Stimulation of dopamine D4 receptors in the paraventricular nucleus of the hypothalamus of male rats induces hyperphagia: involvement of glutamate.

PubMed

Tejas-Juárez, Juan Gabriel; Cruz-Martínez, Ana María; López-Alonso, Verónica Elsa; García-Iglesias, Brenda; Mancilla-Díaz, Juan Manuel; Florán-Garduño, Benjamín; Escartín-Pérez, Rodrigo Erick

2014-06-22

Obesity is a serious worldwide health problem, affecting 20-40% of the population in several countries. According to animal models, obesity is related to changes in the expression of proteins that control energy homeostasis and in neurotransmission associated to regulation of food intake. For example, it has been reported that diet-induced obesity produces overexpression of dopamine D4 receptor (D4R) mRNA in the ventromedial hypothalamic nucleus (VMH) of mice. Neurons in the VMH send dense glutamatergic projections to other hypothalamic regions as the paraventricular nucleus (PVN), where multiple signals are integrated to finely regulate energy homeostasis and food intake. Although it is well established that dopaminergic transmission in the hypothalamus plays a key role in modulating feeding, the specific mechanisms involved in the activation of D4R in the PVN and its modulatory action on glutamate release and feeding behavior have remained unexplored. To fill this gap, we characterize the behavioral and neurochemical role of D4R in the PVN. In behavioral experiments, we examined the effects of activation of dopamine D4 receptors in the PVN on food intake and on the behavioral satiety sequence in rats exposed to a food-restricted feeding program. In vitro experiments were conducted to study the effects of activation of dopamine D4 receptors on [(3)H]glutamate release and on plasma corticosterone in explants of the PVN. We found that activation of D4R in the PVN induced inhibition of glutamate release and stimulated food intake by inhibiting satiety. Furthermore, activation of D4R in the PVN decreased plasma levels of corticosterone, and this effect was reverted by NMDA. According to our findings, D4R in the PVN may be a target for the pharmacotherapy for obesity as well as eating disorder patients who show restrictive patterns and overweight. Copyright © 2014 Elsevier Inc. All rights reserved.

Active action potential propagation but not initiation in thalamic interneuron dendrites

PubMed Central

Casale, Amanda E.; McCormick, David A.

2012-01-01

Inhibitory interneurons of the dorsal lateral geniculate nucleus of the thalamus modulate the activity of thalamocortical cells in response to excitatory input through the release of inhibitory neurotransmitter from both axons and dendrites. The exact mechanisms by which release can occur from dendrites are, however, not well understood. Recent experiments using calcium imaging have suggested that Na/K based action potentials can evoke calcium transients in dendrites via local active conductances, making the back-propagating action potential a candidate for dendritic neurotransmitter release. In this study, we employed high temporal and spatial resolution voltage-sensitive dye imaging to assess the characteristics of dendritic voltage deflections in response to Na/K action potentials in interneurons of the mouse dorsal lateral geniculate nucleus. We found that trains or single action potentials elicited by somatic current injection or local synaptic stimulation led to action potentials that rapidly and actively back-propagated throughout the entire dendritic arbor and into the fine filiform dendritic appendages known to release GABAergic vesicles. Action potentials always appeared first in the soma or proximal dendrite in response to somatic current injection or local synaptic stimulation, and the rapid back-propagation into the dendritic arbor depended upon voltage-gated sodium and TEA-sensitive potassium channels. Our results indicate that thalamic interneuron dendrites integrate synaptic inputs that initiate action potentials, most likely in the axon initial segment, that then back-propagate with high-fidelity into the dendrites, resulting in a nearly synchronous release of GABA from both axonal and dendritic compartments. PMID:22171033

Pyridostigmine-Induced Neurodegeneration: Role of Neuronal Apoptosis.

DTIC Science & Technology

1999-10-01

carbachol releases glutamate and glycine from dorsal cochlear nucleus brain slices (Chen et al, 1999). No other amino acids were released from brain...Sivasamy (1997) reported that the anticholinesterase, phosphamidon, caused apoptosis in spermatogenic line cells. Also, muscarinic agonists, carbachol and...1999) Glutamergic transmission of neuronal responses to carbachol in rat cochlear nucleus slices. Neurosci. 90: 2043-2049. Crews, F.T., Steck, J.C

Increases in extracellular zinc in the amygdala in acquisition and recall of fear experience and their roles in response to fear.

PubMed

Takeda, A; Tamano, H; Imano, S; Oku, N

2010-07-14

The amygdala is enriched with histochemically reactive zinc, which is dynamically coupled with neuronal activity and co-released with glutamate. The dynamics of the zinc in the amygdala was analyzed in rats, which were subjected to inescapable stress, to understand the role of the zinc in emotional behavior. In the communication box, two rats were subjected to foot shock stress and anxiety stress experiencing emotional responses of foot-shocked rat under amygdalar perfusion. Extracellular zinc was increased by foot shock stress, while decreased by anxiety stress, suggesting that the differential changes in extracellular zinc are associated with emotional behavior. In rats conditioned with foot shock, furthermore, extracellular zinc was increased again in the recall of fear (foot shock) in the same box without foot shock. When this recall was performed under perfusion with CaEDTA, a membrane-impermeable zinc chelator, to examine the role of the increase in extracellular zinc, the time of freezing behavior was more increased, suggesting that zinc released in the lateral amygdala during the recall of fear participates in freezing behavior. To examine the role of the increase in extracellular zinc during fear conditioning, fear conditioning was also performed under perfusion with CaEDTA. The time of freezing behavior was more increased in the contextual recall, suggesting that zinc released in the lateral nucleus during fear conditioning also participates in freezing behavior in the recall. In brain slice experiment, CaEDTA enhanced presynaptic activity (exocytosis) in the lateral nucleus after activation of the entorhinal cortex. The present paper demonstrates that zinc released in the lateral amygdala may participate in emotional behavior in response to fear. Copyright 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

Rapid adenosine release in the nucleus tractus solitarii during defence response in rats: real-time measurement in vivo

PubMed Central

Dale, Nicholas; Gourine, Alexander V; Llaudet, Enrique; Bulmer, David; Thomas, Teresa; Spyer, K Michael

2002-01-01

We have measured the release of adenosine and inosine from the dorsal surface of the brainstem and from within the nucleus tractus solitarii (NTS) during the defence response evoked by hypothalamic stimulation in the anaesthetised rat. At the surface of the brainstem, only release of inosine was detected on hypothalamic defence area stimulation. This inosine signal was greatly reduced by addition of the ecto-5′-nucleotidase inhibitor α,β-methylene ADP (200 μM), suggesting that the inosine arose from adenosine that was produced in the extracellular space by the prior release of ATP. By placing a microelectrode biosensor into the NTS under stereotaxic control we have recorded release of adenosine within this nucleus. By contrast to the brainstem surface, a fast increase in adenosine, accompanied only by a much smaller change in inosine levels, was seen following stimulation of the hypothalamic defence area. The release of adenosine following hypothalamic stimulation was mainly confined to a narrow region of the NTS some 500 μm in length around the level of the obex. Interestingly the release of adenosine was depletable: when the defence reaction was evoked at short time intervals, much less adenosine was released on the second stimulus. Our novel techniques have given unprecedented real-time measurement and localisation of adenosine release in vivo and demonstrate that adenosine is released at the right time and in sufficient quantities to contribute to the cardiovascular components of the defence reaction. PMID:12356888

Metabotropic glutamate receptor modulation of dopamine release in the nucleus accumbens shell is unaffected by phencyclidine pretreatment: In vitro assessment using fast-scan cyclic voltammetry rat brain slices.

PubMed

Gupta, Ishan; Young, Andrew M J

2018-05-15

The non-competitive glutamate antagonist, phencyclidine is used in rodents to model behavioural deficits see in schizophrenia. Importantly, these deficits endure long after the cessation of short-term chronic treatment (sub-chronic), indicating that the drug treatment causes long-term changes in the physiology and/or chemistry of the brain. There is evidence that this may occur through glutamatergic modulation of mesolimbic dopamine release, perhaps involving metabotropic glutamate receptors (mGluR). This study sought to investigate the effect of sub-chronic phencyclidine pretreatment on modulation of dopamine neurotransmission by metabotropic glutamate receptors 2 and 5 (mGluR2 and mGluR5) in the nucleus accumbens shell in vitro, with the hypothesis that phencyclidine pretreatment would disrupt the mGluR-mediated modulation of dopamine release. We showed that the orthosteric mGluR2 agonist LY379268 (0.1 µM, 1 µM and 10 µM) and mGluR5 positive allosteric modulator CDPPB (1 µM and 10 µM) both attenuated potassium-evoked dopamine release, underscoring their role in modulating dopamine neurotransmission in the nucleus accumbens. Sub-chronic PCP treatment, which caused cognitive deficits measured by performance in the novel object recognition task, modelling aspects of behavioral deficits seen in schizophrenia, induced neurobiological changes that enhanced dopamine release in the nucleus accumbens, but had no effect on mGluR2 or mGluR5 mediated changes in dopamine release. Therefore it is unlikely that schizophrenia-related behavioural changes seen after sub-chronic phencyclidine pre-treatment are mediated through mGluR modulation of dopamine release. Copyright © 2018 Elsevier B.V. All rights reserved.

