; Mormina, Enricomaria; Calamuneri, Alessandro; Bruschetta, Daniele; Cutroneo, Giuseppina; Trimarchi, Fabio; Quartarone, Angelo

    2016-01-01

    The connections between the cerebellum and basal ganglia were assumed to occur at the level of neocortex. However evidences from animal data have challenged this old perspective showing extensive subcortical pathways linking the cerebellum with the basal ganglia. Here we tested the hypothesis if these connections also exist between the cerebellum and basal ganglia in the human brain by using diffusion magnetic resonance imaging and tractography. Fifteen healthy subjects were analyzed by using constrained spherical deconvolution technique obtained with a 3T magnetic resonance imaging scanner. We found extensive connections running between the subthalamic nucleus and cerebellar cortex and, as novel result, we demonstrated a direct route linking the dentate nucleus to the internal globus pallidus as well as to the substantia nigra. These findings may open a new scenario on the interpretation of basal ganglia disorders. PMID:27047348

  4. Role of α-synuclein in adult neurogenesis and neuronal maturation in the dentate gyrus

    PubMed Central

    Regensburger, Martin; Schreglmann, Sebastian; Boyer, Leah; Prots, Iryna; Rockenstein, Edward; Mante, Michael; Zhao, Chunmei; Winkler, Jürgen; Masliah, Eliezer; Gage, Fred H.

    2016-01-01

    Summary α-Synuclein has been reported to be important in modulating brain plasticity and to be a key protein in neurodegenerative diseases, including Lewy body dementia (LBD). We investigated how α-synuclein levels modulate adult neurogenesis and the development of dendritic arborization and spines in the dentate gyrus (DG), where new neurons are constantly added. In the human hippocampus, levels of endogenous α-synuclein were increased in LBD and the numbers of SOX2-positive cells were decreased. We investigated whether newly generated neurons were modulated by endogenous α-synuclein and we found increased adult neurogenesis in α/β-synuclein knockout mice. In contrast, overexpression of human wild-type α-synuclein (WTS) decreased the survival and dendritic development of newborn neurons. Endogenous α-synuclein expression levels increased the negative impact of WTS on dendrite development, suggesting a toxic effect of increasing amounts of α-synuclein. To attempt a rescue of the dendritic phenotype, we administered rolipram to activate the cAMP response element-binding protein (CREB) pathway, which led to a partial rescue of neurite development. The current work provides novel insights into the role of α-synuclein in adult hippocampal neurogenesis. PMID:23175842

  5. Objective assessment of mastication predominance in healthy dentate subjects and patients with unilateral posterior missing teeth.

    PubMed

    Yamasaki, Y; Kuwatsuru, R; Tsukiyama, Y; Oki, K; Koyano, K

    2016-08-01

    We aimed to investigate mastication predominance in healthy dentate individuals and patients with unilateral posterior missing teeth using objective and subjective methods. The sample comprised 50 healthy dentate individuals (healthy dentate group) and 30 patients with unilateral posterior missing teeth (partially edentulous group). Subjects were asked to freely chew three kinds of test foods (peanuts, beef jerky and chewing gum). Electromyographic activity of the bilateral masseter muscles was recorded. The chewing side (right side or left side) was judged by the level of root mean square electromyographic amplitude. Mastication predominance was then objectively assessed using the mastication predominant score and the mastication predominant index. Self-awareness of mastication predominance was evaluated using a modified visual analogue scale. Mastication predominance scores of the healthy dentate and partially edentulous groups for each test food were analysed. There was a significant difference in the distribution of the mastication predominant index between the two groups (P < 0·05). The mastication predominant score was weakly correlated with self-awareness of mastication predominance in the healthy dentate group, whereas strong correlation was observed in the partially edentulous group (P < 0·05). The results suggest that the individuals with missing unilateral posterior teeth exhibited greater mastication predominance and were more aware of mastication predominance than healthy dentate individuals. Our findings suggest that an objective evaluation of mastication predominance is more precise than a subjective method. PMID:27121170

  6. Major diencephalic inputs to the hippocampus: supramammillary nucleus and nucleus reuniens. Circuitry and function

    PubMed Central

    Vertes, Robert P.

    2016-01-01

    The hippocampus receives two major external inputs from the diencephalon, that is, from the supramammillary nucleus (SUM) and nucleus reuniens (RE) of the midline thalamus. These two afferents systems project to separate, nonoverlapping, regions of the hippocampus. Specifically, the SUM distributes to the dentate gyrus (DG) and to CA2 of the dorsal and ventral hippocampus, whereas RE projects to CA1 of the dorsal and ventral hippocampus and to the subiculum. SUM and RE fibers to the hippocampus participate in common as well as in separate functions. Both systems would appear to amplify signals from other sources to their respective hippocampal targets. SUM amplifies signals from the entorhinal cortex (EC) to DG, whereas RE may amplify them from CA3 (and EC) to CA1 of the hippocampus. This “amplification” may serve to promote the transfer, encoding, and possibly storage of information from EC to DG and from CA3 and EC to CA1. Regarding their unique actions on the hippocampus, the SUM is a vital part of an ascending brainstem to hippocampal system generating the theta rhythm of the hippocampus, whereas RE importantly routes information from the medial prefrontal cortex to the hippocampus to thereby mediate functions involving both structures. In summary, although, to date, SUM and RE afferents to the hippocampus have not been extensively explored, the SUM and RE exert a profound influence on the hippocampus in processes of learning and memory. PMID:26072237

  7. PKCε signalling activates ERK1/2, and regulates aggrecan, ADAMTS5, and miR377 gene expression in human nucleus pulposus cells.

    PubMed

    Tsirimonaki, Emmanouella; Fedonidis, Constantinos; Pneumaticos, Spiros G; Tragas, Adamantios A; Michalopoulos, Ioannis; Mangoura, Dimitra

    2013-01-01

    The protein kinase C (PKC) signaling, a major regulator of chondrocytic differentiation, has been also implicated in pathological extracellular matrix remodeling, and here we investigate the mechanism of PKCε-dependent regulation of the chondrocytic phenotype in human nucleus pulposus (NP) cells derived from herniated disks. NP cells from each donor were successfully propagated for 25+ culture passages, with remarkable tolerance to repeated freeze-and-thaw cycles throughout long-term culturing. More specifically, after an initial downregulation of COL2A1, a stable chondrocytic phenotype was attested by the levels of mRNA expression for aggrecan, biglycan, fibromodulin, and lumican, while higher expression of SOX-trio and Patched-1 witnessed further differentiation potential. NP cells in culture also exhibited a stable molecular profile of PKC isoforms: throughout patient samples and passages, mRNAs for PKC α, δ, ε, ζ, η, ι, and µ were steadily detected, whereas β, γ, and θ were not. Focusing on the signalling of PKCε, an isoform that may confer protection against degeneration, we found that activation with the PKCε-specific activator small peptide ψεRACK led sequentially to a prolonged activation of ERK1/2, increased abundance of the early gene products ATF, CREB1, and Fos with concurrent silencing of transcription for Ki67, and increases in mRNA expression for aggrecan. More importantly, ψεRACK induced upregulation of hsa-miR-377 expression, coupled to decreases in ADAMTS5 and cleaved aggrecan. Therefore, PKCε activation in late passage NP cells may represent a molecular basis for aggrecan availability, as part of an PKCε/ERK/CREB/AP-1-dependent transcriptional program that includes upregulation of both chondrogenic genes and microRNAs. Moreover, this pathway should be considered as a target for understanding the molecular mechanism of IVD degeneration and for therapeutic restoration of degenerated disks. PMID:24312401

  8. PKCε Signalling Activates ERK1/2, and Regulates Aggrecan, ADAMTS5, and miR377 Gene Expression in Human Nucleus Pulposus Cells

    PubMed Central

    Pneumaticos, Spiros G.; Tragas, Adamantios A.; Michalopoulos, Ioannis; Mangoura, Dimitra

    2013-01-01

    The protein kinase C (PKC) signaling, a major regulator of chondrocytic differentiation, has been also implicated in pathological extracellular matrix remodeling, and here we investigate the mechanism of PKCε-dependent regulation of the chondrocytic phenotype in human nucleus pulposus (NP) cells derived from herniated disks. NP cells from each donor were successfully propagated for 25+ culture passages, with remarkable tolerance to repeated freeze-and-thaw cycles throughout long-term culturing. More specifically, after an initial downregulation of COL2A1, a stable chondrocytic phenotype was attested by the levels of mRNA expression for aggrecan, biglycan, fibromodulin, and lumican, while higher expression of SOX-trio and Patched-1 witnessed further differentiation potential. NP cells in culture also exhibited a stable molecular profile of PKC isoforms: throughout patient samples and passages, mRNAs for PKC α, δ, ε, ζ, η, ι, and µ were steadily detected, whereas β, γ, and θ were not. Focusing on the signalling of PKCε, an isoform that may confer protection against degeneration, we found that activation with the PKCε-specific activator small peptide ψεRACK led sequentially to a prolonged activation of ERK1/2, increased abundance of the early gene products ATF, CREB1, and Fos with concurrent silencing of transcription for Ki67, and increases in mRNA expression for aggrecan. More importantly, ψεRACK induced upregulation of hsa-miR-377 expression, coupled to decreases in ADAMTS5 and cleaved aggrecan. Therefore, PKCε activation in late passage NP cells may represent a molecular basis for aggrecan availability, as part of an PKCε/ERK/CREB/AP-1-dependent transcriptional program that includes upregulation of both chondrogenic genes and microRNAs. Moreover, this pathway should be considered as a target for understanding the molecular mechanism of IVD degeneration and for therapeutic restoration of degenerated disks. PMID:24312401

  9. Adult neurogenesis in the mammalian hippocampus: Why the dentate gyrus?

    PubMed Central

    Drew, Liam J.; Fusi, Stefano; Hen, René

    2013-01-01

    In the adult mammalian brain, newly generated neurons are continuously incorporated into two networks: interneurons born in the subventricular zone migrate to the olfactory bulb, whereas the dentate gyrus (DG) of the hippocampus integrates locally born principal neurons. That the rest of the mammalian brain loses significant neurogenic capacity after the perinatal period suggests that unique aspects of the structure and function of DG and olfactory bulb circuits allow them to benefit from the adult generation of neurons. In this review, we consider the distinctive features of the DG that may account for it being able to profit from this singular form of neural plasticity. Approaches to the problem of neurogenesis are grouped as “bottom-up,” where the phenotype of adult-born granule cells is contrasted to that of mature developmentally born granule cells, and “top-down,” where the impact of altering the amount of neurogenesis on behavior is examined. We end by considering the primary implications of these two approaches and future directions. PMID:24255101

  10. Dentate Gyrus Circuitry Features Improve Performance of Sparse Approximation Algorithms

    PubMed Central

    Petrantonakis, Panagiotis C.; Poirazi, Panayiota

    2015-01-01

    Memory-related activity in the Dentate Gyrus (DG) is characterized by sparsity. Memory representations are seen as activated neuronal populations of granule cells, the main encoding cells in DG, which are estimated to engage 2–4% of the total population. This sparsity is assumed to enhance the ability of DG to perform pattern separation, one of the most valuable contributions of DG during memory formation. In this work, we investigate how features of the DG such as its excitatory and inhibitory connectivity diagram can be used to develop theoretical algorithms performing Sparse Approximation, a widely used strategy in the Signal Processing field. Sparse approximation stands for the algorithmic identification of few components from a dictionary that approximate a certain signal. The ability of DG to achieve pattern separation by sparsifing its representations is exploited here to improve the performance of the state of the art sparse approximation algorithm “Iterative Soft Thresholding” (IST) by adding new algorithmic features inspired by the DG circuitry. Lateral inhibition of granule cells, either direct or indirect, via mossy cells, is shown to enhance the performance of the IST. Apart from revealing the potential of DG-inspired theoretical algorithms, this work presents new insights regarding the function of particular cell types in the pattern separation task of the DG. PMID:25635776

  11. N-acetyl-S-(N,N-diethylcarbamoyl) cysteine in rat nucleus accumbens, medial prefrontal cortex, and in rat and human plasma after disulfiram administration.

    PubMed

    Winefield, Robert D; Heemskerk, Anthonius A M; Kaul, Swetha; Williams, Todd D; Caspers, Michael J; Prisinzano, Thomas E; McCance-Katz, Elinore F; Lunte, Craig E; Faiman, Morris D

    2015-03-25

    Disulfiram (DSF), a treatment for alcohol use disorders, has shown some clinical effectiveness in treating addiction to cocaine, nicotine, and pathological gambling. The mechanism of action of DSF for treating these addictions is unclear but it is unlikely to involve the inhibition of liver aldehyde dehydrogenase (ALDH2). DSF is a pro-drug and forms a number of metabolites, one of which is N-acetyl-S-(N,N-diethylcarbamoyl) cysteine (DETC-NAC). Here we describe a LCMS/MS method on a QQQ type instrument to quantify DETC-NAC in plasma and intracellular fluid from mammalian brain. An internal standard, the N,N-di-isopropylcarbamoyl homolog (MIM: 291>128) is easily separable from DETC-NAC (MIM: 263>100) on C18 RP media with a methanol gradient. The method's linear range is 0.5-500 nM from plasma and dialysate salt solution with all precisions better than 10% RSD. DETC-NAC and internal standards were recovered at better than 95% from all matrices, perchloric acid precipitation (plasma) or formic acid addition (salt) and is stable in plasma or salt at low pH for up to 24 h. Stability is observed through three freeze-thaw cycles per day for 7 days. No HPLC peak area matrix effect was greater than 10%. A human plasma sample from a prior analysis for S-(N,N-diethylcarbamoyl) glutathione (CARB) was found to have DETC NAC as well. In other human plasma samples from 62.5 mg/d and 250 mg/d dosing, CARB concentration peaks at 0.3 and 4 nM at 3 h followed by DETC-NAC peaks of 11 and 70 nM 2 h later. Employing microdialysis sampling, DETC-NAC levels in the nucleus accumbens (NAc), medial prefrontal cortex (mPFC), and plasma of rats treated with DSF reached 1.1, 2.5 and 80 nM at 6h. The correlation between the appearance and long duration of DETC-NAC concentration in rat brain and the persistence of DSF-induced changes in neurotransmitters observed by Faiman et al. (Neuropharmacology, 2013, 75C, 95-105) is discussed. PMID:25720821

  12. Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults.

    PubMed

    Brickman, Adam M; Khan, Usman A; Provenzano, Frank A; Yeung, Lok-Kin; Suzuki, Wendy; Schroeter, Hagen; Wall, Melanie; Sloan, Richard P; Small, Scott A

    2014-12-01

    The dentate gyrus (DG) is a region in the hippocampal formation whose function declines in association with human aging and is therefore considered to be a possible source of age-related memory decline. Causal evidence is needed, however, to show that DG-associated memory decline in otherwise healthy elders can be improved by interventions that enhance DG function. We addressed this issue by first using a high-resolution variant of functional magnetic resonance imaging (fMRI) to map the precise site of age-related DG dysfunction and to develop a cognitive task whose function localized to this anatomical site. Then, in a controlled randomized trial, we applied these tools to study healthy 50-69-year-old subjects who consumed either a high or low cocoa flavanol-containing diet for 3 months. A high-flavanol intervention was found to enhance DG function, as measured by fMRI and by cognitive testing. Our findings establish that DG dysfunction is a driver of age-related cognitive decline and suggest non-pharmacological means for its amelioration. PMID:25344629

  13. Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults

    PubMed Central

    Brickman, Adam M; Khan, Usman A; Provenzano, Frank A; Yeung, Lok-Kin; Suzuki, Wendy; Schroeter, Hagen; Wall, Melanie; Sloan, Richard P; Small, Scott A

    2016-01-01

    The dentate gyrus (DG) is a region in the hippocampal formation whose function declines in association with human aging and is therefore considered to be a possible source of age-related memory decline. Causal evidence is needed, however, to show that DG-associated memory decline in otherwise healthy elders can be improved by interventions that enhance DG function. We addressed this issue by first using a high-resolution variant of functional magnetic resonance imaging (fMRI) to map the precise site of age-related DG dysfunction and to develop a cognitive task whose function localized to this anatomical site. Then, in a controlled randomized trial, we applied these tools to study healthy 50–69-year-old subjects who consumed either a high or low cocoa–containing diet for 3 months. A high-flavanol intervention was found to enhance DG function, as measured by fMRI and by cognitive testing. Our findings establish that DG dysfunction is a driver of age-related cognitive decline and suggest non-pharmacological means for its amelioration. PMID:25344629

  14. Corruption of the dentate gyrus by "dominant" granule cells: Implications for dentate gyrus function in health and disease.