Experimental Study on Ice Forming Process of Cryogenic Liquid Releasing underwater

NASA Astrophysics Data System (ADS)

Zhang, Bin; Wu, Wanqing; Zhang, Xingdong; Zhang, Yi; Zhang, Chuanlin; Zhang, Haoran; Wang, Peng

2017-11-01

Cryogenic liquid releasing into water would be a process combines hyperactive boiling with ice forming. There are still few researches on the experimental study on the environmental conditions for deciding ice forming speed and liquid surviving state. In this paper, to advance our understanding of ice forming deciding factors in the process of LN2 releasing underwater, a visualization experimental system is built. The results show that the pressure difference significantly influences the ice forming speed and liquid surviving distance, which is observed by the experiment and theoretically analysed by Kelvin-Helmholtz instability. Adding nucleating agent is helpful to provide ice nucleus which can accelerate the ice forming speed. Water flowing has some effect on changing pressure difference, which can affect the ice forming speed and liquid surviving distance.

Effects of systemic L-tyrosine on dopamine release from rat corpus striatum and nucleus accumbens

NASA Technical Reports Server (NTRS)

During, Matthew J.; Acworth, Ian N.; Wurtman, Richard J.

1988-01-01

Intracerebral dialysis was used to monitor extracellular fluid from rat striatum and nucleus accumbens following the intraperitoneal administration of tyrosine. Dopamine concentrations in dialysates from both the striatum and the nucleus accumbens increased significantly in response to the tyrosine. The magnitude of the tyrosine effect was greater in the nucleus accumbens than in the striatum. Hence, mesolimbic dopaminergic neurons may be especially responsive to precursor availability.

Functional Fast Scan Cyclic Voltammetry Assay to Characterize Dopamine D2 and D3 Autoreceptors in the Mouse Striatum

PubMed Central

2010-01-01

Dopamine D2 and D3 autoreceptors are located on presynaptic terminals and are known to control the release and synthesis of dopamine. Dopamine D3 receptors have a fairly restricted pattern of expression in the mammalian brain. Their localization in the nucleus accumbens core and shell is of particular interest because of their association with the rewarding properties of drugs of abuse. Using background subtracted fast scan cyclic voltammetry, we investigated the effects of dopamine D2 and D3 agonists on electrically stimulated dopamine release and uptake rates in the mouse caudate putamen and nucleus accumbens core and shell. The dopamine D2 agonists (−)-quinpirole hydrochloride and 5,6,7,8-tetrahydro-6-(2-propen-1-yl)-4H-thiazolo[4,5-d]azepin-2-amine dihydrochloride (B-HT 920) had the same dopamine release inhibition effects on caudate putamen and nucleus accumbens (core and shell) on the basis of their EC50 values and efficacies. This suggests that the dopamine D2 autoreceptor functionality is comparable in all three striatal regions investigated. The dopamine D3 agonists (4aR,10bR)-3,4a,4,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol hydrochloride ((+)-PD 128907) and (±)-7-Hydroxy-2-dipropylaminotetralin hydrobromide (7-OH-DPAT) had a significantly greater effect on dopamine release inhibition in the nucleus accumbens shell than in the caudate putamen. This study confirms that, the dopamine D3 autoreceptor functionality is greater in the nucleus accumbens shell followed by the nucleus accumbens core, with the caudate putamen having the least. Neither dopamine D2 nor D3 agonists affected the uptake rates in nucleus accumbens but concentrations greater than 0.1 μM lowered the uptake rate in caudate putamen. To validate our method of evaluating dopamine D2 and D3 autoreceptors, sulpiride (D2 antagonist) and nafadotride (D3 antagonist) were used to reverse the effects of the dopamine agonists to approximately 100% of the preagonist dopamine release concentration. Finally, these results demonstrate a functional voltammetric assay that characterizes dopamine D2-like agonists as either D2- or D3-preferring agonists by taking advantage of the unique receptor density within the striatum. PMID:20567609

Phasic dopamine release in the rat nucleus accumbens predicts approach and avoidance performance

PubMed Central

Gentry, Ronny N.; Lee, Brian; Roesch, Matthew R.

2016-01-01

Dopamine (DA) is critical for reward processing, but significantly less is known about its role in punishment avoidance. Using a combined approach-avoidance task, we measured phasic DA release in the nucleus accumbens (NAc) of rats during presentation of cues that predicted reward, punishment or neutral outcomes and investigated individual differences based on avoidance performance. Here we show that DA release within a single microenvironment is higher for reward and avoidance cues compared with neutral cues and positively correlated with poor avoidance behaviour. We found that DA release delineates trial-type during sessions with good avoidance but is non-selective during poor avoidance, with high release correlating with poor performance. These data demonstrate that phasic DA is released during cued approach and avoidance within the same microenvironment and abnormal processing of value signals is correlated with poor performance. PMID:27786172

Activation of the reticulothalamic cholinergic pathway by the major metabolites of aniracetam.

PubMed

Nakamura, K; Shirane, M

1999-09-10

The aim of the study was to further investigate the effects of aniracetam, a cognition enhancer, and its metabolites on the brain cholinergic system. We measured choline acetyltransferase activity and acetylcholine release using in vivo brain microdialysis in stroke-prone spontaneously hypertensive rats (SHRSP). The enzyme activity in the pons-midbrain and hippocampus, and basal acetylcholine release in the nucleus reticularis thalami were lower in SHRSP than in age-matched Wistar Kyoto rats, indicating central cholinergic deficits in SHRSP. Repeated treatment of aniracetam (50 mg/kg p.o. x 11 for 6 days) preferentially increased the enzyme activity in the thalamus, whereas decreased it in the striatum. Among the metabolites of aniracetam, local perfusion of N-anisoyl-gamma-aminobutyric acid (GABA, 0.1 and/or 1 microM) and p-anisic acid (1 microM) into the nucleus reticularis thalami, dorsal hippocampus and prefrontal cortex of SHRSP produced a significant but delayed increase of acetylcholine release. We failed, however, to find any effect of aniracetam itself. A direct injection of N-anisoyl-GABA (1 nmol) into the pedunculopontine tegmental nucleus of SHRSP enhanced the release in the nucleus reticularis thalami. Thus, these data prove that aniracetam can facilitate central cholinergic neurotransmission via both metabolites. Based on its pharmacokinetic profile, N-anisoyl-GABA may contribute to the clinical effects of aniracetam, mainly by acting on the reticulothalamic cholinergic pathway.

Regulation of calcium signals in the nucleus by a nucleoplasmic reticulum

PubMed Central

Echevarría, Wihelma; Leite, M. Fatima; Guerra, Mateus T.; Zipfel, Warren R.; Nathanson, Michael H.

2013-01-01

Calcium is a second messenger in virtually all cells and tissues1. Calcium signals in the nucleus have effects on gene transcription and cell growth that are distinct from those of cytosolic calcium signals; however, it is unknown how nuclear calcium signals are regulated. Here we identify a reticular network of nuclear calcium stores that is continuous with the endoplasmic reticulum and the nuclear envelope. This network expresses inositol 1,4,5-trisphosphate (InsP3) receptors, and the nuclear component of InsP3-mediated calcium signals begins in its locality. Stimulation of these receptors with a little InsP3 results in small calcium signals that are initiated in this region of the nucleus. Localized release of calcium in the nucleus causes nuclear protein kinase C (PKC) to translocate to the region of the nuclear envelope, whereas release of calcium in the cytosol induces translocation of cytosolic PKC to the plasma membrane. Our findings show that the nucleus contains a nucleoplasmic reticulum with the capacity to regulate calcium signals in localized subnuclear regions. The presence of such machinery provides a potential mechanism by which calcium can simultaneously regulate many independent processes in the nucleus. PMID:12717445

Familiar companions diminish cocaine conditioning and attenuate cocaine-stimulated dopamine release in the nucleus accumbens.

PubMed

Tzeng, Wen-Yu; Cherng, Chian-Fang G; Wang, Shyi-Wu; Yu, Lung

2016-06-01

This study aimed to assess the impact of companions on the rewarding effects of cocaine. Three cage mates, serving as companions, were housed with each experimental mouse throughout cocaine-place conditioning in a cocaine-induced conditioned place preference (CPP) paradigm using conditioning doses of 10 and 20mg/kg. The presence of companions decreased the magnitude of the CPP. At 20mg/kg, cocaine stimulated dopamine (DA) release in the nucleus accumbens as evidenced by a significant decrease in total (spontaneous and electrical stimulation-provoked) DA release in accumbal superfusate samples. The presence of companions prevented this cocaine-stimulated DA release; such a reduction in cocaine-induced DA release may account for the reduction in the magnitude of the CPP in the presence of the companions. Furthermore, cocaine pretreatment (2.5mg/kg) was found to prevent the companion-produced decreases in cocaine (10mg/kg/conditioning)-induced CPP as well as the cocaine (10mg/kg)-stimulated DA release. Moreover, the presence of methamphetamine (MA) (1mg/kg)-treated companions decreased cocaine (20mg/kg/conditioning)-induced CPP and prevented the cocaine (20mg/kg)-stimulated DA release. Finally, the presence of companions decreased the magnitude of the CPP could not seem to be accounted for by cocaine-stimulated corticosterone (CORT) release. Taken together, these results indicate that familiar companions, regardless of their pharmacological status, may exert dampening effects on CPP induced by moderate to high conditioning doses of cocaine, at least in part, by preventing cocaine-stimulated DA release in the nucleus accumbens. Copyright © 2016 Elsevier B.V. All rights reserved.

Neurochemical evidence that cocaine- and amphetamine-regulated transcript (CART) 55-102 peptide modulates the dopaminergic reward system by decreasing the dopamine release in the mouse nucleus accumbens.

PubMed

Rakovska, Angelina; Baranyi, Maria; Windisch, Katalin; Petkova-Kirova, Polina; Gagov, Hristo; Kalfin, Reni

2017-09-01

CART (Cocaine- and Amphetamine-Regulated Transcript) peptide is a neurotransmitter naturally occurring in the CNS and found mostly in nucleus accumbens, ventrotegmental area, ventral pallidum, amygdalae and striatum, brain regions associated with drug addiction. In the nucleus accumbens, known for its significant role in motivation, pleasure, reward and reinforcement learning, CART peptide inhibits cocaine and amphetamine-induced dopamine-mediated increases in locomotor activity and behavior, suggesting a CART peptide interaction with the dopaminergic system. Thus in the present study, we examined the effect of CART (55-102) peptide on the basal, electrical field stimulation-evoked (EFS-evoked) (30V, 2Hz, 120 shocks) and returning basal dopamine (DA) release and on the release of the DA metabolites 3,4-dihydroxyphenyl acetaldehyde (DOPAL), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3,4-dihydroxyphenylethanol (DOPET), 3-methoxytyramine (3-MT) as well as on norepinephrine (NE) and dopamine-o-quinone (Daq) in isolated mouse nucleus accumbens, in a preparation, in which any CART peptide effects on the dendrites or soma of ventral tegmental projection neurons have been excluded. We further extended our study to assess the effect of CART (55-102) peptide on basal cocaine-induced release of dopamine and its metabolites DOPAL, DOPAC, HVA, DOPET and 3-MT as well as on NE and Daq. To analyze the amount of [ 3 H]dopamine, dopamine metabolites, Daq and NE in the nucleus accumbens superfusate, a high-pressure liquid chromatography (HPLC), coupled with electrochemical, UV and radiochemical detections was used. CART (55-102) peptide, 0.1μM, added alone, exerted: (i) a significant decrease in the basal and EFS-evoked levels of extracellular dopamine (ii) a significant increase in the EFS-evoked and returning basal levels of the dopamine metabolites DOPAC and HVA, major products of dopamine degradation and (iii) a significant decrease in the returning basal levels of DOPET. At the same concentration, 0.1μM, CART (55-102) peptide did not have any effect on the release of noradrenaline. In the presence of CART (55-102) peptide, 0.1μM, the effect of cocaine, 30μM, on the basal dopamine release was inhibited and the effect on the basal DOPAC release substantially increased. To our knowledge, our findings are the first to show direct neurochemical evidence that CART (55-102) peptide plays a neuromodulatory role on the dopaminergic reward system by decreasing dopamine in the mouse nucleus accumbens and by attenuating cocaine-induced effects on dopamine release. Copyright © 2017 Elsevier Inc. All rights reserved.

Temporal and Spatial Aspects of Gas Release During the 2010 Apparition of Comet 103P/Hartley-2

NASA Technical Reports Server (NTRS)

Mumma, M. J.; Bonev, B. P.; Villanueva, G. L.; Paganini, L.; DiSanti, M. A.; Gibb, E. L.; Keane, J. V.; Meech, K. J.; Blake, G. A.; Ellis, R. S.;

Lack of effect of nucleus accumbens dopamine D1 receptor blockade on consumption during the first two days of operant self-administration of sweetened ethanol in adult Long-Evans rats.

PubMed

Doherty, James M; Gonzales, Rueben A

2015-09-01

The mechanisms underlying ethanol self-administration are not fully understood; however, it is clear that ethanol self-administration stimulates nucleus accumbens dopamine release in well-trained animals. During operant sweetened ethanol self-administration behavior, an adaptation in the nucleus accumbens dopamine system occurs between the first and second exposure, paralleling a dramatic increase in sweetened ethanol intake, which suggests a single exposure to sweetened ethanol may be sufficient to learn the association between sweetened ethanol cues and its reinforcing properties. In the present experiment, we test the effects of blockade of nucleus accumbens dopamine D1 receptors on operant sweetened ethanol self-administration behavior during the first 2 days of exposure. Adult male Long-Evans rats were first trained to self-administer 10% sucrose (10S) across 6 days in an appetitive and consummatory operant model (appetitive interval: 10-min pre-drinking wait period and a lever response requirement of 4; consummatory interval: 20-min access to the drinking solution). After training on 10S, the drinking solution was switched to 10% sucrose plus 10% ethanol (10S10E); control rats continued drinking 10S throughout the experiment. Bilateral nucleus accumbens microinjections of the dopamine D1 antagonist, SCH-23390 (0, 1.0, or 3.0 μg/side), immediately preceded the first two sessions of drinking 10S10E. Results show that blocking nucleus accumbens dopamine D1 receptors has little or no influence on consumption during the first 2 days of exposure to the sweetened ethanol solution or maintenance of sucrose-only drinking. Furthermore, the high dose of SCH-23390, 3.0 μg/side, reduced open-field locomotor activity. In conclusion, we found no evidence to suggest that nucleus accumbens D1 receptor activation is involved in consumption of a sweetened ethanol solution during the first 2 days of exposure or maintenance of sucrose drinking, but rather D1 receptors seem necessary for general locomotor activity that contributes to initiation of appetitive behavior. Copyright © 2015 Elsevier Inc. All rights reserved.

Dust release rates and dust-to-gas mass ratios of eight comets

NASA Technical Reports Server (NTRS)

Singh, P. D.; De Almeida, A. A.; Huebner, W. F.

1992-01-01

Mass release rates of dust and mass ratios of dust-to-gas release rates of Comets Thiele (1985m), Wilson (1986l), P/Borrelly (1987p), Liller (1988a), Bradfield (1987s), Hartley-Good (1985l), P/Giacobini-Zinner (1984e), and P/Halley (1982i) are estimated from the analysis of continuum flux measurements at optical wavelengths. An attempt is made to estimate the size of each comet nucleus on the basis of water-ice sublimation (vaporization), assuming that the nucleus is spherical and only a fraction of its surface area is active. Where possible, the dust mass release rates are compared with those obtained by other investigators in the optical and IR wavelength regions. Good agreement with results based on IR observations is found.

MAM (E17) rodent developmental model of neuropsychiatric disease: disruptions in learning and dysregulation of nucleus accumbens dopamine release, but spared executive function.

PubMed

Howe, William M; Tierney, Patrick L; Young, Damon A; Oomen, Charlotte; Kozak, Rouba

2015-11-01

Gestational day 17 methylazoxymethanol (MAM) treatment has been shown to reproduce, in rodents, some of the alterations in cortical and mesolimbic circuitries thought to contribute to schizophrenia. We characterized the behavior of MAM animals in tasks dependent on these circuitries to see what behavioral aspects of schizophrenia the model captures. We then characterized the integrity of mesolimbic dopamine neurotransmission in a subset of animals used in the behavioral experiments. MAM animals' capacity for working memory, attention, and resilience to distraction was tested with two different paradigms. Cue-reward learning and motivation were assayed with Pavlovian conditioned approach. Measurements of electrically stimulated phasic and tonic DA release in the nucleus accumbens with fast-scan cyclic voltammetry were obtained from the same animals used in the Pavlovian task. MAM animals' basic attentional capacities were intact. MAM animals took longer to acquire the working memory task, but once learned, performed at the same level as shams. MAM animals were also slower to develop a Pavlovian conditioned response, but otherwise no different from controls. These same animals showed alterations in terminal DA release that were unmasked by an amphetamine challenge. The predominant behavioral-cognitive feature of the MAM model is a learning impairment that is evident in acquisition of executive function tasks as well as basic Pavlovian associations. MAM animals also have dysregulated terminal DA release, and this may contribute to observed behavioral differences. The MAM model captures some functional impairments of schizophrenia, particularly those related to acquisition of goal-directed behavior.