    PubMed

    Scharfman, Helen E; Myers, Catherine E

    2016-03-01

    The dentate gyrus (DG) and area CA3 of the hippocampus are highly organized lamellar structures which have been implicated in specific cognitive functions such as pattern separation and pattern completion. Here we describe how the anatomical organization and physiology of the DG and CA3 are consistent with structures that perform pattern separation and completion. We then raise a new idea related to the complex circuitry of the DG and CA3 where CA3 pyramidal cell 'backprojections' play a potentially important role in the sparse firing of granule cells (GCs), considered important in pattern separation. We also propose that GC axons, the mossy fibers, already known for their highly specialized structure, have a dynamic function that imparts variance--'mossy fiber variance'--which is important to pattern separation and completion. Computational modeling is used to show that when a subset of GCs become 'dominant,' one consequence is loss of variance in the activity of mossy fiber axons and a reduction in pattern separation and completion in the model. Empirical data are then provided using an example of 'dominant' GCs--subsets of GCs that develop abnormally and have increased excitability. Notably, these abnormal GCs have been identified in animal models of disease where DG-dependent behaviors are impaired. Together these data provide insight into pattern separation and completion, and suggest that behavioral impairment could arise from dominance of a subset of GCs in the DG-CA3 network. PMID:26391451

  15. Mechanics of the Nucleus

    PubMed Central

    Lammerding, Jan

    2015-01-01

    The nucleus is the distinguishing feature of eukaryotic cells. Until recently, it was often considered simply as a unique compartment containing the genetic information of the cell and associated machinery, without much attention to its structure and mechanical properties. This article provides compelling examples that illustrate how specific nuclear structures are associated with important cellular functions, and how defects in nuclear mechanics can cause a multitude of human diseases. During differentiation, embryonic stem cells modify their nuclear envelope composition and chromatin structure, resulting in stiffer nuclei that reflect decreased transcriptional plasticity. In contrast, neutrophils have evolved characteristic lobulated nuclei that increase their physical plasticity, enabling passage through narrow tissue spaces in their response to inflammation. Research on diverse cell types further demonstrates how induced nuclear deformations during cellular compression or stretch can modulate cellular function. Pathological examples of disturbed nuclear mechanics include the many diseases caused by mutations in the nuclear envelope proteins lamin A/C and associated proteins, as well as cancer cells that are often characterized by abnormal nuclear morphology. In this article, we will focus on determining the functional relationship between nuclear mechanics and cellular (dys-)function, describing the molecular changes associated with physiological and pathological examples, the resulting defects in nuclear mechanics, and the effects on cellular function. New insights into the close relationship between nuclear mechanics and cellular organization and function will yield a better understanding of normal biology and will offer new clues into therapeutic approaches to the various diseases associated with defective nuclear mechanics. PMID:23737203

  16. Alpha-CaMKII deficiency causes immature dentate gyrus, a novel candidate endophenotype of psychiatric disorders

    PubMed Central

    Yamasaki, Nobuyuki; Maekawa, Motoko; Kobayashi, Katsunori; Kajii, Yasushi; Maeda, Jun; Soma, Miho; Takao, Keizo; Tanda, Koichi; Ohira, Koji; Toyama, Keiko; Kanzaki, Kouji; Fukunaga, Kohji; Sudo, Yusuke; Ichinose, Hiroshi; Ikeda, Masashi; Iwata, Nakao; Ozaki, Norio; Suzuki, Hidenori; Higuchi, Makoto; Suhara, Tetsuya; Yuasa, Shigeki; Miyakawa, Tsuyoshi

    2008-01-01

    Elucidating the neural and genetic factors underlying psychiatric illness is hampered by current methods of clinical diagnosis. The identification and investigation of clinical endophenotypes may be one solution, but represents a considerable challenge in human subjects. Here we report that mice heterozygous for a null mutation of the alpha-isoform of calcium/calmodulin-dependent protein kinase II (alpha-CaMKII+/-) have profoundly dysregulated behaviours and impaired neuronal development in the dentate gyrus (DG). The behavioral abnormalities include a severe working memory deficit and an exaggerated infradian rhythm, which are similar to symptoms seen in schizophrenia, bipolar mood disorder and other psychiatric disorders. Transcriptome analysis of the hippocampus of these mutants revealed that the expression levels of more than 2000 genes were significantly changed. Strikingly, among the 20 most downregulated genes, 5 had highly selective expression in the DG. Whereas BrdU incorporated cells in the mutant mouse DG was increased by more than 50 percent, the number of mature neurons in the DG was dramatically decreased. Morphological and physiological features of the DG neurons in the mutants were strikingly similar to those of immature DG neurons in normal rodents. Moreover, c-Fos expression in the DG after electric footshock was almost completely and selectively abolished in the mutants. Statistical clustering of human post-mortem brains using 10 genes differentially-expressed in the mutant mice were used to classify individuals into two clusters, one of which contained 16 of 18 schizophrenic patients. Nearly half of the differentially-expressed probes in the schizophrenia-enriched cluster encoded genes that are involved in neurogenesis or in neuronal migration/maturation, including calbindin, a marker for mature DG neurons. Based on these results, we propose that an "immature DG" in adulthood might induce alterations in behavior and serve as a promising

  17. Transforming growth factor-beta 3 stimulates cartilage matrix elaboration by human marrow-derived stromal cells encapsulated in photocrosslinked carboxymethylcellulose hydrogels: potential for nucleus pulposus replacement.

    PubMed

    Gupta, Michelle S; Cooper, Elana S; Nicoll, Steven B

    2011-12-01

    Degeneration of the nucleus pulposus (NP) has been implicated as a major cause of low back pain. Tissue engineering strategies using marrow-derived stromal cells (MSCs) have been used to develop cartilaginous tissue constructs, which may serve as viable NP replacements. Supplementation with growth factors, such as transforming growth factor-beta 3 (TGF-β3), has been shown to enhance the differentiation of MSCs and promote functional tissue development of such constructs. A potential candidate material that may be useful as a scaffold for NP tissue engineering is carboxymethylcellulose (CMC), a biocompatible, cost-effective derivative of cellulose. Photocrosslinked CMC hydrogels have been shown to support NP cell viability and promote phenotypic matrix deposition capable of maintaining mechanical properties when cultured in serum-free, chemically defined medium (CDM) supplemented with TGF-β3. However, MSCs have not been characterized using this hydrogel system. In this study, human MSCs (hMSCs) were encapsulated in photocrosslinked CMC hydrogels and cultured in CDM with and without TGF-β3 to determine the effect of the growth factor on the differentiation of hMSCs toward an NP-like phenotype. Constructs were evaluated for matrix elaboration and functional properties consistent with native NP tissue. CDM supplemented with TGF-β3 resulted in significantly higher glycosaminoglycan content (762.69±220.79 ng/mg wet weight) and type II collagen (COL II) content (6.25±1.64 ng/mg wet weight) at day 21 compared with untreated samples. Immunohistochemical analyses revealed uniform, pericellular, and interterritorial staining for chondroitin sulfate proteoglycan and COL II in growth factor-supplemented constructs compared with faint, strictly pericellular staining in untreated constructs at 21 days. Consistent with matrix deposition, mechanical properties of hydrogels treated with TGF-β3 increased over time and exhibited the highest peak stress in stress-relaxation (

  18. Microinjection of histamine into the dentate gyrus produces antinociception in the formalin test in rats.

    PubMed

    Khalilzadeh, Emad; Tamaddonfard, Esmaeal; Farshid, Amir Abbas; Erfanparast, Amir

    2010-12-01

    The present study was aimed to investigate the effects of microinjection of histamine, chlorpheniramine (a histamine H(1) receptor antagonist), ranitidine (a histamine H(2) receptor antagonist) and thioperamide (a histamine H(3) receptor antagonist) into the dentate gyrus on the formalin-induced pain. A biphasic pattern (first phase: 0-5min and second phase: 15-60min) in nociceptive responses was induced after subcutaneous injection of formalin (50μl, 2.5%) into the ventral surface of the right hind paw. Microinjection of histamine (1 and 2μg) into the dentate gyrus decreased the intensity of nociceptive responses. Intra-dentate gyrus microinjection of chlorpheniramine and ranitidine at the same doses of 1 and 4μg had no effects, whereas thioperamide at a dose of 4μg suppressed both phases of formalin-induced pain. Pretreatments with chlorpheniramine and ranitidine at the same dose of 4μg prevented histamine (2μg)-induced antinociception, while thioperamide (4μg) increased histamine (2μg)-induced antinociception. These results indicated that activation of brain neuronal histamine at the levels of dentate gyrus produced antinociception. The post-synaptic H(1), H(2) receptors and pre-synaptic H(3) receptors of histamine may be involved in the histamine-induced antinociception at the level of the dentate gyrus. PMID:20826178

  19. Hypertrophy of the inferior olivary nucleus in patients with progressive supranuclear palsy.

    PubMed

    Hanihara, T; Amano, N; Takahashi, T; Itoh, Y; Yagishita, S

    1998-01-01

    Hypertrophic changes in the inferior olivary nuclei have been occasionally described in patients with progressive supranuclear palsy (PSP). To elucidate the incidence of olivary hypertrophy, we investigated morphologically the olives and their associated pathways in 20 autopsied cases: 11 cases of PSP, 3 cases of Machado-Joseph disease and 6 cases of dentatorubropallidoluysian atrophy (DRPLA) as control diseases that usually exhibited lesions of the cerebellofugal pathway. Olivary hypertrophy was observed in 5 of 11 PSP cases, but not in the other diseases, except for 1 case of DRPLA with an old infarct in the dentate nucleus. In the olivopetal pathway, grumose degeneration of the dentate nucleus and mild neuronal loss in the red nucleus were observed in all patients with PSP and in the control subjects. Atrophy and fibrillary gliosis of the tegmentum of the pons, including that of the bilateral central tegmental tracts, were observed in all patients with PSP, more severe in the cases with hypertrophic neurons in the olives. We speculate that a lesion that involves the central tegmental tracts may play a major role in inducing hypertrophy of the olives in patients with PSP. PMID:9520070

  20. The Nucleus Introduced

    PubMed Central

    Pederson, Thoru

    2011-01-01

    Now is an opportune moment to address the confluence of cell biological form and function that is the nucleus. Its arrival is especially timely because the recognition that the nucleus is extremely dynamic has now been solidly established as a paradigm shift over the past two decades, and also because we now see on the horizon numerous ways in which organization itself, including gene location and possibly self-organizing bodies, underlies nuclear functions. PMID:20660024

  1. Oscillatory dynamics in the hippocampus support dentate gyrus–CA3 coupling

    PubMed Central

    Akam, Thomas; Oren, Iris; Mantoan, Laura; Ferenczi, Emily; Kullmann, Dimitri M

    2012-01-01

    Gamma oscillations in the dentate gyrus and hippocampal CA3 show variable coherence in vivo, but the mechanisms and relevance for information flow are unknown. We found that carbachol-induced oscillations in rat CA3 have biphasic phase-response curves, consistent with the ability to couple with oscillations in afferent projections. Differences in response to stimulation of either the intrinsic feedback circuit or the dentate gyrus were well described by varying an impulse vector in a two-dimensional dynamical system, representing the relative input to excitatory and inhibitory neurons. Responses to sinusoidally modulated optogenetic stimulation confirmed that the CA3 network oscillation can entrain to periodic inputs, with a steep dependence of entrainment phase on input frequency. CA3 oscillations are therefore suited to coupling with oscillations in the dentate gyrus over a broad range of frequencies. PMID:22466505

  2. The ventral hippocampus is the embryonic origin for adult neural stem cells in the dentate gyrus

    PubMed Central

    Li, Guangnan; Fang, Li; Fernández, Gloria; Pleasure, Samuel J.

    2013-01-01

    SUMMARY Adult neurogenesis represents a unique form of plasticity in the dentate gyrus requiring the presence of long-lived neural stem cells (LL-NSCs). However, the embryonic origin of these LL-NSCs remains unclear. The prevailing model assumes that the dentate neuroepithelium throughout the longitudinal axis of the hippocampus generates both the LL-NSCs and embryonically produced granule neurons. Here we show that the NSCs initially originate from the ventral hippocampus during late gestation and then relocate into the dorsal hippocampus. The descendants of these cells are the source for the LL-NSCs in the subgranular zone (SGZ). Furthermore, we show that the origin of these cells and their maintenance in the dentate are controlled by distinct sources of Sonic Hedgehog (Shh). The revelation of the complexity of both the embryonic origin of hippocampal LL-NSCs and the sources of Shh has important implications for the functions of LL-NSCs in the adult hippocampus. PMID:23643936

  3. Oscillatory dynamics in the hippocampus support dentate gyrus–CA3 coupling.

    PubMed

    Akam, Thomas; Oren, Iris; Mantoan, Laura; Ferenczi, Emily; Kullmann, Dimitri M

    2012-05-01

    Gamma oscillations in the dentate gyrus and hippocampal CA3 show variable coherence in vivo, but the mechanisms and relevance for information flow are unknown. We found that carbachol-induced oscillations in rat CA3 have biphasic phase-response curves, consistent with the ability to couple with oscillations in afferent projections. Differences in response to stimulation of either the intrinsic feedback circuit or the dentate gyrus were well described by varying an impulse vector in a two-dimensional dynamical system, representing the relative input to excitatory and inhibitory neurons. Responses to sinusoidally modulated optogenetic stimulation confirmed that the CA3 network oscillation can entrain to periodic inputs, with a steep dependence of entrainment phase on input frequency. CA3 oscillations are therefore suited to coupling with oscillations in the dentate gyrus over a broad range of frequencies. PMID:22466505

  4. Rapid erasure of hippocampal memory following inhibition of dentate gyrus granule cells

    PubMed Central

    Madroñal, Noelia; Delgado-García, José M.; Fernández-Guizán, Azahara; Chatterjee, Jayanta; Köhn, Maja; Mattucci, Camilla; Jain, Apar; Tsetsenis, Theodoros; Illarionova, Anna; Grinevich, Valery; Gross, Cornelius T.; Gruart, Agnès

    2016-01-01

    The hippocampus is critical for the acquisition and retrieval of episodic and contextual memories. Lesions of the dentate gyrus, a principal input of the hippocampus, block memory acquisition, but it remains unclear whether this region also plays a role in memory retrieval. Here we combine cell-type specific neural inhibition with electrophysiological measurements of learning-associated plasticity in behaving mice to demonstrate that dentate gyrus granule cells are not required for memory retrieval, but instead have an unexpected role in memory maintenance. Furthermore, we demonstrate the translational potential of our findings by showing that pharmacological activation of an endogenous inhibitory receptor expressed selectively in dentate gyrus granule cells can induce a rapid loss of hippocampal memory. These findings open a new avenue for the targeted erasure of episodic and contextual memories. PMID:26988806

  5. Rapid erasure of hippocampal memory following inhibition of dentate gyrus granule cells.

    PubMed

    Madroñal, Noelia; Delgado-García, José M; Fernández-Guizán, Azahara; Chatterjee, Jayanta; Köhn, Maja; Mattucci, Camilla; Jain, Apar; Tsetsenis, Theodoros; Illarionova, Anna; Grinevich, Valery; Gross, Cornelius T; Gruart, Agnès

    2016-01-01

    The hippocampus is critical for the acquisition and retrieval of episodic and contextual memories. Lesions of the dentate gyrus, a principal input of the hippocampus, block memory acquisition, but it remains unclear whether this region also plays a role in memory retrieval. Here we combine cell-type specific neural inhibition with electrophysiological measurements of learning-associated plasticity in behaving mice to demonstrate that dentate gyrus granule cells are not required for memory retrieval, but instead have an unexpected role in memory maintenance. Furthermore, we demonstrate the translational potential of our findings by showing that pharmacological activation of an endogenous inhibitory receptor expressed selectively in dentate gyrus granule cells can induce a rapid loss of hippocampal memory. These findings open a new avenue for the targeted erasure of episodic and contextual memories. PMID:26988806

  6. Impaired long-term potentiation induction in dentate gyrus of calretinin-deficient mice

    PubMed Central

    Schurmans, Stéphane; Schiffmann, Serge N.; Gurden, Hirac; Lemaire, Martine; Lipp, Hans-Peter; Schwam, Valérie; Pochet, Roland; Imperato, Assunta; Böhme, Georg Andrees; Parmentier, Marc

    1997-01-01

    Calretinin (Cr) is a Ca2+ binding protein present in various populations of neurons distributed in the central and peripheral nervous systems. We have generated Cr-deficient (Cr−/−) mice by gene targeting and have investigated the associated phenotype. Cr−/− mice were viable, and a large number of morphological, biochemical, and behavioral parameters were found unaffected. In the normal mouse hippocampus, Cr is expressed in a widely distributed subset of GABAergic interneurons and in hilar mossy cells of the dentate gyrus. Because both types of cells are part of local pathways innervating dentate granule cells and/or pyramidal neurons, we have explored in Cr−/− mice the synaptic transmission between the perforant pathway and granule cells and at the Schaffer commissural input to CA1 pyramidal neurons. Cr−/− mice showed no alteration in basal synaptic transmission, but long-term potentiation (LTP) was impaired in the dentate gyrus. Normal LTP could be restored in the presence of the GABAA receptor antagonist bicuculline, suggesting that in Cr−/− dentate gyrus an excess of γ-aminobutyric acid (GABA) release interferes with LTP induction. Synaptic transmission and LTP were normal in CA1 area, which contains only few Cr-positive GABAergic interneurons. Cr−/− mice performed normally in spatial memory task. These results suggest that expression of Cr contributes to the control of synaptic plasticity in mouse dentate gyrus by indirectly regulating the activity of GABAergic interneurons, and that Cr−/− mice represent a useful tool to understand the role of dentate LTP in learning and memory. PMID:9294225

  7. Injection of human umbilical tissue–derived cells into the nucleus pulposus alters the course of intervertebral disc degeneration in vivo

    PubMed Central

    Leckie, Steven K.; Sowa, Gwendolyn A.; Bechara, Bernard P.; Hartman, Robert A.; Coelho, Joao Paulo; Witt, William T.; Dong, Qing D.; Bowman, Brent W.; Bell, Kevin M.; Vo, Nam V.; Kramer, Brian C.; Kang, James D.