JAK/STAT1 signaling promotes HMGB1 hyperacetylation and nuclear translocation

PubMed Central

Lu, Ben; Antoine, Daniel J.; Kwan, Kevin; Lundbäck, Peter; Wähämaa, Heidi; Schierbeck, Hanna; Robinson, Melissa; Van Zoelen, Marieke A. D.; Yang, Huan; Li, Jianhua; Erlandsson-Harris, Helena; Chavan, Sangeeta S.; Wang, Haichao; Andersson, Ulf; Tracey, Kevin J.

2014-01-01

Extracellular high-mobility group box (HMGB)1 mediates inflammation during sterile and infectious injury and contributes importantly to disease pathogenesis. The first critical step in the release of HMGB1 from activated immune cells is mobilization from the nucleus to the cytoplasm, a process dependent upon hyperacetylation within two HMGB1 nuclear localization sequence (NLS) sites. The inflammasomes mediate the release of cytoplasmic HMGB1 in activated immune cells, but the mechanism of HMGB1 translocation from nucleus to cytoplasm was previously unknown. Here, we show that pharmacological inhibition of JAK/STAT1 inhibits LPS-induced HMGB1 nuclear translocation. Conversely, activation of JAK/STAT1 by type 1 interferon (IFN) stimulation induces HMGB1 translocation from nucleus to cytoplasm. Mass spectrometric analysis unequivocally revealed that pharmacological inhibition of the JAK/STAT1 pathway or genetic deletion of STAT1 abrogated LPS- or type 1 IFN-induced HMGB1 acetylation within the NLS sites. Together, these results identify a critical role of the JAK/STAT1 pathway in mediating HMGB1 cytoplasmic accumulation for subsequent release, suggesting that the JAK/STAT1 pathway is a potential drug target for inhibiting HMGB1 release. PMID:24469805

The area postrema (AP) and the parabrachial nucleus (PBN) are important sites for salmon calcitonin (sCT) to decrease evoked phasic dopamine release in the nucleus accumbens (NAc).

PubMed

Whiting, Lynda; McCutcheon, James E; Boyle, Christina N; Roitman, Mitchell F; Lutz, Thomas A

2017-07-01

The pancreatic hormone amylin and its agonist salmon calcitonin (sCT) act via the area postrema (AP) and the lateral parabrachial nucleus (PBN) to reduce food intake. Investigations of amylin and sCT signaling in the ventral tegmental area (VTA) and nucleus accumbens (NAc) suggest that the eating inhibitory effect of amylin is, in part, mediated through the mesolimbic 'reward' pathway. Indeed, administration of the sCT directly to the VTA decreased phasic dopamine release (DA) in the NAc. However, it is not known if peripheral amylin modulates the mesolimbic system directly or whether this occurs via the AP and PBN. To determine whether and how peripheral amylin or sCT affect mesolimbic reward circuitry we utilized fast scan cyclic voltammetry under anesthesia to measure phasic DA release in the NAc evoked by electrical stimulation of the VTA in intact, AP lesioned and bilaterally PBN lesioned rats. Amylin (50μg/kg i.p.) did not change phasic DA responses compared to saline control rats. However, sCT (50μg/kg i.p.) decreased evoked DA release to VTA-stimulation over 1h compared to saline treated control rats. Further investigations determined that AP and bilateral PBN lesions abolished the ability of sCT to suppress evoked phasic DA responses to VTA-stimulation. These findings implicate the AP and the PBN as important sites for peripheral sCT to decrease evoked DA release in the NAc and suggest that these nuclei may influence hedonic and motivational processes to modulate food intake. Copyright © 2017 Elsevier Inc. All rights reserved.

Glutamatergic transmission in the nucleus of the solitary tract modulates memory through influences on amygdala noradrenergic systems.

PubMed

Miyashita, Teiko; Williams, Cedric L

2002-02-01

The authors examined whether glutamate release from the vagus nerve onto the nucleus of the solitary tract (NTS) is one mechanism by which the vagus influences memory and neural activity in limbic structures. Rats trained to drink from a spout were given a footshock (0.35 mA) on Day 5 after approaching the spout. Phosphate-buffered saline or 5.0, 50.0, or 100.0 nmol/0.5 microl glutamate was then infused into the NTS. Glutamate (5.0 or 50.0 nmol) significantly enhanced memory on the retention test. In Experiment 2, this effect was attenuated by blocking noradrenergic receptors in the amygdala with propranolol (0.3 microg/0.5 microl). Experiment 3 used in vivo microdialysis to determine whether footshock plus glutamate (50.0 nmol) alters noradrenergic output in the amygdala. These treatments caused a significant and long-lasting increase in amygdala noradrenergic concentrations. The results indicate that glutamate may be one transmitter that conveys the effects of vagal activation on brain systems that process memory.

Effect of beta-phenylethylamine on extracellular concentrations of dopamine in the nucleus accumbens and prefrontal cortex.

PubMed

Murata, Mikio; Katagiri, Nobuyuki; Ishida, Kota; Abe, Kenji; Ishikawa, Masago; Utsunomiya, Iku; Hoshi, Keiko; Miyamoto, Ken-ichi; Taguchi, Kyoji

2009-05-07

It is known that psychostimulants stimulate dopamine transmission in the nucleus accumbens. In the present study, we examined the effects of systemically administered beta-phenylethylamine (beta-PEA), a psychomotor-stimulating trace amine, on dopamine concentrations in the nucleus accumbens and prefrontal cortex in freely moving rats, using an in vivo microdialysis technique. Intraperitoneal administration of beta-PEA (12.5 and 25 mg/kg) significantly increased extracellular dopamine levels in the nucleus accumbens shell. The observed increase in the dopamine concentration in nucleus accumbens shell dialysate after intraperitoneal administration of 25 mg/kg beta-PEA was inhibited by pre-treatment with a dopamine uptake inhibitor, GBR12909 (10 mg/kg, i.p.). In contrast, beta-PEA (25 mg/kg, i.p.) did not affect dopamine release in the nucleus accumbens core. Although a high dose of beta-PEA (50 mg/kg) significantly increased dopamine levels in the nucleus accumbens core, the dopamine increasing effect of beta-PEA was more potent in the nucleus accumbens shell. Systemic administration of 12.5 and 25 mg/kg beta-PEA also increased extracellular dopamine levels in the prefrontal cortex of rats. However, systemic 25 mg/kg beta-PEA-induced increases in extracellular dopamine levels were not blocked by GBR12909 within the prefrontal cortex. These results suggest that beta-PEA has a greater effect in the shell than in the core and low-dose beta-PEA stimulates dopamine release in the nucleus accumbens shell through uptake by a dopamine transporter. Similarly, beta-PEA increased extracellular dopamine levels in the prefrontal cortex. Thus, beta-PEA may increase extracellular dopamine concentrations in the mesocorticolimbic pathway.

Striatal dopamine dynamics in mice following acute and repeated toluene exposure.

PubMed

Apawu, Aaron K; Mathews, Tiffany A; Bowen, Scott E

2015-01-01

The abused inhalant toluene has potent behavioral effects, but only recently has progress been made in understanding the neurochemical actions that mediate the action of toluene in the brain. Available evidence suggests that toluene inhalation alters dopamine (DA) neurotransmission, but toluene's mechanism of action is unknown. The present study evaluated the effect of acute and repeated toluene inhalation (0, 2,000, or 4,000 ppm) on locomotor activity as well as striatal DA release and uptake using slice fast-scan cyclic voltammetry. Acutely, 2,000 and 4,000 ppm toluene increased locomotor activity, while neurochemically only 4,000 ppm toluene potentiated electrically evoked DA release across the caudate-putamen and the nucleus accumbens. Repeated administration of toluene resulted in sensitization to toluene's locomotor activity effects. Brain slices obtained from mice repeatedly exposed to toluene demonstrated no difference in stimulated DA release in the caudate-putamen as compared to control animals. Repeated exposure to 2,000 and 4,000 ppm toluene caused a concentration-dependent decrease of 25-50 % in evoked DA release in the nucleus accumbens core and shell relative to air-exposed mice. These voltammetric neurochemical findings following repeated toluene exposure suggest that there may be a compensatory downregulation of the DA system. Acute or repeated toluene exposure had no effect on the DA uptake kinetics. Taken together, these results demonstrate that acute toluene inhalation potentiates DA release, while repeated toluene exposure attenuates DA release in the nucleus accumbens only.

Corticotropin-Releasing Factor Mediates Pain-Induced Anxiety through the ERK1/2 Signaling Cascade in Locus Coeruleus Neurons

PubMed Central

Borges, Gisela Patrícia; Micó, Juan Antonio; Neto, Fani Lourença

2015-01-01

Background: The corticotropin-releasing factor is a stress-related neuropeptide that modulates locus coeruleus activity. As locus coeruleus has been involved in pain and stress-related patologies, we tested whether the pain-induced anxiety is a result of the corticotropin-releasing factor released in the locus coeruleus. Methods: Complete Freund’s adjuvant-induced monoarthritis was used as inflammatory chronic pain model. α-Helical corticotropin-releasing factor receptor antagonist was microinjected into the contralateral locus coeruleus of 4-week-old monoarthritic animals. The nociceptive and anxiety-like behaviors, as well as phosphorylated extracellular signal-regulated kinases 1/2 and corticotropin-releasing factor receptors expression, were quantified in the paraventricular nucleus and locus coeruleus. Results: Monoarthritic rats manifested anxiety and increased phosphorylated extracellular signal-regulated kinases 1/2 levels in the locus coeruleus and paraventricular nucleus, although the expression of corticotropin-releasing factor receptors was unaltered. α-Helical corticotropin-releasing factor antagonist administration reversed both the anxiogenic-like behavior and the phosphorylated extracellular signal-regulated kinases 1/2 levels in the locus coeruleus. Conclusions: Pain-induced anxiety is mediated by corticotropin-releasing factor neurotransmission in the locus coeruleus through extracellular signal-regulated kinases 1/2 signaling cascade. PMID:25716783

Difference in Energy Metabolism of Annulus Fibrosus and Nucleus Pulposus Cells of the Intervertebral Disc

PubMed Central

Salvatierra, Jessica Czamanski; Yuan, Tai Yi; Fernando, Hanan; Castillo, Andre; Gu, Wei Yong; Cheung, Herman S.; Huant, C.-Y. Charles

2011-01-01

Low back pain is associated with intervertebral disc degeneration. One of the main signs of degeneration is the inability to maintain extracellular matrix integrity. Extracellular matrix synthesis is closely related to production of adenosine triphosphate (i.e. energy) of the cells. The intervertebral disc is composed of two major anatomical regions: annulus fibrosus and nucleus pulposus, which are structurally and compositionally different, indicating that their cellular metabolisms may also be distinct. The objective of this study was to investigate energy metabolism of annulus fibrosus and nucleus pulposus cells with and without dynamic compression, and examine differences between the two cell types. Porcine annulus and nucleus tissues were harvested and enzymatically digested. Cells were isolated and embedded into agarose constructs. Dynamically loaded samples were subjected to a sinusoidal displacement at 2 Hz and 15% strain for 4 h. Energy metabolism of cells was analyzed by measuring adenosine triphosphate content and release, glucose consumption, and lactate/nitric oxide production. A comparison of those measurements between annulus and nucleus cells was conducted. Annulus and nucleus cells exhibited different metabolic pathways. Nucleus cells had higher adenosine triphosphate content with and without dynamic loading, while annulus cells had higher lactate production and glucose consumption. Compression increased adenosine triphosphate release from both cell types and increased energy production of annulus cells. Dynamic loading affected energy metabolism of intervertebral disc cells, with the effect being greater in annulus cells. PMID:21625336

Encoding of aversion by dopamine and the nucleus accumbens.

PubMed

McCutcheon, James E; Ebner, Stephanie R; Loriaux, Amy L; Roitman, Mitchell F

2012-01-01

Adaptive motivated behavior requires rapid discrimination between beneficial and harmful stimuli. Such discrimination leads to the generation of either an approach or rejection response, as appropriate, and enables organisms to maximize reward and minimize punishment. Classically, the nucleus accumbens (NAc) and the dopamine projection to it are considered an integral part of the brain's reward circuit, i.e., they direct approach and consumption behaviors and underlie positive reinforcement. This reward-centered framing ignores important evidence about the role of this system in encoding aversive events. One reason for bias toward reward is the difficulty in designing experiments in which animals repeatedly experience punishments; another is the challenge in dissociating the response to an aversive stimulus itself from the reward/relief experienced when an aversive stimulus is terminated. Here, we review studies that employ techniques with sufficient time resolution to measure responses in ventral tegmental area and NAc to aversive stimuli as they are delivered. We also present novel findings showing that the same stimulus - intra-oral infusion of sucrose - has differing effects on NAc shell dopamine release depending on the prior experience. Here, for some rats, sucrose was rendered aversive by explicitly pairing it with malaise in a conditioned taste aversion paradigm. Thereafter, sucrose infusions led to a suppression of dopamine with a similar magnitude and time course to intra-oral infusions of a bitter quinine solution. The results are discussed in the context of regional differences in dopamine signaling and the implications of a pause in phasic dopamine release within the NAc shell. Together with our data, the emerging literature suggests an important role for differential phasic dopamine signaling in aversion vs. reward.

Role of the Bed Nucleus of the Stria Terminalis in Aversive Learning and Memory

ERIC Educational Resources Information Center

Goode, Travis D.; Maren, Stephen

2017-01-01

Surviving threats in the environment requires brain circuits for detecting (or anticipating) danger and for coordinating appropriate defensive responses (e.g., increased cardiac output, stress hormone release, and freezing behavior). The bed nucleus of the stria terminalis (BNST) is a critical interface between the "affective…

Regional influence of cocaine on evoked dopamine release in the nucleus accumbens core: A role for the caudal brainstem.

PubMed

Gerth, Ashlynn I; Alhadeff, Amber L; Grill, Harvey J; Roitman, Mitchell F

2017-01-15

Cocaine increases dopamine concentration in the nucleus accumbens through competitive binding to the dopamine transporter (DAT). However, it also increases the frequency of dopamine release events, a finding that cannot be explained by action at the DAT alone. Rather, this effect may be mediated by cocaine-induced modulation of brain regions that project to dopamine neurons. To explore regional contributions of cocaine to dopamine signaling, we administered cocaine to the lateral or fourth ventricles and compared the effects on dopamine release in the nucleus accumbens evoked by electrical stimulation of the ventral tegmental area to that of systemically-delivered cocaine. Stimulation trains caused a sharp rise in dopamine followed by a slower return to baseline. The magnitude of dopamine release ([DA]max) as well as the latency to decay to fifty percent of the maximum (t(1/2); index of DAT activity) by each stimulation train were recorded. All routes of cocaine delivery caused an increase in [DA]max; only systemic cocaine caused an increase in t(1/2). Importantly, these data are the first to show that hindbrain (fourth ventricle)-delivered cocaine modulates phasic dopamine signaling. Fourth ventricular cocaine robustly increased cFos immunoreactivity in the nucleus of the solitary tract (NTS), suggesting a neural substrate for hindbrain cocaine-mediated effects on [DA]max. Together, the data demonstrate that cocaine-induced effects on phasic dopamine signaling are mediated via actions throughout the brain including the hindbrain. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Structures and functions in the crowded nucleus: new biophysical insights

NASA Astrophysics Data System (ADS)

Hancock, Ronald

2014-09-01

Concepts and methods from the physical sciences have catalysed remarkable progress in understanding the cell nucleus in recent years. To share this excitement with physicists and encourage their interest in this field, this review offers an overview of how the physics which underlies structures and functions in the nucleus is becoming more clear thanks to methods which have been developed to simulate and study macromolecules, polymers, and colloids. The environment in the nucleus is very crowded with macromolecules, making entropic (depletion) forces major determinants of interactions. Simulation and experiments are consistent with their key role in forming membraneless compartments such as nucleoli, PML and Cajal bodies, and discrete "territories" for chromosomes. The chromosomes, giant linear polyelectrolyte polymers, exist in vivo in a state like a polymer melt. Looped conformations are predicted in crowded conditions, and have been confirmed experimentally and are central to the regulation of gene expression. Polymer theory has revealed how the chromosomes are so highly compacted in the nucleus, forming a "crumpled globule" with fractal properties which avoids knots and entanglements in DNA while allowing facile accessibility for its replication and transcription. Entropic repulsion between looped polymers can explain the confinement of each chromosome to a discrete region of the nucleus. Crowding and looping are predicted to facilitate finding the specific targets of factors which modulate activities of DNA. Simulation shows that entropic effects contribute to finding and repairing potentially lethal double-strand breaks in DNA by increasing the mobility of the broken ends, favouring their juxtaposition for repair. Signaling pathways are strongly influenced by crowding, which favours a processive mode of response (consecutive reactions without releasing substrates). This new information contributes to understanding the sometimes counter-intuitive consequences.

Hypothalamic interactions between neuropeptide Y, agouti-related protein, cocaine- and amphetamine-regulated transcript and alpha-melanocyte-stimulating hormone in vitro in male rats.