    2016-01-01

    Background context Patients often present to spine clinic with evidence of intervertebral disc degeneration (IDD). If conservative management fails, a safe and effective injection directly into the disc might be preferable to the risks and morbidity of surgery. Purpose To determine whether injecting human umbilical tissue–derived cells (hUTC) into the nucleus pulposus (NP) might improve the course of IDD. Design Prospective, randomized, blinded placebo–controlled in vivo study. Patient sample Skeletally mature New Zealand white rabbits. Outcome measures Degree of IDD based on magnetic resonance imaging (MRI), biomechanics, and histology. Methods Thirty skeletally mature New Zealand white rabbits were used in a previously validated rabbit annulotomy model for IDD. Discs L2–L3, L3–L4, and L4–L5 were surgically exposed and punctured to induce degeneration and then 3 weeks later the same discs were injected with hUTC with or without a hydrogel carrier. Serial MRIs obtained at 0, 3, 6, and 12 weeks were analyzed for evidence of degeneration qualitatively and quantitatively via NP area and MRI Index. The rabbits were sacrificed at 12 weeks and discs L4–L5 were analyzed histologically. The L3–L4 discs were fixed to a robotic arm and subjected to uniaxial compression, and viscoelastic displacement curves were generated. Results Qualitatively, the MRIs demonstrated no evidence of degeneration in the control group over the course of 12 weeks. The punctured group yielded MRIs with the evidence of disc height loss and darkening, suggestive of degeneration. The three treatment groups (cells alone, carrier alone, or cells+carrier) generated MRIs with less qualitative evidence of degeneration than the punctured group. MRI Index and area for the cell and the cell+carrier groups were significantly distinct from the punctured group at 12 weeks. The carrier group generated MRI data that fell between control and punctured values but failed to reach a statistically

  8. In vivo 7 Tesla imaging of the dentate granule cell layer in Schizophrenia

    PubMed Central

    Kirov, Ivan I.; Hardy, Caitlin J.; Matsuda, Kant; Messinger, Julie; Cankurtaran, Ceylan Z.; Warren, Melina; Wiggins, Graham C.; Perry, Nissa N.; Babb, James S.; Goetz, Raymond R.; George, Ajax; Malaspina, Dolores; Gonen, Oded

    2013-01-01

    PURPOSE The hippocampus is central to the pathophysiology of schizophrenia. Histology shows abnormalities in the dentate granule cell layer (DGCL), but its small size (~100 micron thickness) has precluded in vivo human studies. We used ultra high field magnetic resonance imaging (MRI) to compare DGCL morphology of schizophrenic patients to matched controls’. METHOD Bilateral hippocampi of 16 schizophrenia patients (10 male) 40.7±10.6 years old (mean ±standard deviation) were imaged at 7 Tesla MRI with heavily T2*-weighted gradient-echo sequence at 232 micron in-plane resolution (0.08 μL image voxels). Fifteen matched controls (8 male, 35.6±9.4 years old) and one ex vivo post mortem hippocampus (that also underwent histopathology) were scanned with same protocol. Three blinded neuroradiologists rated each DGCL on a qualitative scale of 1 to 6 (from “not discernible” to “easily visible, appearing dark gray or black”) and mean left and right DGCL scores were compared using a non-parametric Mann-Whitney test. RESULTS MRI identification of the DGCL was validated with histopathology. Mean right and left DGCL ratings in patients (3.2±1.0 and 3.5±1.2) were not statistically different from controls’ (3.9±1.1 and 3.8±0.8), but patients’ had a trend for lower right DGCL score (p=0.07), which was significantly associated with patient diagnosis (p=0.05). The optimal 48% sensitivity and 80% specificity for schizophrenia was achieved with a DGCL rating of ≤2. CONCLUSION Decreased contrast in the right DGCL in schizophrenia was predictive of schizophrenia diagnosis. Better utility of this metric as a schizophrenia biomarker may be achieved in future studies of patients with homogeneous disease subtypes and progression rates. PMID:23664589

  9. Kaon-nucleus scattering

    NASA Technical Reports Server (NTRS)

    Hong, Byungsik; Maung, Khin Maung; Wilson, John W.; Buck, Warren W.

    1989-01-01

    The derivations of the Lippmann-Schwinger equation and Watson multiple scattering are given. A simple optical potential is found to be the first term of that series. The number density distribution models of the nucleus, harmonic well, and Woods-Saxon are used without t-matrix taken from the scattering experiments. The parameterized two-body inputs, which are kaon-nucleon total cross sections, elastic slope parameters, and the ratio of the real to the imaginary part of the forward elastic scattering amplitude, are presented. The eikonal approximation was chosen as our solution method to estimate the total and absorptive cross sections for the kaon-nucleus scattering.

  10. Convergence of the nucleus-nucleus Glauber multiple scattering series

    SciTech Connect

    Usmani, A.A.; Ahmad, I. )

    1991-05-01

    The Glauber {ital S}-matrix operator for nucleus-nucleus scattering is expressed as a finite series of matrix elements involving Bell's polynomials. Analyzing {alpha}{sup 4}He elastic-scattering data at the incident momentum of 4.32 GeV/{ital c}, we infer that our expansion is appreciably converging. Further, by applying closure over target and projectile states and neglecting a certain class of terms involving intermediate excitations, we arrive at a recurrence relation for nucleus-nucleus multiple scattering series terms, which invites further study as it seems to provide a simple method for calculating the nucleus-nucleus elastic-scattering cross section.

  11. Dentate Gyrus Is Necessary for Disambiguating Similar Object-Place Representations

    ERIC Educational Resources Information Center

    Lee, Inah; Solivan, Frances

    2010-01-01

    Objects are often remembered with their locations, which is an important aspect of event memory. Despite the well-known involvement of the hippocampus in event memory, detailed intrahippocampal mechanisms are poorly understood. In particular, no experimental evidence has been provided in support of the role of the dentate gyrus (DG) in…

  12. Differential susceptibility to chronic social defeat stress relates to the number of Dnmt3a-immunoreactive neurons in the hippocampal dentate gyrus.

    PubMed

    Hammels, Caroline; Prickaerts, Jos; Kenis, Gunter; Vanmierlo, Tim; Fischer, Maximilian; Steinbusch, Harry W M; van Os, Jim; van den Hove, Daniel L A; Rutten, Bart P F

    2015-01-01

    The enzyme DNA methyltransferase 3a (Dnmt3a) is crucially involved in DNA methylation and recent studies have demonstrated that Dnmt3a is functionally involved in mediating and moderating the impact of environmental exposures on gene expression and behavior. Findings in rodents have suggested that DNA methylation is involved in regulating neuronal proliferation and differentiation. So far, it has been shown that chronic social defeat might influence neurogenesis, while susceptibility to social defeat stress is dependent on gene expression changes in the nucleus accumbens and the mesolimbic dopaminergic system. However, the role of Dnmt3a herein has not been fully characterized. Our earlier immunohistochemical work has revealed the existence of two types of Dnmt3a-immunoreactive cells in the mouse hippocampus, of which one represents a distinct type with intense Dnmt3a-immunoreactivity (Dnmt3a type II cells) co-localizing with a marker of recent proliferation. Based on this, we hypothesize that behavioral susceptibility to chronic social defeat stress is linked to (i) Dnmt3a protein levels in the nucleus accumbens and hippocampus, and (ii) to the density of Dnmt3a type II cells in the hippocampal dentate gyrus. While no differences were found in global levels of Dnmt3a protein expression in the nucleus accumbens and hippocampus, our stereological quantifications indicated a significantly increased density of Dnmt3a type II cells in the dentate gyrus of animals resilient to social defeat stress compared to susceptible and control animals. Further characterization of the Dnmt3a type II cells revealed that these cells were mostly doublecortin (25%) or NeuN (60%) immunopositive, thus defining them as immature and mature neurons. Moreover, negative associations between the density of Dnmt3a type II cells and indices of depressive-like behavior in the sucrose intake and forced swim test were found. These correlational data suggest that DNA methylation via Dnmt3a in the

  13. Nucleus Course in Japanese.

    ERIC Educational Resources Information Center

    Akiyama, Nobuo; Flamm, Carol S.

    The "Nucleus Course in Japanese," based on the Institute of Modern Languages'"Situational Reinforcement" approach, is designed for 80 to 100 hours of instruction. Each lesson has several sections--Response drills, Appropriate Response Sequence, and Reading. Most of the lessons also include optional sections with Sentences for Repetition or a…

  14. Cell nucleus in context

    SciTech Connect

    Lelievre, Sophie A.; Bissell, Mina J.; Pujuguet, Philippe

    1999-11-11

    The molecular pathways that participate in regulation of gene expression are being progressively unraveled. Extracellular signals, including the binding of extracellular matrix and soluble molecules to cell membrane receptors, activate specific signal transducers that convey information inside the cell and can alter gene products. Some of these transducers when translocated to the cell nucleus may bind to transcription complexes and thereby modify the transcriptional activity of specific genes. However, the basic molecules involved in the regulation of gene expression are found in many different cell and tissue types; thus the mechanisms underlying tissue-specific gene expression are still obscure. In this review, we focus on the study of signals that are conveyed to the nucleus. We propose that the way in which extracellular signals are integrated may account for tissue-specific gene expression. We argue that the integration of signals depends on the structural organization of cells ( i.e., extracellular matrix, cell membrane, cytoskeleton, nucleus) which a particular cell type within a tissue. Putting the nuclei in context allows us to envision gene expression as being regulated not only by the communication between the extracellular environment and the nucleus, but also by the influence of organized assemblies of cells on extracellular-nuclear communications.

  15. Effect of chronic stress on synaptic currents in rat hippocampal dentate gyrus neurons.

    PubMed

    Karst, Henk; Joëls, Marian

    2003-01-01

    We investigated the effect of chronic stress on synaptic responses of rat dentate granule cells to perforant path stimulation. Rats were subjected for 3 wk to unpredictable stressors twice daily or to control handling. One day after the last stressor, hippocampal slices were prepared and synaptic responses were determined with whole-cell recording. At that time, adrenal weight was found to be increased and thymus weight as well as gain in body weight were decreased in the stressed versus control animals, indicative of corticosterone hypersecretion during the stress period. In slices from rats with basal corticosteroid levels (at the circadian trough, under rest), no effect of prior stress exposure was observed on synaptic responses. However, synaptic responses of dentate granule cells from chronically stressed and control rats were differently affected by in vitro activation of glucocorticoid receptors, i.e., 1-4 h after administration of 100 nM corticosterone for 20 min. Thus the maximal response to synaptic activation of dentate cells at holding potential of -70 mV [when N-methyl-D-aspartate (NMDA) receptors are blocked by magnesium] was significantly enhanced after corticosterone administration in chronically stressed but not in control animals. In accordance, the amplitude of alpha-amino-3-hydroxy-5-methylisolazole-4-propionic acid (AMPA) but not of NMDA receptor-mediated currents was increased by corticosterone in stressed rats, over the entire voltage range. Corticosterone treatment also decreased the time to peak of AMPA currents, but this effect did not depend on prior stress exposure. The data indicate that following chronic stress exposure synaptic excitation of dentate granule cells may be enhanced when corticosterone levels rise. This enhanced synaptic flow could contribute to enhanced excitation of projection areas of the dentate gyrus, most notably the CA3 hippocampal region. PMID:12522207

  16. Impact of rearrangements of function and position of chromosomes in the interphase nucleus: Relevance to karyotype-phenotype correlation, birth defects, and other human pathologic conditions

    SciTech Connect

    Oumsiyeh, M.B.

    1994-09-01

    There has been considerable work on the interphase nuclear architecture in the 100 years since the suggestion that chromosomes occupy specific domains in the interphase nucleus. The arrangement of chromatin in the interphase nucleus plays a significant role in gene replication, recombination, and transcription. Here I present data relevant to the question of chromosome rearrangements and nuclear stability. Specifically I show that: (1) balanced chromosome rearrangement associated with congenital anomalies result in nuclear instability/micronucleus formation (data on a patient with frontonasal dysplasia and a complex balanced translocation), (2) gene amplification as homogeneously staining regions is associated with nuclear instability (studies in a hamster cell lines following rounds of amplification), (3) the presence of one rearrangement predisposes to acquiring additional rearrangements (statistical studies), and (4) autosomal imbalance syndromes (deletions and duplications) exert part of their effects by changing nuclear architecture (FISH studies) and thus cause differential gene expression. My observations are related to earlier work demonstrating changes in nuclear structures with cell differentiation, aging, cell cycle events, and certain pathologic conditions. I suggest that position changes after chromosomes go through meiosis or mitosis could explain why some balanced rearrangements result in a phenotypic expression while others don`t. Data from chromosome lengths support this hypothesis. The result of the synthesis of these data and published information provides evidence that chromosome position changes play a role in mental retardation, phenotypic effects of rearrangements, and cancer progression.

  17. Onset of deconfinement in nucleus-nucleus collisions

    SciTech Connect

    Gazdzicki, M.; Gorenstein, M. I.; Seyboth, P.

    2012-05-15

    The energy dependence of hadron production in relativistic nucleus-nucleus collisions reveals anomalies-the kink, horn, and step. They were predicted as signals of the deconfinement phase transition and observed by the NA49 Collaboration in central PbPb collisions at the CERN SPS. This indicates the onset of the deconfinement in nucleus-nucleus collisions at about 30 A GeV.

  18. Contralateral cerebello-thalamo-cortical pathways with prominent involvement of associative areas in humans in vivo.

    PubMed

    Palesi, Fulvia; Tournier, Jacques-Donald; Calamante, Fernando; Muhlert, Nils; Castellazzi, Gloria; Chard, Declan; D'Angelo, Egidio; Wheeler-Kingshott, Claudia A M

    2015-11-01

    In addition to motor functions, it has become clear that in humans the cerebellum plays a significant role in cognition too, through connections with associative areas in the cerebral cortex. Classical anatomy indicates that neo-cerebellar regions are connected with the contralateral cerebral cortex through the dentate nucleus, superior cerebellar peduncle, red nucleus and ventrolateral anterior nucleus of the thalamus. The anatomical existence of these connections has been demonstrated using virus retrograde transport techniques in monkeys and rats ex vivo. In this study, using advanced diffusion MRI tractography we show that it is possible to calculate streamlines to reconstruct the pathway connecting the cerebellar cortex with contralateral cerebral cortex in humans in vivo. Corresponding areas of the cerebellar and cerebral cortex encompassed similar proportion (about 80%) of the tract, suggesting that the majority of streamlines passing through the superior cerebellar peduncle connect the cerebellar hemispheres through the ventrolateral thalamus with contralateral associative areas. This result demonstrates that this kind of tractography is a useful tool to map connections between the cerebellum and the cerebral cortex and moreover could be used to support specific theories about the abnormal communication along these pathways in cognitive dysfunctions in pathologies ranging from dyslexia to autism. PMID:25134682

  19. Blockade of intracellular Zn2+ signaling in the dentate gyrus erases recognition memory via impairment of maintained LTP.

    PubMed

    Tamano, Haruna; Minamino, Tatsuya; Fujii, Hiroaki; Takada, Shunsuke; Nakamura, Masatoshi; Ando, Masaki; Takeda, Atsushi

    2015-08-01

    There is no evidence on the precise role of synaptic Zn2+ signaling on the retention and recall of recognition memory. On the basis of the findings that intracellular Zn2+ signaling in the dentate gyrus is required for object recognition, short-term memory, the present study deals with the effect of spatiotemporally blocking Zn2+ signaling in the dentate gyrus after LTP induction and learning. Three-day-maintained LTP was impaired 1 day after injection of clioquinol into the dentate gyrus, which transiently reduced intracellular Zn2+ signaling in the dentate gyrus. The irreversible impairment was rescued not only by co-injection of ZnCl2 , which ameliorated the loss of Zn2+ signaling, but also by pre-injection of Jasplakinolide, a stabilizer of F-actin, prior to clioquinol injection. Simultaneously, 3-day-old space recognition memory was impaired 1 day after injection of clioquinol into the dentate gyrus, but not by pre-injection of Jasplakinolide. Jasplakinolide also rescued both impairments of 3-day-maintained LTP and 3-day-old memory after injection of ZnAF-2DA into the dentate gyrus, which blocked intracellular Zn2+ signaling in the dentate gyrus. The present paper indicates that the blockade and/or loss of intracellular Zn2+ signaling in the dentate gyrus coincidently impair maintained LTP and recognition memory. The mechanism maintaining LTP via intracellular Zn2+ signaling in dentate granule cells, which may be involved in the formation of F-actin, may retain space recognition memory. PMID:25603776

  20. Proton Nucleus Elastic Scattering Data.

    Energy Science and Technology Software Center (ESTSC)

    1993-08-18

    Version 00 The Proton Nucleus Elastic Scattering Data file PNESD contains the numerical data and the related bibliography for the differential elastic cross sections, polarization and integral nonelastic cross sections for elastic proton-nucleus scattering.

  1. Kindled seizures selectively reduce a subpopulation of (/sup 3/H)quinuclidinyl benzilate binding sites in rat dentate gyrus

    SciTech Connect

    Savage, D.D.; McNamara, J.O.

    1982-09-01

    Amygdala-kindled seizures reduced significantly the total number of (/sup 3/H)quinuclidinyl benzilate binding sites in both dentate and hippocampal gyri compared to electrode implanted unstimulated controls. Both high and low affinity carbachol displaceable binding site populations were significantly reduced in hippocampal gyrus. By contrast, a selective decline of low affinity sites was found in dentate gyrus membranes. The selectivity of the decline in dentate but not hippocampus gyrus underscores the specificity of this molecular response to amygdala-kindled seizures. We suggest that these receptor alterations underlie adaptive mechanisms which antagonize kindled epileptogenesis.

  2. Protein quality control in the nucleus.

    PubMed

    Jones, Ramon D; Gardner, Richard G

    2016-06-01

    The nucleus is the repository for the eukaryotic cell's genetic blueprint, which must be protected from harm to ensure survival. Multiple quality control (QC) pathways operate in the nucleus to maintain the integrity of the DNA, the fidelity of the DNA code during replication, its transcription into mRNA, and the functional structure of the proteins that are required for DNA maintenance, mRNA transcription, and other important nuclear processes. Although we understand a great deal about DNA and RNA QC mechanisms, we know far less about nuclear protein quality control (PQC) mechanisms despite that fact that many human diseases are causally linked to protein misfolding in the nucleus. In this review, we discuss what is known about nuclear PQC and we highlight new questions that have emerged from recent developments in nuclear PQC studies. PMID:27015023

  3. Postnatal changes in glucose transporter 3 expression in the dentate gyrus of the C57BL/6 mouse model

    PubMed Central

    Jung, Hyo Young; Yim, Hee Sun; Yoo, Dae Young; Kim, Jong Whi; Chung, Jin Young; Seong, Je Kyung; Yoon, Yeo Sung; Kim, Dae Won

    2016-01-01

    In this study, we observed the ontogenetic changes in glucose transporter 3 (GLUT3) immunoreactivity, a major neuronal GLUT, in the dentate gyrus of mouse brains at various ages: postnatal day (P) 1, 7, 14, 28, and 56. At P1, cresyl violet staining showed abundant neurons in the dentate gyrus, whereas the granule cell layer was ill-defined. At P7, the granule cell layer was observed, and cresyl violet-positive cells were dispersed throughout the polymorphic layer. At P14, the granule cell layer was well-defined, and cresyl violet positive cells were detected abundantly in the polymorphic layer. At P28 and P56, cresyl violet-positive cells were observed in the granule cell layer, as well as in the polymorphic layer. At P1, GLUT3 immunoreactivity was detected in the dentate gyrus. At P7, GLUT3 immunoreactive cells were scattered in the polymorphic and molecular layer. However, at P14, GLUT3 immunoreactivity was observed in the polymorphic layer as well as subgranular zone of the dentate gyrus. At P28, GLUT3 immunoreactivity was detected in the polymorphic layer of the dentate gyrus. At P56, GLUT3 immunoreactivity was observed predominantly in the subgranular zone of the dentate gyrus. GLUT3 immunoreactive cells were mainly colocalized with doublecortin, which is a marker for differentiated neuroblasts, in the polymorphic layer and subgranular zone of dentate gyrus at P14 and P56. These results suggest that the expression of GLUT3 is closely associated with postnatal development of the dentate gyrus and adult neurogenesis. PMID:27051437

  4. Young Dentate Granule Cells Mediate Pattern Separation whereas Old Granule Cells Contribute to Pattern Completion

    PubMed Central

    Nakashiba, Toshiaki; Cushman, Jesse D.; Pelkey, Kenneth A.; Renaudineau, Sophie; Buhl, Derek L.; McHugh, Thomas J.; Barrera, Vanessa Rodriguez; Chittajallu, Ramesh; Iwamoto, Keisuke S.; McBain, Chris J.; Fanselow, Michael S.; Tonegawa, Susumu

    2012-01-01

    Summary Adult-born granule cells (GCs), a minor population of cells in the hippocampal dentate gyrus, are highly active during the first few weeks following functional integration into the neuronal network (young GCs), distinguishing them from less active older adult-born GCs and the major population of dentate GCs generated developmentally (together, old GCs). We created a transgenic mouse in which output of old GCs was specifically inhibited while leaving a substantial portion of young GCs intact. These mice exhibited enhanced or normal pattern separation between similar contexts that was reduced following removal of young GCs by X-ray irradiation. Furthermore, mutant mice exhibited deficits in rapid pattern completion. Therefore, pattern separation of similar contexts requires adult-born young GCs while old GCs are unnecessary, whereas older GCs contribute to the rapid recall by pattern completion. Our data suggest that as adult-born GCs age, their function switches from pattern separation to rapid pattern completion. PMID:22365813

  5. Adult-born hippocampal dentate granule cells undergoing maturation modulate learning and memory in the brain

    PubMed Central

    Deng, Wei; Saxe, Michael D.; Gallina, Iryna S.; Gage, Fred H.

    2009-01-01

    Adult-born dentate granule cells (DGCs) contribute to learning and memory, yet it remains unknown when adult-born DGCs become involved in the cognitive processes. During neurogenesis, immature dentate granule cells (DGCs) display distinctive physiological characteristics while undergoing morphological maturation before final integration into the neural circuits. The survival and activity of the adult-born DGCs can be influenced by the experience of the animal during a critical period when newborn DGCs are still immature. To assess the temporal importance of adult neurogenesis, we developed a transgenic mouse model that allowed us to transiently reduce the numbers of adult-born DGCs in a temporally regulatable manner. We found that mice with a reduced population of adult-born DGCs at the immature stage were deficient in forming robust, long-term spatial memory and displayed impaired performance in extinction tasks. These results suggest that immature DGCs that undergo maturation make important contributions to learning and memory. PMID:19864566

  6. Plasticity of intrinsic excitability in mature granule cells of the dentate gyrus

    PubMed Central

    Lopez-Rojas, Jeffrey; Heine, Martin; Kreutz, Michael R.

    2016-01-01

    The dentate gyrus is the main entry gate for cortical input to the hippocampus and one of the few brain areas where adult neurogenesis occurs. Several studies have shown that it is relatively difficult to induce synaptic plasticity in mature but not in newborn dentate granule cells. In the present work we have systematically addressed how classical protocols to induce synaptic plasticity affect action potential firing and intrinsic excitability in mature granule cells. We found that stimulation paradigms considered to be relevant for learning processes consistently modified the probability to generate action potentials in response to a given synaptic input in mature cells, in some paradigms even without any modification of synaptic strength. Collectively the results suggest that plasticity of intrinsic dendritic excitability has a lower induction-threshold than synaptic plasticity in mature granule cells and that this form of plasticity might be an important mechanism by which mature granule cells contribute to hippocampal function. PMID:26857841

  7. Dopaminergic inputs in the dentate gyrus direct the choice of memory encoding.

    PubMed

    Du, Huiyun; Deng, Wei; Aimone, James B; Ge, Minyan; Parylak, Sarah; Walch, Keenan; Zhang, Wei; Cook, Jonathan; Song, Huina; Wang, Liping; Gage, Fred H; Mu, Yangling

    2016-09-13

    Rewarding experiences are often well remembered, and such memory formation is known to be dependent on dopamine modulation of the neural substrates engaged in learning and memory; however, it is unknown how and where in the brain dopamine signals bias episodic memory toward preceding rather than subsequent events. Here we found that photostimulation of channelrhodopsin-2-expressing dopaminergic fibers in the dentate gyrus induced a long-term depression of cortical inputs, diminished theta oscillations, and impaired subsequent contextual learning. Computational modeling based on this dopamine modulation indicated an asymmetric association of events occurring before and after reward in memory tasks. In subsequent behavioral experiments, preexposure to a natural reward suppressed hippocampus-dependent memory formation, with an effective time window consistent with the duration of dopamine-induced changes of dentate activity. Overall, our results suggest a mechanism by which dopamine enables the hippocampus to encode memory with reduced interference from subsequent experience. PMID:27573822

  8. Low excitatory innervation balances high intrinsic excitability of immature dentate neurons

    PubMed Central

    Dieni, Cristina V.; Panichi, Roberto; Aimone, James B.; Kuo, Chay T.; Wadiche, Jacques I.; Overstreet-Wadiche, Linda

    2016-01-01

    Persistent neurogenesis in the dentate gyrus produces immature neurons with high intrinsic excitability and low levels of inhibition that are predicted to be more broadly responsive to afferent activity than mature neurons. Mounting evidence suggests that these immature neurons are necessary for generating distinct neural representations of similar contexts, but it is unclear how broadly responsive neurons help distinguish between similar patterns of afferent activity. Here we show that stimulation of the entorhinal cortex in mouse brain slices paradoxically generates spiking of mature neurons in the absence of immature neuron spiking. Immature neurons with high intrinsic excitability fail to spike due to insufficient excitatory drive that results from low innervation rather than silent synapses or low release probability. Our results suggest that low synaptic connectivity prevents immature neurons from responding broadly to cortical activity, potentially enabling excitable immature neurons to contribute to sparse and orthogonal dentate representations. PMID:27095423

  9. Low excitatory innervation balances high intrinsic excitability of immature dentate neurons.

    PubMed

    Dieni, Cristina V; Panichi, Roberto; Aimone, James B; Kuo, Chay T; Wadiche, Jacques I; Overstreet-Wadiche, Linda

    2016-01-01

    Persistent neurogenesis in the dentate gyrus produces immature neurons with high intrinsic excitability and low levels of inhibition that are predicted to be more broadly responsive to afferent activity than mature neurons. Mounting evidence suggests that these immature neurons are necessary for generating distinct neural representations of similar contexts, but it is unclear how broadly responsive neurons help distinguish between similar patterns of afferent activity. Here we show that stimulation of the entorhinal cortex in mouse brain slices paradoxically generates spiking of mature neurons in the absence of immature neuron spiking. Immature neurons with high intrinsic excitability fail to spike due to insufficient excitatory drive that results from low innervation rather than silent synapses or low release probability. Our results suggest that low synaptic connectivity prevents immature neurons from responding broadly to cortical activity, potentially enabling excitable immature neurons to contribute to sparse and orthogonal dentate representations. PMID:27095423

  10. Gas1 is present in germinal niches of developing dentate gyrus and cortex.

    PubMed

    Estudillo, E; Zavala, P; Pérez-Sánchez, G; Ayala-Sarmiento, A E; Segovia, J

    2016-05-01

    Gas1 is a pleiotropic protein that inhibits cell growth when overexpressed in tumors but during development, it acts as a co-receptor for sonic hedgehog to promote the proliferation and survival of various growing organs and systems. This protein has been extensively studied during development in the cerebellum. However, in other structures of the central nervous system, information concerning Gas1 is limited to in situ hybridization studies. We investigate the pattern of Gas1 expression during various developmental stages of the cortex and dentate gyrus of the mouse brain. The levels of Gas1 decrease in the developing brain and the protein is mainly found in progenitor cells during the development of the cortex and dentate gyrus. PMID:26714727

  11. Low excitatory innervation balances high intrinsic excitability of immature dentate neurons

    DOE PAGESBeta

    Dieni, Cristina V.; Panichi, Roberto; Aimone, James B.; Kuo, Chay T.; Wadiche, Jacques I.; Overstreet-Wadiche, Linda

    2016-04-20

    Persistent neurogenesis in the dentate gyrus produces immature neurons with high intrinsic excitability and low levels of inhibition that are predicted to be more broadly responsive to afferent activity than mature neurons. Mounting evidence suggests that these immature neurons are necessary for generating distinct neural representations of similar contexts, but it is unclear how broadly responsive neurons help distinguish between similar patterns of afferent activity. Here we show that stimulation of the entorhinal cortex in mouse brain slices paradoxically generates spiking of mature neurons in the absence of immature neuron spiking. Immature neurons with high intrinsic excitability fail to spikemore » due to insufficient excitatory drive that results from low innervation rather than silent synapses or low release probability. Here, our results suggest that low synaptic connectivity prevents immature neurons from responding broadly to cortical activity, potentially enabling excitable immature neurons to contribute to sparse and orthogonal dentate representations.« less

  12. Effect of Fluoxetine on Neurogenesis in Hippocampal Dentate Gyrus after Global Transient Cerebral Ischemia in Rats.

    PubMed

    Khodanovich, M Yu; Kisel', A A; Chernysheva, G A; Smol'yakova, V I; Savchenko, R R; Plotnikov, M B

    2016-07-01

    Changes in cerebral neurogenesis provoked by ischemia and the effect of fluoxetine on this process were studied using a three-vessel occlusion model of global transient cerebral ischemia. The global transient cerebral ischemia was modeled on male Wistar rats by transient occlusion of three major vessels originating from the aortic arch and supplying the brain (brachiocephalic trunk, left subclavian artery, and left common carotid artery). The cells expressing doublecortin (DCX, a marker of young neurons) were counted in the hippocampal dentate gyrus on day 31 after ischemia modeling. It was found that ischemia inhibited neurogenesis in the dentate gyrus in comparison with sham-operated controls (p<0.05), while fluoxetine (20 mg/kg/day) injected over 10 days after surgery restored neurogenesis to the control level (p<0.001). PMID:27496030

  13. Inverse relationship between adult hippocampal cell proliferation and synaptic rewiring in the dentate gyrus.

    PubMed

    Butz, Markus; Teuchert-Noodt, Gertraud; Grafen, Keren; van Ooyen, Arjen

    2008-01-01

    Adult neurogenesis is a key feature of the hippocampal dentate gyrus (DG). Neurogenesis is accompanied by synaptogenesis as new cells become integrated into the circuitry of the hippocampus. However, little is known to what extent the embedding of new neurons rewires the pre-existing network. Here we investigate synaptic rewiring in the DG of gerbils (Meriones unguiculatus) under different rates of adult cell proliferation caused by different rearing conditions as well as juvenile methamphetamine treatment. Surprisingly, we found that an increased cell proliferation reduced the amount of synaptic rewiring. To help explain this unexpected finding, we developed a novel model of dentate network formation incorporating neurogenesis and activity-dependent synapse formation and remodelling. In the model, we show that homeostasis of neuronal activity can account for the inverse relationship between cell proliferation and synaptic rewiring. PMID:18481284

  14. Analytic optical potentials for nucleon-nucleus nucleus-nucleus collisions involving light and medium nuclei

    NASA Technical Reports Server (NTRS)

    Bidasaria, H. B.; Townsend, L. W.

    1982-01-01

    Utilizing an optical model potential approximation to the exact nucleus-nucleus multiple-scattering series, optical potentials for nucleon-nucleus and nucleus-nucleus collisions are analytically derived. These expressions are applicable to light and medium cosmic ray nuclei as their single-particle density distributions are analytically determined, without approximation, from their actual harmonic well charge density distributions. Pauli correlation effects are included through the use of a simple Gaussian function to replace the usual expression obtained in the infinite nuclear matter approximation.

  15. Dentate transport discs can be used to reconstruct large segmental mandibular defects

    PubMed Central

    Elsalanty, Mohammed E.; Malavia, Veera; Zakhary, Ibrahim; Mulone, Timothy; Kontogiorgos, Elias D.; Dechow, Paul C.; Opperman, Lynne A.