PubMed

Dhillo, W S; Small, C J; Stanley, S A; Jethwa, P H; Seal, L J; Murphy, K G; Ghatei, M A; Bloom, S R

2002-09-01

A number of neuropeptides implicated in the hypothalamic regulation of appetite are synthesized in the arcuate nucleus (Arc). Neuropeptide Y (NPY) and agouti-related protein (Agrp) are orexigenic. The pro-opiomelanocortin (POMC) product alpha-melanocyte-stimulating hormone (alpha-MSH) is anorectic. Intracerebroventricular administration of cocaine- and amphetamine-regulated transcript (CART) decreases food intake. However, recent results show that CART is orexigenic when injected into discrete hypothalamic nuclei. There is almost complete coexpression of NPY and Agrp mRNA in Arc neurones, and the majority of CART-containing neurones in the Arc also contain POMC mRNA. We investigated possible interactions between these neuropeptides in vitro using a rat hypothalamic explant system. Administration of 1, 10 and 100 nm of NPY to hypothalamic explants significantly increased release of Agrp(83-132)-immunoreactivity (IR). NPY (10 and 100 nm) significantly increased the release of CART(55-102)-IR and alpha-MSH-IR from hypothalamic explants. Agrp(83-132) (10 nm) administered to hypothalamic explants significantly increased the release of NPY-IR. Agrp(83-132) (10 and 100 nm) significantly decreased the release of CART(55-102)-IR from hypothalamic explants. Administration of 1, 10 and 100 nm CART(55-102) to hypothalamic explants resulted in a significant increase in NPY-IR release. Administration of 10 nm CART(55-102) to hypothalamic explants significantly increased the release of Agrp(83-132)-IR. NDP-MSH (10 nm) administered to hypothalamic explants significantly increased the release of NPY-IR. NDP-MSH (10 and 100 nm) significantly increased the release of Agrp(83-132)-IR from hypothalamic explants. These data suggest that orexigenic neuropeptides in the arcuate nucleus stimulate the release of each other, perhaps reinforcing orexigenic behaviour via a positive-feedback loop. Our results are also in keeping with the possibility that the melanocortin-3 receptor in the arcuate nucleus may influence the release of arcuate neuropeptides.

Tetrodotoxin-dependent glutamate release in the rat nucleus accumbens during concurrent presentation of appetitive and conditioned aversive stimuli.

PubMed

Saulskaya, Natalia B; Soloviova, Nina A

2004-12-30

In vivo microdialysis combined with a high-performance liquid chromatography was used to monitor extracellular glutamate (GLU) levels in the nucleus accumbens (N.Acc) of Sprague-Dawley rats during their behavioral responses to the concurrent presentation of appetitive and conditioned aversive stimuli. The presentation of a highly palatable diet followed by a tone previously paired with footshock to rats trained to take a pellet of the diet under these experimental conditions resulted in a marked and short lasting increase in extracellular glutamate, whereas the tone alone had no effect. A similar increase of the glutamate release was observed during the presentation of a piece of rubber instead of the diet. In both cases, the increase in extracellular glutamate was completely prevented by intra-accumbal infusions through the dialysis probe of 1 microM tetrodotoxin (a voltage-dependent Na(+) channel blocker), whereas (S)-4-carboxyphenylglycine (a cystine/glutamate exchange blocker, 5 microM) had no effect. The data obtained suggest that behavioral responses to unpredicted change in motivational value of expected reward appear to be associated with an increase of the extracellular glutamate level in the nucleus accumbens, and impulse-dependent synaptic release, rather than non-vesicular glutamate release via cystine/glutamate exchange, is responsible for this phenomenon.

Optogenetic versus electrical stimulation of dopamine terminals in the nucleus accumbens reveals local modulation of presynaptic release

PubMed Central

Melchior, James R.; Ferris, Mark J.; Stuber, Garret D.; Riddle, David R.; Jones, Sara R.

2015-01-01

The nucleus accumbens is highly heterogeneous, integrating regionally distinct afferent projections and accumbal interneurons, resulting in diverse local microenvironments. Dopamine (DA) neuron terminals similarly express a heterogeneous collection of terminal receptors that modulate DA signaling. Cyclic voltammetry is often used to probe DA terminal dynamics in brain slice preparations; however, this method traditionally requires electrical stimulation to induce DA release. Electrical stimulation excites all of the neuronal processes in the stimulation field, potentially introducing simultaneous, multi-synaptic modulation of DA terminal release. We used optogenetics to selectively stimulate DA terminals and used voltammetry to compare DA responses from electrical and optical stimulation of the same area of tissue around a recording electrode. We found that with multiple pulse stimulation trains, optically stimulated DA release increasingly exceeded that of electrical stimulation. Furthermore, electrical stimulation produced inhibition of DA release across longer duration stimulations. The GABAB antagonist, CGP 55845, increased electrically stimulated DA release significantly more than light stimulated release. The nicotinic acetylcholine receptor antagonist, dihydro-β-erythroidine hydrobromide, inhibited single pulse electrically stimulated DA release while having no effect on optically stimulated DA release. Our results demonstrate that electrical stimulation introduces local multi-synaptic modulation of DA release that is absent with optogenetically targeted stimulation. PMID:26011081

Mechanical stability of the cell nucleus: roles played by the cytoskeleton in nuclear deformation and strain recovery.

PubMed

Wang, Xian; Liu, Haijiao; Zhu, Min; Cao, Changhong; Xu, Zhensong; Tsatskis, Yonit; Lau, Kimberly; Kuok, Chikin; Filleter, Tobin; McNeill, Helen; Simmons, Craig A; Hopyan, Sevan; Sun, Yu

2018-05-18

Extracellular forces transmitted through the cytoskeleton can deform the cell nucleus. Large nuclear deformation increases the risk of disrupting the nuclear envelope's integrity and causing DNA damage. Mechanical stability of the nucleus defines its capability of maintaining nuclear shape by minimizing nuclear deformation and recovering strain when deformed. Understanding the deformation and recovery behavior of the nucleus requires characterization of nuclear viscoelastic properties. Here, we quantified the decoupled viscoelastic parameters of the cell membrane, cytoskeleton, and the nucleus. The results indicate that the cytoskeleton enhances nuclear mechanical stability by lowering the effective deformability of the nucleus while maintaining nuclear sensitivity to mechanical stimuli. Additionally, the cytoskeleton decreases the strain energy release rate of the nucleus and might thus prevent shape change-induced structural damage to chromatin. © 2018. Published by The Company of Biologists Ltd.

The development of the Nucleus Freedom Cochlear implant system.

PubMed

Patrick, James F; Busby, Peter A; Gibson, Peter J

2006-12-01

Cochlear Limited (Cochlear) released the fourth-generation cochlear implant system, Nucleus Freedom, in 2005. Freedom is based on 25 years of experience in cochlear implant research and development and incorporates advances in medicine, implantable materials, electronic technology, and sound coding. This article presents the development of Cochlear's implant systems, with an overview of the first 3 generations, and details of the Freedom system: the CI24RE receiver-stimulator, the Contour Advance electrode, the modular Freedom processor, the available speech coding strategies, the input processing options of Smart Sound to improve the signal before coding as electrical signals, and the programming software. Preliminary results from multicenter studies with the Freedom system are reported, demonstrating better levels of performance compared with the previous systems. The final section presents the most recent implant reliability data, with the early findings at 18 months showing improved reliability of the Freedom implant compared with the earlier Nucleus 3 System. Also reported are some of the findings of Cochlear's collaborative research programs to improve recipient outcomes. Included are studies showing the benefits from bilateral implants, electroacoustic stimulation using an ipsilateral and/or contralateral hearing aid, advanced speech coding, and streamlined speech processor programming.

A search for the production of direct leptons in nucleon-nucleus and nucleus-nucleus collisions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kirk, P.N.

1990-12-01

This report discusses the following topics: subthreshold production experiment; testing and selection of PCOS amplifiers; transverse energy detector; development of a sensitive new amplifiers; single-lepton experiment. (LSP)

The processed isoform of the translation termination factor eRF3 localizes to the nucleus to interact with the ARF tumor suppressor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hashimoto, Yoshifumi; Kumagai, Naomichi; Hosoda, Nao

2014-03-14

Highlights: • So far, eRF3 has been thought to function exclusively in the cytoplasm. • eRF3 is a nucleo-cutoplasmic shuttling protein. • eRF3 has a leptomycin-sensitive nuclear export signal (NES). • Removal of NES by proteolytic cleavage allows eRF3 to translocate to the nucleus. • The processed eRF3 (p-eRF3) interacts with a nuclear tumor suppressor ARF. - Abstract: The eukaryotic releasing factor eRF3 is a multifunctional protein that plays pivotal roles in translation termination as well as the initiation of mRNA decay. eRF3 also functions in the regulation of apoptosis; eRF3 is cleaved at Ala73 by an as yet unidentifiedmore » protease into processed isoform of eRF3 (p-eRF3), which interacts with the inhibitors of apoptosis proteins (IAPs). The binding of p-eRF3 with IAPs leads to the release of active caspases from IAPs, which promotes apoptosis. Although full-length eRF3 is localized exclusively in the cytoplasm, p-eRF3 localizes in the nucleus as well as the cytoplasm. We here focused on the role of p-eRF3 in the nucleus. We identified leptomycin-sensitive nuclear export signal (NES) at amino acid residues 61–71 immediately upstream of the cleavage site Ala73. Thus, the proteolytic cleavage of eRF3 into p-eRF3 leads to release an amino-terminal fragment containing NES to allow the relocalization of eRF3 into the nucleus. Consistent with this, p-eRF3 more strongly interacted with the nuclear ARF tumor suppressor than full-length eRF3. These results suggest that while p-eRF3 interacts with IAPs to promote apoptosis in the cytoplasm, p-eRF3 also has some roles in regulating cell death in the nucleus.« less

GS 455534 selectively suppresses binge eating of palatable food and attenuates dopamine release in the accumbens of sugar-bingeing rats.

PubMed

Bocarsly, Miriam E; Hoebel, Bartley G; Paredes, Daniel; von Loga, Isabell; Murray, Susan M; Wang, Miaoyuan; Arolfo, Maria P; Yao, Lina; Diamond, Ivan; Avena, Nicole M

2014-04-01

Binge eating palatable foods has been shown to have behavioral and neurochemical similarities to drug addiction. GS 455534 is a highly selective reversible aldehyde dehydrogenase 2 inhibitor that has been shown to reduce alcohol and cocaine intake in rats. Given the overlaps between binge eating and drug abuse, we examined the effects of GS 455534 on binge eating and subsequent dopamine release. Sprague-Dawley rats were maintained on a sugar (experiment 1) or fat (experiment 2) binge eating diet. After 25 days, GS 455534 was administered at 7.5 and 15 mg/kg by an intraperitoneal injection, and food intake was monitored. In experiment 3, rats with cannulae aimed at the nucleus accumbens shell were maintained on the binge sugar diet for 25 days. Microdialysis was performed, during which GS 455534 15 mg/kg was administered, and sugar was available. Dialysate samples were analyzed to determine extracellular levels of dopamine. In experiment 1, GS 455534 selectively decreased sugar intake food was made available in the Binge Sugar group but not the Ad libitum Sugar group, with no effect on chow intake. In experiment 2, GS 455534 decreased fat intake in the Binge Fat group, but not the Ad libitum Fat group, however, it also reduced chow intake. In experiment 3, GS 455534 attenuated accumbens dopamine release by almost 50% in binge eating rats compared with the vehicle injection. The findings suggest that selective reversible aldehyde dehydrogenase 2 inhibitors may have the therapeutic potential to reduce binge eating of palatable foods in clinical populations.

Estrogen-2-hydroxylase in the brain of the male African catfish, Clarias gariepinus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Timmers, R.J.; Granneman, J.C.; Lambert, J.G.

1988-11-01

Estrogen-2-hydroxylase activity, involved in the biosynthesis of catecholestrogens, was localized in the brain of the male African catfish, Clarias gariepinus, by means of a radiometric assay using (2-TH)estradiol as substrate. Fore- and midbrain were divided in 18, 500-microns thick, transverse sections from which small defined areas were punched out and assayed. The estrogen-2-hydroxylase activity was calculated from the release of tritium during hydroxylation, and expressed in femtomole catecholestradiol.milligram-1 tissue.hour-1. The enzyme could be demonstrated throughout the brain. A high activity (greater than 350 fmol) was observed in the telencephalon, in particularly the rostral part and the area ventralis pars dorsalis;more » in the diencephalon in the preoptic region, including the magnocellular part of the preoptic nucleus and the rostral part of the anterior periventricular nucleus; and in the area tuberalis, including the nucleus lateralis tuberis, the rostral part of the nucleus anterior tuberis, the caudal part of the nucleus posterior periventricularis, and in the nucleus recessus posterioris. Also a high activity was detected in the mesencephalic tectum opticum and the dorsolateral part of the torus semicircularis. The ventral mesencephalon showed a moderate (200-350 fmol) to low (less than 200 fmol) activity, whereas the lowest activity was found in the hindbrain (118 fmol). The significance of the biosynthesis of catecholestrogens in the brain is discussed in light of the negative feedback mechanism of gonadal steroids on gonadotropin release.« less

Glutamate and Opioid Antagonists Modulate Dopamine Levels Evoked by Innately Attractive Male Chemosignals in the Nucleus Accumbens of Female Rats

PubMed Central

Sánchez-Catalán, María-José; Orrico, Alejandro; Hipólito, Lucía; Zornoza, Teodoro; Polache, Ana; Lanuza, Enrique; Martínez-García, Fernando; Granero, Luis; Agustín-Pavón, Carmen

2017-01-01

Sexual chemosignals detected by vomeronasal and olfactory systems mediate intersexual attraction in rodents, and act as a natural reinforcer to them. The mesolimbic pathway processes natural rewards, and the nucleus accumbens receives olfactory information via glutamatergic projections from the amygdala. Thus, the aim of this study was to investigate the involvement of the mesolimbic pathway in the attraction toward sexual chemosignals. Our data show that female rats with no previous experience with males or their chemosignals display an innate preference for male-soiled bedding. Focal administration of the opioid antagonist β-funaltrexamine into the posterior ventral tegmental area does not affect preference for male chemosignals. Nevertheless, exposure to male-soiled bedding elicits an increase in dopamine efflux in the nucleus accumbens shell and core, measured by microdialysis. Infusion of the opioid antagonist naltrexone in the accumbens core does not significantly affect dopamine efflux during exposure to male chemosignals, although it enhances dopamine levels 40 min after withdrawal of the stimuli. By contrast, infusion of the glutamate antagonist kynurenic acid in the accumbens shell inhibits the release of dopamine and reduces the time that females spend investigating male-soiled bedding. These data are in agreement with previous reports in male rats showing that exposure to opposite-sex odors elicits dopamine release in the accumbens, and with data in female mice showing that the behavioral preference for male chemosignals is not affected by opioidergic antagonists. We hypothesize that glutamatergic projections from the amygdala into the accumbens might be important to modulate the neurochemical and behavioral responses elicited by sexual chemosignals in rats. PMID:28280461

Glutamate and Opioid Antagonists Modulate Dopamine Levels Evoked by Innately Attractive Male Chemosignals in the Nucleus Accumbens of Female Rats.

PubMed

Sánchez-Catalán, María-José; Orrico, Alejandro; Hipólito, Lucía; Zornoza, Teodoro; Polache, Ana; Lanuza, Enrique; Martínez-García, Fernando; Granero, Luis; Agustín-Pavón, Carmen

2017-01-01

Sexual chemosignals detected by vomeronasal and olfactory systems mediate intersexual attraction in rodents, and act as a natural reinforcer to them. The mesolimbic pathway processes natural rewards, and the nucleus accumbens receives olfactory information via glutamatergic projections from the amygdala. Thus, the aim of this study was to investigate the involvement of the mesolimbic pathway in the attraction toward sexual chemosignals. Our data show that female rats with no previous experience with males or their chemosignals display an innate preference for male-soiled bedding. Focal administration of the opioid antagonist β-funaltrexamine into the posterior ventral tegmental area does not affect preference for male chemosignals. Nevertheless, exposure to male-soiled bedding elicits an increase in dopamine efflux in the nucleus accumbens shell and core, measured by microdialysis. Infusion of the opioid antagonist naltrexone in the accumbens core does not significantly affect dopamine efflux during exposure to male chemosignals, although it enhances dopamine levels 40 min after withdrawal of the stimuli. By contrast, infusion of the glutamate antagonist kynurenic acid in the accumbens shell inhibits the release of dopamine and reduces the time that females spend investigating male-soiled bedding. These data are in agreement with previous reports in male rats showing that exposure to opposite-sex odors elicits dopamine release in the accumbens, and with data in female mice showing that the behavioral preference for male chemosignals is not affected by opioidergic antagonists. We hypothesize that glutamatergic projections from the amygdala into the accumbens might be important to modulate the neurochemical and behavioral responses elicited by sexual chemosignals in rats.

Sex, Drugs and Gluttony: How the Brain Controls Motivated Behaviors

PubMed Central

Hull, Elaine M.

2011-01-01

Bart Hoebel has forged a view of an integrated neural network that mediates both natural rewards and drug use. He pioneered the use of microdialysis, and also effectively used electrical stimulation, lesions, microinjections, and immunohistochemistry. He found that feeding, stimulant drug administration, and electrical stimulation of the lateral hypothalamus (LH) all increased dopamine (DA) release in the nucleus accumbens (NAc). However, whereas DA in the NAc enhanced motivation, DA in the LH inhibited motivated behaviors. The Hull lab has pursued some of those ideas. We have suggested that serotonin (5-HT) in the perifornicalLH inhibits sexual behavior by inhibiting orexin/hypocretin neurons (OX/HCRT), which would otherwise excite neurons in the mesocorticolimbic DA tract. We have shown that DA release in the medial preoptic area (MPOA) is very important for male sexual behavior, and that testosterone, glutamate, nitric oxide (NO) and previous sexual experience promote MPOA DA release and mating. Future research should follow Bart Hoebel’s emphasis on neural systems and interactions among brain areas and neurotransmitters. PMID:21554895

Stimuli and consequences of dendritic release of oxytocin within the brain.