    2015-01-01

    Purpose This study tests the use of a dentate transport segment for the reconstruction of a large U-shaped defect in the anterior segment of the canine mandible, using a novel curved reconstruction plate. The quality and quantity of bone regenerate formed by dentate versus edentulous transport segments was compared. Methods In five adult foxhound dogs, a defect of 70–75 mm was created in the canine mandible by excising the mandible anterior to the right and left 4th premolars. Reconstruction was done by trifocal distraction osteogenesis using a bone transport reconstruction plate (BTRP-02™), with two transport units being activated simultaneously, one on either side of the defect, one dentate and one edentulous. Bilateral distraction proceeded at a rate of 1mm/day until the segments docked against each other in midline. After 39–44 days consolidation, the animals were euthanized. The quantity and quality of bone regeneration on both sides were compared using micro-computed tomography. Results The defect reconstruction was successful. The amount and quality of bone formed by the transport segments was similar on both sides. There were no significant differences in the bone volume fraction and density of the regenerate bone formed by the two transport segments. The bone volume fraction and density of the regenerate was significantly lower than that of the host bone in the distal segments, likely due to the short consolidation period. Conclusions Bone transport remains a viable option in reconstructing anterior segmental defects in the mandible. The use of either dentate or edentulous transport segments for reconstruction provides options for the surgeon in often highly compromised patients requiring these surgeries. PMID:25661502

  16. Mosaic organization of the hippocampal neuroepithelium and the multiple germinal sources of dentate granule cells

    SciTech Connect

    Altman, J.; Bayer, S.A. )

    1990-11-15

    This study deals with the site of origin, migration, and settling of the principal cell constituents of the rat hippocampus during the embryonic period. The results indicate that the hippocampal neuroepithelium consists of three morphogenetically discrete components--the Ammonic neuroepithelium, the primary dentate neuroepithelium, and the fimbrial glioepithelium--and that these are discrete sources of the large neurons of Ammon's horn, the smaller granular neurons of the dentate gyrus, and the glial cells of the fimbria. The putative Ammonic neuroepithelium is marked in short-survival thymidine radiograms by a high level of proliferative activity and evidence of interkinetic nuclear migration from day E16 until day E19. On days E16 and E17 a diffuse band of unlabeled cells forms outside the Ammonic neuroepithelium. These postmitotic cells are considered to be stratum radiatum and stratum oriens neurons, which are produced in large numbers as early as day E15. A cell-dense layer, the incipient stratum pyramidale, begins to form on day E18 and spindle-shaped cells can be traced to it from the Ammonic neuroepithelium. This migratory band increases in size for several days, then declines, and finally disappears by day E22. It is inferred that this migration contains the pyramidal cells of Ammon's horn that are produced mostly on days E17 through E20. The putative primary dentate neuroepithelium is distinguished from the Ammonic neuroepithelium during the early phases of embryonic development by its location, shape, and cellular dynamics. It is located around a ventricular indentation, the dentate notch, contains fewer mitotic cells near the lumen of the ventricle than the Ammonic neuroepithelium, and shows a different labeling pattern both in short-survival and sequential-survival thymidine radiograms.

  17. Music and the nucleus accumbens.

    PubMed

    Mavridis, Ioannis N

    2015-03-01

    Music is a universal feature of human societies over time, mainly because it allows expression and regulation of strong emotions, thus influencing moods and evoking pleasure. The nucleus accumbens (NA), the most important pleasure center of the human brain (dominates the reward system), is the 'king of neurosciences' and dopamine (DA) can be rightfully considered as its 'crown' due to the fundamental role that this neurotransmitter plays in the brain's reward system. Purpose of this article was to review the existing literature regarding the relation between music and the NA. Studies have shown that reward value for music can be coded by activity levels in the NA, whose functional connectivity with auditory and frontal areas increases as a function of increasing musical reward. Listening to music strongly modulates activity in a network of mesolimbic structures involved in reward processing including the NA. The functional connectivity between brain regions mediating reward, autonomic and cognitive processing provides insight into understanding why listening to music is one of the most rewarding and pleasurable human experiences. Musical stimuli can significantly increase extracellular DA levels in the NA. NA DA and serotonin were found significantly higher in animals exposed to music. Finally, passive listening to unfamiliar although liked music showed activations in the NA. PMID:25102783

  18. Differential Involvement of the Dentate Gyrus in Adaptive Forgetting in the Rat

    PubMed Central

    Joseph, Mickaël Antoine; Fraize, Nicolas; Ansoud-Lerouge, Jennifer; Sapin, Emilie; Peyron, Christelle; Arthaud, Sébastien; Libourel, Paul-Antoine; Parmentier, Régis; Salin, Paul Antoine; Malleret, Gaël

    2015-01-01

    How does the brain discriminate essential information aimed to be stored permanently from information required only temporarily, and that needs to be cleared away for not saturating our precious memory space? Reference Memory (RM) refers to the long-term storage of invariable information whereas Working Memory (WM) depends on the short-term storage of trial-unique information. Previous work has revealed that WM tasks are very sensitive to proactive interference. In order to prevent such interference, irrelevant old memories must be forgotten to give new ones the opportunity to be stabilized. However, unlike memory, physiological processes underlying this adaptive form of forgetting are still poorly understood. Here, we precisely ask what specific brain structure(s) could be responsible for such process to occur. To answer this question, we trained rats in a radial maze using three paradigms, a RM task and two WM tasks involving or not the processing of interference but strictly identical in terms of locomotion or motivation. We showed that an inhibition of the expression of Zif268 and c-Fos, two indirect markers of neuronal activity and synaptic plasticity, was observed in the dentate gyrus of the dorsal hippocampus when processing such interfering previously stored information. Conversely, we showed that inactivating the dentate gyrus impairs both RM and WM, but improves the processing of interference. Altogether, these results strongly suggest for the first time that the dentate gyrus could be a key structure involved in adaptive forgetting. PMID:26528714

  19. Neutrino-nucleus interactions

    SciTech Connect

    Gallagher, H.; Garvey, G.; Zeller, G.P.; /Fermilab

    2011-01-01

    The study of neutrino oscillations has necessitated a new generation of neutrino experiments that are exploring neutrino-nuclear scattering processes. We focus in particular on charged-current quasi-elastic scattering, a particularly important channel that has been extensively investigated both in the bubble-chamber era and by current experiments. Recent results have led to theoretical reexamination of this process. We review the standard picture of quasi-elastic scattering as developed in electron scattering, review and discuss experimental results, and discuss additional nuclear effects such as exchange currents and short-range correlations that may play a significant role in neutrino-nucleus scattering.

  20. Nucleus from string theory

    NASA Astrophysics Data System (ADS)

    Hashimoto, Koji; Morita, Takeshi

    2011-08-01

    In generic holographic QCD, we find that baryons are bound to form a nucleus, and that its radius obeys the empirically-known mass-number (A) dependence r∝A1/3 for large A. Our result is robust, since we use only a generic property of D-brane actions in string theory. We also show that nucleons are bound completely in a finite volume. Furthermore, employing a concrete holographic model (derived by Hashimoto, Iizuka, and Yi, describing a multibaryon system in the Sakai-Sugimoto model), the nuclear radius is evaluated as O(1)×A1/3[fm], which is consistent with experiments.

  1. Higgs-Boson Production in Nucleus-Nucleus Collisions

    NASA Technical Reports Server (NTRS)

    Norbury, John W.

    1992-01-01

    Cross section calculations are presented for the production of intermediate-mass Higgs bosons produced in ultrarelativistic nucleus-nucleus collisions via two photon fusion. The calculations are performed in position space using Baur's method for folding together the Weizsacker-Williams virtual-photon spectra of the two colliding nuclei. It is found that two photon fusion in nucleus-nucleus collisions is a plausible way of finding intermediate-mass Higgs bosons at the Superconducting Super Collider or the CERN Large Hadron Collider.

  2. Higgs-boson production in nucleus-nucleus collisions

    NASA Technical Reports Server (NTRS)

    Norbury, J. W.; Townsend, L. W. (Principal Investigator)

    1990-01-01

    Cross-section calculations are presented for the production of intermediate-mass Higgs bosons produced in ultrarelativistic nucleus-nucleus collisions via two-photon fusion. The calculations are performed in position space using Baur's method for folding together the Weizsacker-Williams virtual-photon spectra of the two colliding nuclei. It is found that two-photon fusion in nucleus-nucleus collisions is a plausible way of finding intermediate-mass Higgs bosons at the Superconducting Super Collider or the CERN Large Hadron Collider.

  3. Networking the nucleus

    PubMed Central

    Rajapakse, Indika; Scalzo, David; Tapscott, Stephen J; Kosak, Steven T; Groudine, Mark

    2010-01-01

    The nuclei of differentiating cells exhibit several fundamental principles of self-organization. They are composed of many dynamical units connected physically and functionally to each other—a complex network—and the different parts of the system are mutually adapted and produce a characteristic end state. A unique cell-specific signature emerges over time from complex interactions among constituent elements that delineate coordinate gene expression and chromosome topology. Each element itself consists of many interacting components, all dynamical in nature. Self-organizing systems can be simplified while retaining complex information using approaches that examine the relationship between elements, such as spatial relationships and transcriptional information. These relationships can be represented using well-defined networks. We hypothesize that during the process of differentiation, networks within the cell nucleus rewire according to simple rules, from which a higher level of order emerges. Studying the interaction within and among networks provides a useful framework for investigating the complex organization and dynamic function of the nucleus. PMID:20664641

  4. Lentiviral silencing of GSK-3β in adult dentate gyrus impairs contextual fear memory and synaptic plasticity

    PubMed Central

    Chew, Benjamin; Ryu, Jae Ryun; Ng, Teclise; Ma, Dongliang; Dasgupta, Ananya; Neo, Sin Hui; Zhao, Jing; Zhong, Zhong; Bichler, Zoë; Sajikumar, Sreedharan; Goh, Eyleen L. K.

    2015-01-01

    Attempts have been made to use glycogen synthase kinase-3 beta (GSK3β) inhibitors for prophylactic treatment of neurocognitive conditions. However the use of lithium, a non-specific inhibitor of GSK3β results in mild cognitive impairment in humans. The effects of global GSK3β inhibition or knockout on learning and memory in healthy adult mice are also inconclusive. Our study aims to better understand the role of GSK3β in learning and memory through a more regionally, targeted approach, specifically performing lentiviral-mediated knockdown of GSK3β within the dentate gyrus (DG). DG-GSK3β-silenced mice showed impaired contextual fear memory retrieval. However, cue fear memory, spatial memory, locomotor activity and anxiety levels were similar to control. These GSK3β-silenced mice also showed increased induction and maintenance of DG long-term potentiation (DG-LTP) compared to control animals. Thus, this region-specific, targeted knockdown of GSK3β in the DG provides better understanding on the role of GSK3β in learning and memory. PMID:26157370

  5. Lentiviral silencing of GSK-3β in adult dentate gyrus impairs contextual fear memory and synaptic plasticity.

    PubMed

    Chew, Benjamin; Ryu, Jae Ryun; Ng, Teclise; Ma, Dongliang; Dasgupta, Ananya; Neo, Sin Hui; Zhao, Jing; Zhong, Zhong; Bichler, Zoë; Sajikumar, Sreedharan; Goh, Eyleen L K

    2015-01-01

    Attempts have been made to use glycogen synthase kinase-3 beta (GSK3β) inhibitors for prophylactic treatment of neurocognitive conditions. However the use of lithium, a non-specific inhibitor of GSK3β results in mild cognitive impairment in humans. The effects of global GSK3β inhibition or knockout on learning and memory in healthy adult mice are also inconclusive. Our study aims to better understand the role of GSK3β in learning and memory through a more regionally, targeted approach, specifically performing lentiviral-mediated knockdown of GSK3β within the dentate gyrus (DG). DG-GSK3β-silenced mice showed impaired contextual fear memory retrieval. However, cue fear memory, spatial memory, locomotor activity and anxiety levels were similar to control. These GSK3β-silenced mice also showed increased induction and maintenance of DG long-term potentiation (DG-LTP) compared to control animals. Thus, this region-specific, targeted knockdown of GSK3β in the DG provides better understanding on the role of GSK3β in learning and memory. PMID:26157370

  6. Synaptic Changes in the Dentate Gyrus of APP/PS1 Transgenic Mice Revealed by Electron Microscopy

    PubMed Central

    Merino-Serrais, Paula; Gonzalez, Santiago; DeFelipe, Javier

    2013-01-01

    Abstract Numerous studies have reported widespread synaptic dysfunction or loss in early stages of both Alzheimer disease (AD) patients and animal models; it is widely accepted that synapse loss is the major structural correlate of cognitive dysfunction. Elucidation of the changes that may affect synapses is crucial for understanding the pathogenic mechanisms underlying AD, but ultrastructural preservation of human postmortem brain tissue is often poor, and classical methods for quantification of synapses have significant technical limitations. We previously observed changes in dendritic spines in plaque-free regions of the neuropil of the dentate gyrus of double-transgenic APP/PS1 (amyloid precursor protein/presenilin 1) model mice by light microscopy. Here, we used electron microscopy to examine possible synaptic alterations in this region. We used standard stereologic techniques to determine numbers of synapses per volume. We were able to reconstruct and analyze thousands of synapses and their 3-dimensional characteristics using a focused ion beam/scanning electron microscope and 3-dimensional reconstruction software (EspINA), which performs semiautomated segmentation of synapses. Our results show that both numbers of synapses per volume and synaptic morphology are affected in plaque-free regions of APP/PS1 mice. Therefore, changes in the number and morphology of synapses seem to be widespread alterations in this animal model. PMID:23584198

  7. Electric quadrupole excitations in relativistic nucleus-nucleus collisions

    NASA Technical Reports Server (NTRS)

    Norbury, John W.

    1989-01-01

    Calculations are presented for electric quadrupole excitations in relativistic nucleus-nucleus collisions. The theoretical results are compared to an extensive data set and it is found that electric quadrupole effects provide substantial corrections to cross sections, especially for heavier nuclei.

  8. Meson multiplicity versus energy in relativistic nucleus-nucleus collisions

    NASA Technical Reports Server (NTRS)

    Atwater, T. W.; Freier, P. S.

    1986-01-01

    A systematic study of meson multiplicity as a function of energy at energies up to 100 GeV/u in nucleus-nucleus collisions has been made, using cosmic-ray data in nuclear emulsion. The data are consistent with simple nucleon-nucleon superposition models. Multiplicity per interacting nucleon in AA collisions does not appear to differ significantly from pp collisions.

  9. Scaling phenomenon in relativistic nucleus-nucleus collisions

    SciTech Connect

    Wong, C. Y.; Blankenbecler, R.

    1980-01-01

    New scaling variables for proton and pion production in relativistic nucleus-nucleus collisions are introduced which are the generalizations of the Feynmann scaling variable. They allow a simple description of the cross sections at forward and backward angles. 2 figures.

  10. Momentum loss in proton-nucleus and nucleus-nucleus collisions

    NASA Technical Reports Server (NTRS)

    Khan, Ferdous; Townsend, Lawrence W.

    1993-01-01

    An optical model description, based on multiple scattering theory, of longitudinal momentum loss in proton-nucleus and nucleus-nucleus collisions is presented. The crucial role of the imaginary component of the nucleon-nucleon transition matrix in accounting for longitudinal momentum transfer is demonstrated. Results obtained with this model are compared with Intranuclear Cascade (INC) calculations, as well as with predictions from Vlasov-Uehling-Uhlenbeck (VUU) and quantum molecular dynamics (QMD) simulations. Comparisons are also made with experimental data where available. These indicate that the present model is adequate to account for longitudinal momentum transfer in both proton-nucleus and nucleus-nucleus collisions over a wide range of energies.

  11. The orientation of nucleus, nucleus-associated body and protruding nucleolus in aggregating Dictyostelium discoideum.

    PubMed

    Sameshima, M

    1985-02-01

    Dictyostelium discoideum growing or developing on cellulose dialysis membranes were fixed with acrolein vapour for electron microscopy. In interphase amoebae, nucleoli began to protrude from the nuclei. The percentage of cells with protruding nucleoli increased during aggregation by a value approximately twice as high in aggregation streams as in centers. Cells in pseudoplasmodia showed only a low percentage and protrusions disappeared at early culmination stage. The protrusions did not reappear when cells from dissociated pseudoplasmodia migrated toward cAMP. Thus the formation of the protrusions did not depend solely on chemotaxis; rather, it was specific to the aggregation stage. In aggregation streams, the nucleus was anterior in the cell, with the protrusion at its anterior periphery. In contrast, the nucleus associated body (NAB) was evident at the cell's mid-point. This orientation of nucleus and NAB in the aggregating slime mould amoeba is contrary to that seen in human neutrophils or cultured mouse 3T3 cells. PMID:2981691

  12. The Galactic Nucleus

    NASA Astrophysics Data System (ADS)

    Melia, Fulvio

    Exciting new broadband observations of the galactic nucleus have placed the heart of the Milky Way under intense scrutiny in recent years. This has been due in part to the growing interest from theorists motivated to study the physics of black hole accretion, magnetized gas dynamics, and unusual star formation. The center of our Galaxy is now known to harbor the most compelling supermassive black hole candidate, weighing in at 3-4 million solar masses. Its nearby environment is comprised of a molecular dusty ring, clusters of evolved and young stars, diffuse hot gas, ionized gas streamers, and several supernova remnants. This chapter will focus on the physical makeup of this dynamic region and the feasibility of actually imaging the black hole's shadow in the coming decade with mm interferometry.

  13. Comet nucleus and asteroid sample return missions

    NASA Technical Reports Server (NTRS)

    1992-01-01

    Three Advanced Design Projects have been completed this academic year at Penn State. At the beginning of the fall semester the students were organized into eight groups and given their choice of either a comet nucleus or an asteroid sample return mission. Once a mission had been chosen, the students developed conceptual designs. These were evaluated at the end of the fall semester and combined into three separate mission plans, including a comet nucleus same return (CNSR), a single asteroid sample return (SASR), and a multiple asteroid sample return (MASR). To facilitate the work required for each mission, the class was reorganized in the spring semester by combining groups to form three mission teams. An integration team consisting of two members from each group was formed for each mission so that communication and information exchange would be easier among the groups. The types of projects designed by the students evolved from numerous discussions with Penn State faculty and mission planners at the Johnson Space Center Human/Robotic Spacecraft Office. Robotic sample return missions are widely considered valuable precursors to manned missions in that they can provide details about a site's environment and scientific value. For example, a sample return from an asteroid might reveal valuable resources that, once mined, could be utilized for propulsion. These missions are also more adaptable when considering the risk to humans visiting unknown and potentially dangerous locations, such as a comet nucleus.

  14. Comet nucleus and asteroid sample return missions

    NASA Astrophysics Data System (ADS)

    1992-06-01

    Three Advanced Design Projects have been completed this academic year at Penn State. At the beginning of the fall semester the students were organized into eight groups and given their choice of either a comet nucleus or an asteroid sample return mission. Once a mission had been chosen, the students developed conceptual designs. These were evaluated at the end of the fall semester and combined into three separate mission plans, including a comet nucleus same return (CNSR), a single asteroid sample return (SASR), and a multiple asteroid sample return (MASR). To facilitate the work required for each mission, the class was reorganized in the spring semester by combining groups to form three mission teams. An integration team consisting of two members from each group was formed for each mission so that communication and information exchange would be easier among the groups. The types of projects designed by the students evolved from numerous discussions with Penn State faculty and mission planners at the Johnson Space Center Human/Robotic Spacecraft Office. Robotic sample return missions are widely considered valuable precursors to manned missions in that they can provide details about a site's environment and scientific value. For example, a sample return from an asteroid might reveal valuable resources that, once mined, could be utilized for propulsion. These missions are also more adaptable when considering the risk to humans visiting unknown and potentially dangerous locations, such as a comet nucleus.

  15. Alterations in miRNA Levels in the Dentate Gyrus in Epileptic Rats

    PubMed Central

    Bot, Anna Maria; Dębski, Konrad Józef; Lukasiuk, Katarzyna

    2013-01-01

    The aim of this study was to characterize changes in miRNA expression in the epileptic dentate gyrus. Status epilepticus evoked by amygdala stimulation was used to induce epilepsy in rats. The dentate gyri were isolated at 7 d, 14 d, 30 d and 90 d after stimulation (n=5). Sham-operated time-matched controls were prepared for each time point (n=5). The miRNA expression was evaluated using Exiqon microarrays. Additionally, mRNA from the same animals was profiled using Affymetrix microarrays. We detected miRNA expression signatures that differentiate between control and epileptic animals. Significant changes in miRNA expression between stimulated and sham operated animals were observed at 7 and 30 d following stimulation. Moreover, we found that there are ensembles of miRNAs that change expression levels over time. Analysis of the mRNA expression from the same animals revealed that the expression of several mRNAs that are potential targets for miRNA with altered expression level is regulated in the expected direction. The functional characterization of miRNAs and their potential mRNA targets indicate that miRNA can participate in several molecular events that occur in epileptic tissue, including immune response and neuronal plasticity. This is the first report on changes in the expression of miRNA and the potential functional impact of these changes in the dentate gyrus of epileptic animals. Complex changes in the expression of miRNAs suggest an important role for miRNA in the molecular mechanisms of epilepsy. PMID:24146813

  16. Antiproton-nucleus interaction

    NASA Astrophysics Data System (ADS)

    Cugnon, J.; Vandermeulen, J.

    The antiproton-nucleus physics is reviewed. On the experimental side, the recent results obtained at the LEAR, BNL and KEK facilities are analyzed. A brief summary of the main pp and pn experimental data is also given. The antiproton-nucleus interaction can lead to elasic, inelastic and charge exchange scattering and to annihilation. The latter is very dominant. The scattering cross-sections are usually analyzed in terms of complex potential models. The relationship between potentials, charge conjugation and Dirac phenomenology is discussed. Much emphasis is put on the dynamics of the antiproton annihilation on nuclei. The energy transfer, pion absorption and target response are analyzed within the intranuclear cascade model. Special interest is devoted to strangeness production, hypernucleus formation and possible annihilation on two nucleons. Signatures for this new process are searched in experimental data. Finally, the highly debated question of quark-gluon formation is analyzed. Cet article constitue une revue de la physique antiproton-noyau. Du point de vue expérimental, cette revue porte particulièrement sur les récents résultats obtenus à LEAR, BNL et KEK. On y a aussi inclus une mise à jour des faits expérimentaux principaux pour pp et pn. L'interaction antiproton-noyau conduit à la diffusion élastique, inélastique et d'xA9change de charge et à des processus d'annihilation. Habituellement, les expériences de diffusion sont analysées en termes de potentiels complexes. La relation entre ces potentiels, la conjugaison de charge et la phénoménologie de Dirac est discutée. On s'est particulièrement intéressé à la dynamique de l'annihilation d'antiprotons sur des noyaux. Le transfert d'énergie, l'absorption de pions et la réponse de la cible sont analysés dans le cadre du modèle de cascade intranucléaire. Certains autres points sont discutés plus en détail: la production d'étrangeté, la formation d'hypernoyaux et l'annihilation sur

  17. The retrotrapezoid nucleus and breathing.

    PubMed

    Guyenet, Patrice G; Stornetta, Ruth L; Abbott, Stephen B G; Depuy, Seth D; Kanbar, Roy

    2012-01-01

    The retrotrapezoid nucleus (RTN) is located in the rostral medulla oblongata close to the ventral surface and consists of a bilateral cluster of glutamatergic neurons that are non-aminergic and express homeodomain transcription factor Phox2b throughout life. These neurons respond vigorously to increases in local pCO(2) via cell-autonomous and paracrine (glial) mechanisms and receive additional chemosensory information from the carotid bodies. RTN neurons exclusively innervate the regions of the brainstem that contain the respiratory pattern generator (RPG). Lesion or inhibition of RTN neurons largely attenuates the respiratory chemoreflex of adult rats whereas their activation increases respiratory rate, inspiratory amplitude and active expiration. Phox2b mutations that cause congenital central hypoventilation syndrome in humans prevent the development of RTN neurons in mice. Selective deletion of the RTN Phox2b-VGLUT2 neurons by genetic means in mice eliminates the respiratory chemoreflex in neonates.In short, RTN Phox2b-VGLUT2 neurons are a major nodal point of the CNS network that regulates pCO(2) via breathing and these cells are probable central chemoreceptors. PMID:23080151

  18. Unconventional Functions for Clathrin, ESCRTs, and Other Endocytic Regulators in the Cytoskeleton, Cell Cycle, Nucleus, and Beyond: Links to Human Disease

    PubMed Central

    Brodsky, Frances M.; Sosa, R. Thomas; Ybe, Joel A.; O’Halloran, Theresa J.

    2014-01-01

    The roles of clathrin, its regulators, and the ESCRT (endosomal sorting complex required for transport) proteins are well defined in endocytosis. These proteins can also participate in intracellular pathways that are independent of endocytosis and even independent of the membrane trafficking function of these proteins. These nonendocytic functions involve unconventional biochemical interactions for some endocytic regulators, but can also exploit known interactions for nonendocytic functions. The molecular basis for the involvement of endocytic regulators in unconventional functions that influence the cytoskeleton, cell cycle, signaling, and gene regulation are described here. Through these additional functions, endocytic regulators participate in pathways that affect infection, glucose metabolism, development, and cellular transformation, expanding their significance in human health and disease. PMID:25183831

  19. Recombinant human nerve growth factor is biologically active and labels novel high-affinity binding sites in rat brain

    SciTech Connect

    Altar, C.A.; Burton, L.E.; Bennett, G.L.; Dugich-Djordjevic, M. )

    1991-01-01

    Iodinated recombinant human nerve growth factor (125I-rhNGF) stimulated neurite formation in PC12 cell cultures with a half-maximal potency of 35-49 pg/ml, compared with 39-52 pg/ml for rhNGF. In quantitative ligand autoradiography, the in vitro equilibrium binding of 125I-rhNGF to brain sections showed a 10-fold regional variation in density and was saturable, reversible, and specifically displaced by up to 74% with rhNGF or murine NGF (muNGF). At equilibrium, 125I-rhNGF bound to these sites with high affinity and low capacity (Bmax less than or equal to 13.2 fmol/mg of protein). Calculation of 125I-rhNGF binding affinity by kinetic methods gave average Kd values of 24 and 31 pM. Computer-generated maps revealed binding in brain regions not identified previously with 125I-muNGF, including hippocampus; dentate gyrus; amygdala; paraventricular thalamus; frontal, parietal, occipital, and cingulate cortices; nucleus accumbens; olfactory tubercle; subiculum; pineal gland; and medial geniculate nucleus. NGF binding sites were distributed in a 2-fold increasing medial-lateral gradient in the caudate-putamen and a 2-fold lateral-medial gradient in the nucleus accumbens. 125I-rhNGF binding sites were also found in most areas labeled by 125I-muNGF, including the interpedunucular nucleus, cerebellum, forebrain cholinergic nuclei, caudoventral caudate-putamen, and trigeminal nerve nucleus. 125I-rhNGF binding sites were absent from areas replete with low-affinity NGF binding sites, including circumventricular organs, myelinated fiber bundles, and choroid plexus. The present analysis provides an anatomical differentiation of high-affinity 125I-rhNGF binding sites and greatly expands the number of brain structures that may respond to endogenous NGF or exogenously administered rhNGF.

  20. Long-term observation of neuronal degeneration and microgliosis in the gerbil dentate gyrus after transient cerebral ischemia.

    PubMed

    Ahn, Ji Hyeon; Shin, Bich Na; Park, Joon Ha; Kim, In Hye; Cho, Jeong Hwi; Chen, BaiHui; Lee, Tae-Kyeong; Tae, Hyun-Jin; Lee, Jae-Chul; Cho, Jun Hwi; Kang, Il Jun; Kim, Young-Myeong; Lee, Yun Lyul; Won, Moo-Ho; Seo, Jeong Yeol

    2016-04-15

    Ischemic insults in the central nervous system evoke activation of microglia. In this study, we investigated long-term changes of neuronal damage and microglial activation in the gerbil dentate gyrus for 60 days after transient cerebral ischemia using immunohistochemistry and western blot. Neuronal damage or death was hardly found in the dentate gyrus after transient ischemia using cresyl violet staining and NeuN immunohistochemistry; however, neuronal degeneration was detected in the polymorphic layer of the dentate gyrus using Fluoro-Jade (F-J) B staining. F-J B-positive cells were significantly increased after ischemia-reperfusion (I-R) and peaked at 3 days post-ischemia, thereafter, F-J B-positive cells were decreased in a time-dependent manner and shown until 30 days post-ischemia; no F-J B-positive cells were observed 60 days after I-R. On the other hand, Iba-1-immunoreactive microglia were hypertrophied after I-R, and numbers of Iba-1-immunoreactive microglia were significantly increased along with the neuronal degeneration and highest 7 days after I-R, thereafter, numbers of Iba-1-immunoreactive microglia were decreased with time, although microglia activation lasted up to 60 days after I-R. In addition, Iba-1 protein level in the dentate gyrus after I-R was changed like immunohistochemical change. Our results, in brief, indicate that transient ischemia-induced neuronal degeneration in the dentate gyrus is maintained for about 30 days after I-R and that microglial activation lasts up to, at least, 60 days after I-R in the gerbil dentate gyrus after transient cerebral ischemia. PMID:27000214

  1. Two Neutron Removal in Relativistic Nucleus-Nucleus Reactions

    NASA Technical Reports Server (NTRS)

    Norbury, John W.

    1992-01-01

    Significant discrepancies between theory and experiment have previously been noted for double neutron removal via electromagnetic processes in relativistic nucleus-nucleus collisions. The present work examines the cause of these discrepancies and systematically investigates whether the problem might be due to electromagnetic theory, nuclear contributions, or an underestimate of experimental error. Using cross section systematics from other reactions it is found that the discrepancies can be resolved in a plausible manner.

  2. PTEN deletion from adult-generated dentate granule cells disrupts granule cell mossy fiber axon structure

    PubMed Central

    LaSarge, Candi L.; Santos, Victor R; Danzer, Steve C.

    2015-01-01

    Dysregulation of the mTOR-signaling pathway is implicated in the development of temporal lobe epilepsy. In mice, deletion of PTEN from hippocampal dentate granule cells leads to mTOR hyperactivation and promotes the rapid onset of spontaneous seizures. The mechanism by which these abnormal cells initiate epileptogenesis, however, is unclear. PTEN-knockout granule cells develop abnormally, exhibiting morphological features indicative of increased excitatory input. If these cells are directly responsible for seizure genesis, it follows that they should also possess increased output. To test this prediction, dentate granule cell axon morphology was quantified in control and PTEN-knockout mice. Unexpectedly, PTEN deletion increased giant mossy fiber bouton spacing along the axon length, suggesting reduced innervation of CA3. Increased width of the mossy fiber axon pathway in stratum lucidum, however, which likely reflects an unusual increase in mossy fiber axon collateralization in this region, offset the reduction in boutons per axon length. These morphological changes predicts a net increase in granule cell >> CA3 innervation. Increased diameter of axons from PTEN-knockout cells would further enhance granule cell >> CA3 communication. Altogether, these findings suggest that amplified information flow through the hippocampal circuit contributes to seizure occurrence in the PTEN-knockout mouse model of temporal lobe epilepsy. PMID:25600212

  3. Postischemic Anhedonia Associated with Neurodegenerative Changes in the Hippocampal Dentate Gyrus of Rats

    PubMed Central

    Kasahara, Jiro; Uchida, Hiroto; Tezuka, Kenta; Oka, Nanae

    2016-01-01

    Poststroke depression is one of the major symptoms observed in the chronic stage of brain stroke such as cerebral ischemia. Its pathophysiological mechanisms, however, are not well understood. Using the transient right middle cerebral artery occlusion- (MCAO-, 90 min) operated rats as an ischemia model in this study, we first observed that aggravation of anhedonia spontaneously occurred especially after 20 weeks of MCAO, and it was prevented by chronic antidepressants treatment (imipramine or fluvoxamine). The anhedonia specifically associated with loss of the granular neurons in the ipsilateral side of hippocampal dentate gyrus and was also prevented by an antidepressant imipramine. Immunohistochemical analysis showed increased apoptosis inside the granular cell layer prior to and associated with the neuronal loss, and imipramine seemed to recover the survival signal rather than suppressing the death signal to prevent neurons from apoptosis. Proliferation and development of the neural stem cells were increased transiently in the subgranular zone of both ipsi- and contralateral hippocampus within one week after MCAO and then decreased and almost ceased after 6 weeks of MCAO, while chronic imipramine treatment prevented them partially. Overall, our study suggests new insights for the mechanistic correlation between poststroke depression and the delayed neurodegenerative changes in the hippocampal dentate gyrus with effective use of antidepressants on them. PMID:27057366

  4. The role of the dorsal dentate gyrus in object and object-context recognition.

    PubMed

    Dees, Richard L; Kesner, Raymond P

    2013-11-01

    The aim of this study was to determine the role of the dorsal dentate gyrus (dDG) in object recognition memory using a black box and object-context recognition memory using a clear box with available cues that define a spatial context. Based on a 10 min retention interval between the study phase and the test phase, the results indicated that dDG lesioned rats are impaired when compared to controls in the object-context recognition test in the clear box. However, there were no reliable differences between the dDG lesioned rats and the control group for the object recognition test in the black box. Even though the dDG lesioned rats were more active in object exploration, the habituation gradients did not differ. These results suggest that the dentate gyrus lesioned rats are clearly impaired when there is an important contribution of context. Furthermore, based on a 24 h retention interval in the black box the dDG lesioned rats were impaired compared to controls. PMID:23880567

  5. Spatial firing correlates of physiologically distinct cell types of the rat dentate gyrus

    PubMed Central

    Neunuebel, Joshua P.; Knierim, James J.

    2012-01-01

    The dentate gyrus (DG) occupies a key position in information flow through the hippocampus. Its principal cell, the granule cell, has spatially selective place fields. However, the behavioral correlates of cells located in the hilus of the rat dentate gyrus are unknown. We report here that cells below the granule layer show spatially selective firing that consists of multiple subfields. Other cells recorded from the DG had single place fields. Compared to cells with multiple fields, cells with single fields fired at lower rates during sleep; were less bursty; and were more likely to be recorded simultaneously with large populations of neurons that were active during sleep and silent during behavior. We propose that cells with single fields are likely to be mature granule cells that use sparse encoding to potentially disambiguate input patterns. Furthermore, we hypothesize that cells with multiple fields might be cells of the hilus or newborn granule cells. These data are the first demonstration, based on physiological criteria, that single-field and multiple-field cells constitute at least two distinct cell classes in the DG. Because of the heterogeneity of firing correlates and cell types in the DG, understanding which cell types correspond to which firing patterns, and how these correlates change with behavioral state and between different environments, are critical questions for testing longstanding computational theories that the DG performs a pattern separation function using a very sparse coding strategy. PMID:22423105

  6. Hippocampus and dentate area of the European hedgehog. Comparative histochemical study.

    PubMed

    Crutcher, K A; Danscher, G; Geneser, F A

    1988-01-01

    The hippocampal formation in the European hedgehog was examined with acetylcholinesterase (AChE) histochemistry and catecholamine histofluorescence in order to define the normal distribution of septohippocampal fibers and noradrenergic fibers, respectively, as well as to compare these inputs with the hippocampal cytoarchitecture as revealed with Nissl stain. In addition, alterations in the histochemical appearance following septohippocampal denervation were examined. Although the overall pattern of AChE-positive and noradrenergic fibers is similar to that observed in other mammals, some striking variations were observed, particularly within the dentate area. Thus, except for a heavily stained supragranular band, the AChE activity of the molecular layer is uniformly low without any obvious lamination, contrasting with the situation in most other mammalian species. The noradrenergic innervation of the dentate area showed the same density of fibers in the molecular layer and hilus, a pattern differing strikingly from the predominance of noradrenergic fibers in the hilus of other mammalian species. Such variations may reflect greater phylogenetic diversity in diffuse modulatory connections as compared with more precise topographical pathways. PMID:3233486

  7. Clonal Analysis of Newborn Hippocampal Dentate Granule Cell Proliferation and Development in Temporal Lobe Epilepsy123

    PubMed Central

    LaSarge, Candi L.; McAuliffe, John J.

    2015-01-01

    Abstract Hippocampal dentate granule cells are among the few neuronal cell types generated throughout adult life in mammals. In the normal brain, new granule cells are generated from progenitors in the subgranular zone and integrate in a typical fashion. During the development of epilepsy, granule cell integration is profoundly altered. The new cells migrate to ectopic locations and develop misoriented “basal” dendrites. Although it has been established that these abnormal cells are newly generated, it is not known whether they arise ubiquitously throughout the progenitor cell pool or are derived from a smaller number of “bad actor” progenitors. To explore this question, we conducted a clonal analysis study in mice expressing the Brainbow fluorescent protein reporter construct in dentate granule cell progenitors. Mice were examined 2 months after pilocarpine-induced status epilepticus, a treatment that leads to the development of epilepsy. Brain sections were rendered translucent so that entire hippocampi could be reconstructed and all fluorescently labeled cells identified. Our findings reveal that a small number of progenitors produce the majority of ectopic cells following status epilepticus, indicating that either the affected progenitors or their local microenvironments have become pathological. By contrast, granule cells with “basal” dendrites were equally distributed among clonal groups. This indicates that these progenitors can produce normal cells and suggests that global factors sporadically disrupt the dendritic development of some new cells. Together, these findings strongly predict that distinct mechanisms regulate different aspects of granule cell pathology in epilepsy. PMID:26756038

  8. Fluoxetine enhances cell proliferation and prevents apoptosis in dentate gyrus of maternally separated rats.

    PubMed

    Lee, H J; Kim, J W; Yim, S V; Kim, M J; Kim, S A; Kim, Y J; Kim, C J; Chung, J H

    2001-11-01

    The mother-infant relationship is an instinctive phenomenon, and loss of maternal care in early life influences neonatal development, behavior and physiologic responses.(1,2) Furthermore, the early loss may affect the vulnerability of the infant to neuropsychiatric disorders, such as childhood anxiety disorders, personality disorders and depression, over its lifespan.(3,4) Fluoxetine is prescribed worldwide for depression and is often used in the treatment of childhood mental problems related to maternal separation or loss of maternal care.(5,6) In the present study, fluoxetine was administrated to rats with maternal separation to determine its effects on neuronal development, in particular with respect to cell proliferation and apoptosis in the dentate gyrus of the hippocampus. Rat pups were separated from their mothers and socially isolated on postnatal day 14 and were treated with fluoxetine (5 mg kg(-1)) and 5-bromo-2'-deoxyuridine (BrdU) (50 mg kg(-1)) for 7 days, after which immunohistochemistry and a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining were carried out. In the pups with maternal separation treated with fluoxetine, the number of BrdU-positive cells was significantly increased and that of TUNEL-positive cells was significantly decreased in the dentate gyrus compared to pups with maternal separation that did not receive fluoxetine treatment. These findings indicate that fluoxetine affects new cell proliferation and apoptosis, and we propose that fluoxetine may be useful in the treatment of maternal separation-related diseases. PMID:11673802

  9. [Prospective study on tooth loss in a cohort of dentate elderly].

    PubMed

    Teixeira, Doralice Severo da Cruz; Frazão, Paulo; Alencar, Gizelton Pereira; Baquero, Oswaldo Santos; Narvai, Paulo Capel; Lebrão, Maria Lucia; Duarte, Yeda Aparecida de Oliveira

    2016-08-01

    The aim of this study was to assess factors associated with tooth loss in elderly 60 years or older during a four-year observation period. A representative cohort of dentate elderly from the city of São Paulo, Brazil, participated in the study. The outcome was teeth loss incidence from 2006 to 2010. Demographic and socioeconomic characteristics, health services access and use, behavior, reported diseases, cognitive status, functional status, state of dentition, and use of dental prosthesis were recorded as independent variables in 2006 and the outcome was measured in 2010. Negative binomial regression models were used. Participation included 440 dentate elderly. Increased likelihood of tooth loss was associated with use of two removable prostheses (RR = 1.57; 95%CI: 1.02-2.41), fair self-rated oral health (RR = 1.62; 95%CI: 1.11-2.36), bad/very bad self-rated oral health (RR = 1.87; 95%CI: 1.11-3.17), male gender (RR = 1.74; 95%CI: 1.28-2.37), and living alone (RR = 2.03; 95%CI: 1.11-3.72). PMID:27509546

  10. The lysine acetyltransferase activator Brpf1 governs dentate gyrus development through neural stem cells and progenitors.

    PubMed

    You, Linya; Yan, Kezhi; Zou, Jinfeng; Zhou, Jinfeng; Zhao, Hong; Bertos, Nicholas R; Park, Morag; Wang, Edwin; Yang, Xiang-Jiao

    2015-03-01

    Lysine acetylation has recently emerged as an important post-translational modification in diverse organisms, but relatively little is known about its roles in mammalian development and stem cells. Bromodomain- and PHD finger-containing protein 1 (BRPF1) is a multidomain histone binder and a master activator of three lysine acetyltransferases, MOZ, MORF and HBO1, which are also known as KAT6A, KAT6B and KAT7, respectively. While the MOZ and MORF genes are rearranged in leukemia, the MORF gene is also mutated in prostate and other cancers and in four genetic disorders with intellectual disability. Here we show that forebrain-specific inactivation of the mouse Brpf1 gene causes hypoplasia in the dentate gyrus, including underdevelopment of the suprapyramidal blade and complete loss of the infrapyramidal blade. We trace the developmental origin to compromised Sox2+ neural stem cells and Tbr2+ intermediate neuronal progenitors. We further demonstrate that Brpf1 loss deregulates neuronal migration, cell cycle progression and transcriptional control, thereby causing abnormal morphogenesis of the hippocampus. These results link histone binding and acetylation control to hippocampus development and identify an important epigenetic regulator for patterning the dentate gyrus, a brain structure critical for learning, memory and adult neurogenesis. PMID:25757017

  11. The Lysine Acetyltransferase Activator Brpf1 Governs Dentate Gyrus Development through Neural Stem Cells and Progenitors

    PubMed Central

    You, Linya; Yan, Kezhi; Zhou, Jinfeng; Zhao, Hong; Bertos, Nicholas R.; Park, Morag; Wang, Edwin; Yang, Xiang-Jiao

    2015-01-01

    Lysine acetylation has recently emerged as an important post-translational modification in diverse organisms, but relatively little is known about its roles in mammalian development and stem cells. Bromodomain- and PHD finger-containing protein 1 (BRPF1) is a multidomain histone binder and a master activator of three lysine acetyltransferases, MOZ, MORF and HBO1, which are also known as KAT6A, KAT6B and KAT7, respectively. While the MOZ and MORF genes are rearranged in leukemia, the MORF gene is also mutated in prostate and other cancers and in four genetic disorders with intellectual disability. Here we show that forebrain-specific inactivation of the mouse Brpf1 gene causes hypoplasia in the dentate gyrus, including underdevelopment of the suprapyramidal blade and complete loss of the infrapyramidal blade. We trace the developmental origin to compromised Sox2+ neural stem cells and Tbr2+ intermediate neuronal progenitors. We further demonstrate that Brpf1 loss deregulates neuronal migration, cell cycle progression and transcriptional control, thereby causing abnormal morphogenesis of the hippocampus. These results link histone binding and acetylation control to hippocampus development and identify an important epigenetic regulator for patterning the dentate gyrus, a brain structure critical for learning, memory and adult neurogenesis. PMID:25757017

  12. Housing Complexity Alters GFAP-Immunoreactive Astrocyte Morphology in the Rat Dentate Gyrus

    PubMed Central

    Salois, Garrick; Smith, Jeffrey S.

    2016-01-01

    Rats used in research are typically housed singly in cages with limited sensory stimulation. There is substantial evidence that housing rats in these conditions lead to numerous neuroanatomical and behavioral abnormalities. Alternatively, rats can be housed in an enriched environment in which rats are housed in groups and given room for exercise and exploration. Enriched environments result in considerable neuroplasticity in the rodent brain. In the dentate gyrus of the hippocampus, enriched environments evoke especially profound neural changes, including increases in the number of neurons and the number of dendritic spines. However, whether changes in astrocytes, a type of glia increasingly implicated in mediating neuroplasticity, are concurrent with these neural changes remains to be investigated. In order to assess morphological changes among astrocytes of the rat dentate gyrus, piSeeDB was used to optically clear 250 μm sections of tissue labeled using GFAP immunohistochemistry. Confocal imaging and image analysis were then used to measure astrocyte morphology. Astrocytes from animals housed in EE demonstrated a reduced distance between filament branch points. Furthermore, the most complex astrocytes were significantly more complex among animals housed in EE compared to standard environments. PMID:26989515

  13. Postischemic Anhedonia Associated with Neurodegenerative Changes in the Hippocampal Dentate Gyrus of Rats.

    PubMed

    Kasahara, Jiro; Uchida, Hiroto; Tezuka, Kenta; Oka, Nanae

    2016-01-01

    Poststroke depression is one of the major symptoms observed in the chronic stage of brain stroke such as cerebral ischemia. Its pathophysiological mechanisms, however, are not well understood. Using the transient right middle cerebral artery occlusion- (MCAO-, 90 min) operated rats as an ischemia model in this study, we first observed that aggravation of anhedonia spontaneously occurred especially after 20 weeks of MCAO, and it was prevented by chronic antidepressants treatment (imipramine or fluvoxamine). The anhedonia specifically associated with loss of the granular neurons in the ipsilateral side of hippocampal dentate gyrus and was also prevented by an antidepressant imipramine. Immunohistochemical analysis showed increased apoptosis inside the granular cell layer prior to and associated with the neuronal loss, and imipramine seemed to recover the survival signal rather than suppressing the death signal to prevent neurons from apoptosis. Proliferation and development of the neural stem cells were increased transiently in the subgranular zone of both ipsi- and contralateral hippocampus within one week after MCAO and then decreased and almost ceased after 6 weeks of MCAO, while chronic imipramine treatment prevented them partially. Overall, our study suggests new insights for the mechanistic correlation between poststroke depression and the delayed neurodegenerative changes in the hippocampal dentate gyrus with effective use of antidepressants on them. PMID:27057366

  14. Unexpected doubly-magic nucleus.

    SciTech Connect

    Janssens, R. V. F.; Physics

    2009-01-01

    Nuclei with a 'magic' number of both protons and neutrons, dubbed doubly magic, are particularly stable. The oxygen isotope {sup 24}O has been found to be one such nucleus - yet it lies just at the limit of stability.

  15. Expression in the human brain of retinoic acid induced 1, a protein associated with neurobehavioural disorders.

    PubMed

    Fragoso, Yara Dadalti; Stoney, Patrick N; Shearer, Kirsty D; Sementilli, Angelo; Nanescu, Sonia E; Sementilli, Pietro; McCaffery, Peter

    2015-03-01

    Retinoic acid induced 1 (RAI1) is a protein of uncertain mechanism of action which nevertheless has been the focus of attention because it is a major contributing factor in several human developmental disorders including Smith-Magenis and Potocki-Lupski syndromes. Further, RAI1 may be linked to adult neural disorders with developmental origins such as schizophrenia and autism. The protein has been extensively examined in the rodent but very little is known about its distribution in the human central nervous system. This study demonstrated the presence of RAI1 transcript in multiple regions of the human brain. The cellular expression of RAI1 protein in the human brain was found to be similar to that described in the mouse, with high levels in neurons, but not glia, of the dentate gyrus and cornus ammonis of the hippocampus. In the cerebellum, a second region of high expression, RAI1 was present in Purkinje cells, but not granule cells. RAI1 was also found in neurons of the occipital cortex. The expression of this retinoic acid-induced protein matched well in the hippocampus with expression of the retinoic acid receptors. The subcellular distribution of human neuronal RAI1 indicated its presence in both cytoplasm and nucleus. Overall, human RAI1 protein was found to be a highly expressed neuronal protein whose distribution matches well with its role in cognitive and motor skills. PMID:24519454

  16. Cognitive Enhancing Treatment with a PPARγ Agonist Normalizes Dentate Granule Cell Presynaptic Function in Tg2576 APP Mice

    PubMed Central

    Nenov, Miroslav N.; Laezza, Fernanda; Haidacher, Sigmund J.; Zhao, Yingxin; Sadygov, Rovshan G.; Starkey, Jonathan M.; Spratt, Heidi; Luxon, Bruce A.; Dineley, Kelly T.

    2014-01-01

    Hippocampal network hyperexcitability is considered an early indicator of Alzheimer's disease (AD) memory impairment. Some AD mouse models exhibit similar network phenotypes. In this study we focused on dentate gyrus (DG) granule cell spontaneous and evoked properties in 9-month-old Tg2576 mice that model AD amyloidosis and cognitive deficits. Using whole-cell patch-clamp recordings, we found that Tg2576 DG granule cells exhibited spontaneous EPSCs that were higher in frequency but not amplitude compared with wild-type mice, suggesting hyperactivity of DG granule cells via a presynaptic mechanism. Further support of a presynaptic mechanism was revealed by increased I–O relationships and probability of release in Tg2576 DG granule cells. Since we and others have shown that activation of the peroxisome proliferator-activated receptor gamma (PPARγ) axis improves hippocampal cognition in mouse models for AD as well as benefitting memory performance in some humans with early AD, we investigated how PPARγ agonism affected synaptic activity in Tg2576 DG. We found that PPARγ agonism normalized the I–O relationship of evoked EPSCs, frequency of spontaneous EPSCs, and probability of release that, in turn, correlated with selective expression of DG proteins essential for presynaptic SNARE function that are altered in patients with AD. These findings provide evidence that DG principal cells may contribute to early AD hippocampal network hyperexcitability via a presynaptic mechanism, and that hippocampal cognitive enhancement via PPARγ activation occurs through regulation of presynaptic vesicular proteins critical for proper glutamatergic neurotransmitter release, synaptic transmission, and short-term plasticity. PMID:24431460

  17. Sensitivity of cross sections for elastic nucleus-nucleus scattering to halo nucleus density distributions

    SciTech Connect

    Alkhazov, G. D.; Sarantsev, V. V.

    2012-12-15

    In order to clear up the sensitivity of the nucleus-nucleus scattering to the nuclear matter distributions in exotic halo nuclei, we have calculated differential cross sections for elastic scattering of the {sup 6}He and {sup 11}Li nuclei on several nuclear targets at the energy of 0.8 GeV/nucleon with different assumed nuclear density distributions in {sup 6}He and {sup 11}Li.

  18. Chronic mild stress inhibits BDNF protein expression and CREB activation in the dentate gyrus but not in the hippocampus proper.

    PubMed

    Grønli, Janne; Bramham, Clive; Murison, Robert; Kanhema, Tambudzai; Fiske, Eldbjørg; Bjorvatn, Bjørn; Ursin, Reidun; Portas, Chiara M

    2006-12-01

    Chronic stress is linked to development of depression and may trigger neurobiological changes underlying the disease. Downregulation of the secretory peptide brain-derived neurotrophic factor (BDNF) and the transcriptional regulator calcium/cyclic-AMP responsive binding protein (CREB) have been implicated in stress and depression-related pathology in animal studies. When animals are exposed to the chronic mild stress (CMS) protocol, multiple depression-like symptoms are observed. Here we investigated the effect of CMS on BDNF protein expression and CREB activation in the dentate gyrus and hippocampus proper. Rats exposed for 5 weeks to repeated, unpredictable, mild stressors showed reduced BDNF expression and inhibited phosphorylation of CREB (Ser-133) in the dentate gyrus (-25.0%+/-3.5% and -29.7+/-7.3%, respectively), whereas no significant effects were observed in the hippocampus proper. CMS-treated rats consumed less sucrose compared to control rats, indicating a state of anhedonia. Moreover, phospho-CREB levels in the dentate gyrus were positively correlated with the animals' sucrose intake at the end of the CMS protocol. These results couple chronic mild stress to a downregulation of CREB activity and BDNF protein expression specifically within the dentate gyrus and support the possibility that the BDNF-CREB system plays an important role in the response to environmental challenges. PMID:17204313

  19. Somatostatin-immunoreactive interneurons contribute to lateral inhibitory circuits in the dentate gyrus of control and epileptic rats.

    PubMed

    Boyett, J M; Buckmaster, P S

    2001-01-01

    Lateral inhibition, a feature of neuronal circuitry that enhances signaling specificity, has been demonstrated in the rat dentate gyrus. However, neither the underlying neuronal circuits, nor the ways in which these circuits are altered in temporal lobe epilepsy, are completely understood. This study examines the potential contribution of one class of inhibitory interneurons to lateral inhibitory circuits in the dentate gyrus of both control and epileptic rats. The retrograde tracer wheat germ ag-glutinin-apo-horse radish peroxidase-gold (WGA-apo-HRP-gold) was injected into the septal dentate gyrus. Neurons double-labeled for glutamic acid decarboxylase (GAD) and the retrograde tracer are concentrated in the hilus and may contribute to lateral inhibition. Neurons double-labeled for somatostatin and the retrograde tracer account for at least 28% of GAD-positive neurons with axon projections appropriate for generating lateral inhibition in control rats. Despite an overall loss of somatostatin-expressing cells in epileptic animals, the number of somatostatin-positive interneurons with axon projections appropriate for generating lateral inhibition is similar to that seen in controls. These findings suggest that somatostatinergic interneurons participate in lateral inhibitory circuits in the dentate gyrus of both control and epileptic rats, and that surviving somatostatinergic interneurons might sprout new axon collaterals in epileptic animals. PMID:11530846

  20. Ethanol extract of Oenanthe javanica increases cell proliferation and neuroblast differentiation in the adolescent rat dentate gyrus

    PubMed Central

    Chen, Bai Hui; Park, Joon Ha; Cho, Jeong Hwi; Kim, In Hye; Shin, Bich Na; Ahn, Ji Hyeon; Hwang, Seok Joon; Yan, Bing Chun; Tae, Hyun Jin; Lee, Jae Chul; Bae, Eun Joo; Lee, Yun Lyul; Kim, Jong Dai; Won, Moo-Ho; Kang, Il Jun

    2015-01-01

    Oenanthe javanica is an aquatic perennial herb that belongs to the Oenanthe genus in Apiaceae family, and it displays well-known medicinal properties such as protective effects against glutamate-induced neurotoxicity. However, few studies regarding effects of Oenanthe javanica on neurogenesis in the brain have been reported. In this study, we examined the effects of a normal diet and a diet containing ethanol extract of Oenanthe javanica on cell proliferation and neuroblast differentiation in the subgranular zone of the hippocampal dentate gyrus of adolescent rats using Ki-67 (an endogenous marker for cell proliferation) and doublecortin (a marker for neuroblast). Our results showed that Oenanthe javanica extract significantly increased the number of Ki-67-immunoreactive cells and doublecortin-immunoreactive neuroblasts in the subgranular zone of the dentate gyrus in the adolescent rats. In addition, the immunoreactivity of brain-derived neurotrophic factor was significantly increased in the dentate gyrus of the Oenanthe javanica extract-treated group compared with the control group. However, we did not find that vascular endothelial growth factor expression was increased in the Oenanthe javanica extract-treated group compared with the control group. These results indicate that Oenanthe javanica extract improves cell proliferation and neuroblast differentiation by increasing brain-derived neurotrophic factor immunoreactivity in the rat dentate gyrus. PMID:25883627

  1. D1/D5 Receptors and Histone Deacetylation Mediate the Gateway Effect of LTP in Hippocampal Dentate Gyrus

    ERIC Educational Resources Information Center

    Huang, Yan-You; Lavine, Amir; Kandel, Denise B.; Yin, Deqi; Colnaghi, Luca; Drisaldi, Bettina; Kandel, Eric R.

    2014-01-01

    The dentate gyrus (DG) of the hippocampus is critical for spatial memory and is also thought to be involved in the formation of drug-related associative memory. Here, we attempt to test an aspect of the Gateway Hypothesis, by studying the effect of consecutive exposure to nicotine and cocaine on long-term synaptic potentiation (LTP) in the DG. We…

  2. Erythropoietin improves neuronal proliferation in dentate gyrus of hippocampal formation in an animal model of Alzheimer's disease

    PubMed Central

    Arabpoor, Zohreh; Hamidi, Gholamali; Rashidi, Bahman; Shabrang, Moloud; Alaei, Hojjatallah; Sharifi, Mohammad Reza; Salami, Mahmoud; Dolatabadi, Hamid Reza Dehghani; Reisi, Parham

    2012-01-01

    Background: Alzheimer's disease (AD) is a prevalent disorder with severe learning and memory defects. Because it has been demonstrated that erythropoietin (EPO) has positive effects on the central nervous system, the aim of this study was to evaluate the effect of EPO on neuronal proliferation in dentate gyrus of hippocampal formation in a well-defined model for AD. Materials and Methods: A rat model of sporadic dementia of Alzheimer's type was established by a bilateral intracerebroventricular injection of streptozotocin (ICV-STZ). Impairment of learning and memory was confirmed 2 weeks after ICV-STZ injection by passive avoidance learning test and then rats were divided into fourgroups:Control, control-EPO, Alzheimer and Alzheimer-EPO. EPO was injected intraperitoneally every other day with a dose of 5000 IU/kg and, finally, the rats were anesthetized and decapitated for immunohistochemical study and neurogenesis investigation (by Ki67 method) in dentate gyrus of hippocampal formation. Results: The results driven from the histological study showed that EPO significantly increases neuronal proliferation in dentate gyrus of hippocampus in the Alzheimer-EPO group compared with the control, control-EPO and Alzheimer groups; however, there were no differences between the other groups. Conclusion: Our results show that even though EPO in intact animals doesnot change neurogenesis in dentate gyrus, it can nonetheless significantly increase neurogenesis if there is an underlying disorder like neurodegenerative diseases. PMID:23326781

  3. Dentate Gyrus-Specific Knockdown of Adult Neurogenesis Impairs Spatial and Object Recognition Memory in Adult Rats

    ERIC Educational Resources Information Center

    Jessberger, Sebastian; Clark, Robert E.; Broadbent, Nicola J.; Clemenson, Gregory D., Jr.; Consiglio, Antonella; Lie, D. Chichung; Squire, Larry R.; Gage, Fred H.

    2009-01-01

    New granule cells are born throughout life in the dentate gyrus of the hippocampal formation. Given the fundamental role of the hippocampus in processes underlying certain forms of learning and memory, it has been speculated that newborn granule cells contribute to cognition. However, previous strategies aiming to causally link newborn neurons…

  4. 5-HT1a Receptor Antagonists Block Perforant Path-Dentate LTP Induced in Novel, but Not Familiar, Environments

    ERIC Educational Resources Information Center

    Sanberg, Cyndy Davis; Jones, Floretta L.; Do, Viet H.; Dieguez, Dario, Jr.; Derrick, Brian E.

    2006-01-01

    Numerous studies suggest roles for monoamines in modulating long-term potentiation (LTP). Previously, we reported that both induction and maintenance of perforant path-dentate gyrus LTP is enhanced when induced while animals explore novel environments. Here we investigate the contribution of serotonin and 5-HT1a receptors to the novelty-mediated…

  5. Double Nucleus in M83

    NASA Astrophysics Data System (ADS)

    Mast, Damián; Díaz, Rubén J.; Agüero, M. Paz

    2006-03-01

    M83 is one of the nearest galaxies with enhanced nuclear star formation, and it presents one of the best opportunities to study the kinematics and physical properties of a circumnuclear starburst. Our three-dimensional spectroscopy data in the R band confirm the presence of a secondary nucleus or mass concentration (previously suggested by Thatte and coworkers). We determine the position of this hidden nucleus, which would be more massive than the visible one and was not detected in the optical Hubble Space Telescope images due, probably, to the strong dust extinction. Using a Keplerian approximation, we estimated for the optical nucleus a mass of (5.0+/-0.8)×106 Msolar/sini (r<1.5"), and for the hidden nucleus, located 4''+/-1'' to the northwest (position angle of 271deg+/-15deg) of the optical nucleus, a mass of (1.00+/-0.08)×107 Msolar/sini (r<1.5"). The emission-line ratio map also unveils the presence of a second circumnuclear ring structure, previously discovered by IR imaging (Elmegreen and coworkers). The data allow us to resolve the behavior of the interstellar medium inside the circumnuclear ring and around the binary mass concentration.

  6. A million-plus neuron model of the hippocampal dentate gyrus: Dependency of spatio-temporal network dynamics on topography.

    PubMed

    Hendrickson, Phillip J; Yu, Gene J; Song, Dong; Berger, Theodore W

    2015-01-01

    This paper describes a million-plus granule cell compartmental model of the rat hippocampal dentate gyrus, including excitatory, perforant path input from the entorhinal cortex, and feedforward and feedback inhibitory input from dentate interneurons. The model includes experimentally determined morphological and biophysical properties of granule cells, together with glutamatergic AMPA-like EPSP and GABAergic GABAA-like IPSP synaptic excitatory and inhibitory inputs, respectively. Each granule cell was composed of approximately 200 compartments having passive and active conductances distributed throughout the somatic and dendritic regions. Modeling excitatory input from the entorhinal cortex was guided by axonal transport studies documenting the topographical organization of projections from subregions of the medial and lateral entorhinal cortex, plus other important details of the distribution of glutamatergic inputs to the dentate gyrus. Results showed that when medial and lateral entorhinal cortical neurons maintained Poisson random firing, dentate granule cells expressed, throughout the million-cell network, a robust, non-random pattern of spiking best described as spatiotemporal "clustering". To identify the network property or properties responsible for generating such firing "clusters", we progressively eliminated from the model key mechanisms such as feedforward and feedback inhibition, intrinsic membrane properties underlying rhythmic burst firing, and/or topographical organization of entorhinal afferents. Findings conclusively identified topographical organization of inputs as the key element responsible for generating a spatio-temporal distribution of clustered firing. These results uncover a functional organization of perforant path afferents to the dentate gyrus not previously recognized: topography-dependent clusters of granule cell activity as "functional units" that organize the processing of entorhinal signals. PMID:26737346

  7. A Million-Plus Neuron Model of the Hippocampal Dentate Gyrus: Dependency of Spatio-Temporal Network Dynamics on Topography

    PubMed Central

    Hendrickson, Phillip J.; Yu, Gene J.; Song, Dong; Berger, Theodore W.

    2016-01-01

    This paper describes a million-plus granule cell compartmental model of the rat hippocampal dentate gyrus, including excitatory, perforant path input from the entorhinal cortex, and feedforward and feedback inhibitory input from dentate interneurons. The model includes experimentally determined morphological and biophysical properties of granule cells, together with glutamatergic AMPA-like EPSP and GABAergic GABAA-like IPSP synaptic excitatory and inhibitory inputs, respectively. Each granule cell was composed of approximately 200 compartments having passive and active conductances distributed throughout the somatic and dendritic regions. Modeling excitatory input from the entorhinal cortex was guided by axonal transport studies documenting the topographical organization of projections from subregions of the medial and lateral entorhinal cortex, plus other important details of the distribution of glutamatergic inputs to the dentate gyrus. Results showed that when medial and lateral entorhinal cortical neurons maintained Poisson random firing, dentate granule cells expressed, throughout the million-cell network, a robust, non-random pattern of spiking best described as spatiotemporal “clustering”. To identify the network property or properties responsible for generating such firing “clusters”, we progressively eliminated from the model key mechanisms such as feedforward and feedback inhibition, intrinsic membrane properties underlying rhythmic burst firing, and/or topographical organization of entorhinal afferents. Findings conclusively identified topographical organization of inputs as the key element responsible for generating a spatio-temporal distribution of clustered firing. These results uncover a functional organization of perforant path afferents to the dentate gyrus not previously recognized: topography-dependent clusters of granule cell activity as “functional units” that organize the processing of entorhinal signals. PMID:26737346

  8. Anatomical gradients of adult neurogenesis and activity: young neurons in the ventral dentate gyrus are activated by water maze training

    PubMed Central

    Snyder, Jason S.; Radik, Ruvim; Wojtowicz, J. Martin; Cameron, Heather A.

    2009-01-01

    Hippocampal function varies in a subregion-specific fashion: spatial processing is thought to rely on the dorsal hippocampus, while anxiety-related behavior relies more on the ventral hippocampus. During development, neurogenesis in the dentate gyrus proceeds along ventral to dorsal as well as suprapyramidal to infrapyramidal gradients, but it is unclear whether regional differences in neurogenesis are maintained in adulthood. Moreover, it is unknown whether young neurons in the adult exhibit subregion-specific patterns of activation. We therefore examined the magnitude of neurogenesis and the activation of young and mature granule cells in dentate gyrus subregions in adult rats that learned a spatial water maze task, swam with no platform, or were left untouched. We found that both adult neurogenesis and granule cell activation, as defined by c-fos expression in the granule cell population as a whole, were higher in the dorsal than the ventral dentate gyrus. In contrast, c-fos expression in adult-born granule cells, identified by PSA-NCAM or location in the subgranular zone, occurred at a higher rate in the opposite subregion, the ventral dentate gyrus. Interestingly, c-fos expression in the entire granule cell population was equivalent in water maze-trained rats and swim control rats, but was increased in the young granule cells only in the learning condition. These results provide new evidence that hippocampally-relevant experience activates young and mature neurons in different dentate gyrus subregions and with different experiential specificity, and suggest that adult-born neurons may play a specific role in anxiety-related behavior or other non-spatial aspects of hippocampal function. PMID:19004012

  9. Differential control of learning and anxiety along the dorso-ventral axis of the dentate gyrus

    PubMed Central

    Kheirbek, Mazen A.; Drew, Liam J.; Burghardt, Nesha S.; Costantini, Daniel O.; Tannenholz, Lindsay; Ahmari, Susanne E.; Zeng, Hongkui; Fenton, André A.; Hen, René

    2013-01-01

    The dentate gyrus (DG), in addition to its role in learning and memory, is increasingly implicated in the pathophysiology of anxiety disorders. Here, we show that, dependent on their position along the dorso-ventral axis of the hippocampus, DG granule cells (GCs) control specific features of anxiety and contextual learning. Using optogenetic techniques to either elevate or decrease GC activity, we demonstrate that GCs in the dorsal DG control exploratory drive and encoding, not retrieval, of contextual fear memories. In contrast, elevating the activity of GCs in the ventral DG has no effect on contextual learning but powerfully suppresses innate anxiety. These results suggest that strategies aimed at modulating the excitability of the ventral DG may be beneficial for the treatment of anxiety disorders. PMID:23473324

  10. Activation of local inhibitory circuits in the dentate gyrus by adult-born neurons.

    PubMed

    Drew, Liam J; Kheirbek, Mazen A; Luna, Victor M; Denny, Christine A; Cloidt, Megan A; Wu, Melody V; Jain, Swati; Scharfman, Helen E; Hen, René

    2016-06-01

    Robust incorporation of new principal cells into pre-existing circuitry in the adult mammalian brain is unique to the hippocampal dentate gyrus (DG). We asked if adult-born granule cells (GCs) might act to regulate processing within the DG by modulating the substantially more abundant mature GCs. Optogenetic stimulation of a cohort of young adult-born GCs (0 to 7 weeks post-mitosis) revealed that these cells activate local GABAergic interneurons to evoke strong inhibitory input to mature GCs. Natural manipulation of neurogenesis by aging-to decrease it-and housing in an enriched environment-to increase it-strongly affected the levels of inhibition. We also demonstrated that elevating activity in adult-born GCs in awake behaving animals reduced the overall number of mature GCs activated by exploration. These data suggest that inhibitory modulation of mature GCs may be an important function of adult-born hippocampal neurons. © 2015 Wiley Periodicals, Inc. PMID:26662922