PubMed

Neumann, I D

2007-11-01

The brain oxytocin system has served as a distinguished model system in neuroendocrinology to study detailed mechanisms of intracerebral release, in particular of somatodendritic release, and its behavioural and neuroendocrine consequences. It has been shown that oxytocin is released within various brain regions, but evidence for dendritic release is limited to the main sites of oxytocin synthesis, i.e. the hypothalamic SON (supraoptic nucleus) and PVN (paraventricular nucleus). In the present paper, stimuli of dendritic release of oxytocin and the related neuropeptide vasopressin are discussed, including parturition and suckling, i.e. the period of a highly activated brain oxytocin system. Also, exposure to various pharmacological, psychological or physical stressors triggers dendritic oxytocin release, as monitored by intracerebral microdialysis within the SON and PVN during ongoing behavioural testing. So far, dendritic release of the neuropeptide has only been demonstrated within the hypothalamus, but intracerebral oxytocin release has also been found within the central amygdala and the septum in response to various stimuli including stressor exposure. Such a locally released oxytocin modulates physiological and behavioural reproductive functions, emotionality and hormonal stress responses, as it exerts, for example, pro-social, anxiolytic and antistress actions within restricted brain regions. These discoveries make oxytocin a promising neuromodulator of the brain for psychotherapeutic intervention and treatment of numerous psychiatric illnesses, for example, anxiety-related diseases, social phobia, autism and postpartum depression.

[The effects of lesions in the compact part of the substantia nigra on glutamate and GABA release in the pedunculopontine nucleus].

PubMed

Blanco-Lezcano, L; Rocha-Arrieta, L L; Alvarez-González, L; Martínez-Martí, L; Pavón-Fuentes, N; González-Fraguela, M E; Bauzá-Calderín, Y; Coro-Grave de Peralta, Y

The pedunculopontine nucleus (PPN), co-localized with the mesencephalic locomotor region, has been proposed as a key structure in the physiopathology of Parkinson's disease. The goal of the present study was to assess if the aminoacid neurotransmitter release in the PPN is modified by the degeneration of dopaminergic cells, from substantia nigra pars compacta in 6-hydroxidopamine (6-OHDA)-lesioned rats. In addition, it was studied the aminoacid neurotransmitter release in the PPN of rats with lesion of the subthalamic nucleus by quinolinic acid (QUIN) (100 nmol) intracerebral injection. Rats were assigned to five groups: untreated rats (I) (n = 13), 6-OHDA lesion (II) (n = 11), 6-OHDA + QUIN lesion (III) (n = 9), sham-operated (IV) (n = 10), QUIN, STN (V) lesioned (n = 9). The extracellular concentrations of glutamic acid (GLU) and gamma-aminobutyric acid (GABA) were determined by brain microdialysis and high performance liquid chromatography (HPLC). RESULTS. GLU released in PPN from 6-OHDA lesioned rats (group II), was significantly increased in comparison with the others groups (F(4, 47) = 18.21, p < 0.001). GABA released shows significant differences between experimental groups (F(4, 45) = 12.75, p < 0.001). It was detected a higher valour (p < 0.05) in-group II. The groups III and IV exhibited intermeddle valour (p < 0.001) and groups I and IV (p < 0.001) showed the lower GABA extracellular concentrations. The infusion of artificial cerebrospinal fluid with higher potassium (100 mmol) induced an increase in the GLU and GABA released in all groups, which confirm the neuronal origin of the extracellular content. These results are in agreement with the current model of basal ganglia functioning and suggest the role of STN-PPN projection in the physiopathology of Parkinson's disease.

Distinctive Modulation of Dopamine Release in the Nucleus Accumbens Shell Mediated by Dopamine and Acetylcholine Receptors.

PubMed

Shin, Jung Hoon; Adrover, Martin F; Alvarez, Veronica A

2017-11-15

Nucleus accumbens (NAc) shell shows unique dopamine (DA) signals in vivo and plays a unique role in DA-dependent behaviors such as reward-motivated learning and the response to drugs of abuse. A disynaptic mechanism for DA release was reported and shown to require synchronized firing of cholinergic interneurons (CINs) and activation of nicotinic acetylcholine (ACh) receptors (nAChRs) in DA neuron (DAN) axons. The properties of this disynaptic mechanism of DA transmission are not well understood in the NAc shell. In this study, in vitro fast-scan cyclic voltammetry was used to examine the modulation of DA transmission evoked by CINs firing in the shell of mice and compared with other striatal regions. We found that DA signals in the shell displayed significant degree of summation in response to train stimulation of CINs, contrary to core and dorsal striatum. The summation was amplified by a D2-like receptor antagonist and experiments with mice with targeted deletion of D2 receptors to DANs or CINs revealed that D2 receptors in CINs mediate a fast inhibition observed within 100 ms of the first pulse, whereas D2 autoreceptors in DAN terminals are engaged in a slower inhibition that peaks at ∼500 ms. ACh also contributes to the use-dependent inhibition of DA release through muscarinic receptors only in the shell, where higher activity of acetylcholinesterase minimizes nAChR desensitization and promotes summation. These findings show that DA signals are modulated differentially by endogenous DA and ACh in the shell, which may underlie the unique features of shell DA signals in vivo SIGNIFICANCE STATEMENT The present study reports that dopamine (DA) release evoked by activation of cholinergic interneurons displays a high degree of summation in the shell and shows unique modulation by endogenous DA and acetylcholine. Desensitization of nicotinic receptors, which is a prevailing mechanism for use-dependent inhibition in the nucleus accumbens core and dorsal striatum, is also minimal in the shell in part due to elevated acetylcholinesterase activity. This distinctive modulation of DA transmission in the shell may have functional implications in the acquisition of reward-motivated behaviors and reward seeking. Copyright © 2017 the authors 0270-6474/17/3711166-15$15.00/0.

Sexual behavior induction of c-Fos in the nucleus accumbens and amphetamine-stimulated locomotor activity are sensitized by previous sexual experience in female Syrian hamsters.

PubMed

Bradley, K C; Meisel, R L

2001-03-15

Dopamine transmission in the nucleus accumbens can be activated by drugs, stress, or motivated behaviors, and repeated exposure to these stimuli can sensitize this dopamine response. The objectives of this study were to determine whether female sexual behavior activates nucleus accumbens neurons and whether past sexual experience cross-sensitizes neuronal responses in the nucleus accumbens to amphetamine. Using immunocytochemical labeling, c-Fos expression in different subregions (shell vs core at the rostral, middle, and caudal levels) of the nucleus accumbens was examined in female hamsters that had varying amounts of sexual experience. Female hamsters, given either 6 weeks of sexual experience or remaining sexually naive, were tested for sexual behavior by exposure to adult male hamsters. Previous sexual experience increased c-Fos labeling in the rostral and caudal levels but not in the middle levels of the nucleus accumbens. Testing for sexual behavior increased labeling in the core, but not the shell, of the nucleus accumbens. To validate that female sexual behavior can sensitize neurons in the mesolimbic dopamine pathway, the locomotor responses of sexually experienced and sexually naive females to an amphetamine injection were then compared. Amphetamine increased general locomotor activity in all females. However, sexually experienced animals responded sooner to amphetamine than did sexually naive animals. These data indicate that female sexual behavior can activate neurons in the nucleus accumbens and that sexual experience can cross-sensitize neuronal responses to amphetamine. In addition, these results provide additional evidence for functional differences between the shell and core of the nucleus accumbens and across its anteroposterior axis.

Dynamic subcellular partitioning of the nucleolar transcription factor TIF-IA under ribotoxic stress.

PubMed

Szymański, Jedrzej; Mayer, Christine; Hoffmann-Rohrer, Urs; Kalla, Claudia; Grummt, Ingrid; Weiss, Matthias

2009-07-01

TIF-IA is a basal transcription factor of RNA polymerase I (Pol I) that is a major target of the JNK2 signaling pathway in response to ribotoxic stress. Using advanced fluorescence microscopy and kinetic modeling we elucidated the subcellular localization of TIF-IA and its exchange dynamics between the nucleolus, nucleoplasm and cytoplasm upon ribotoxic stress. In steady state, the majority of (GFP-tagged) TIF-IA was in the cytoplasm and the nucleus, a minor portion (7%) localizing to the nucleoli. We observed a rapid shuttling of GFP-TIF-IA between the different cellular compartments with a mean residence time of approximately 130 s in the nucleus and only approximately 30 s in the nucleoli. The import rate from the cytoplasm to the nucleus was approximately 3-fold larger than the export rate, suggesting an importin/exportin-mediated transport rather than a passive diffusion. Upon ribotoxic stress, GFP-TIF-IA was released from the nucleoli with a half-time of approximately 24 min. Oxidative stress and inhibition of protein synthesis led to a relocation of GFP-TIF-IA with slower kinetics while osmotic stress had no effect. The observed relocation was much slower than the nucleo-cytoplasmic and nucleus-nucleolus exchange rates of GFP-TIF-IA, indicating a time-limiting step upstream of the JNK2 pathway. In support of this, time-course experiments on the activity of JNK2 revealed the activation of the JNK kinase as the rate-limiting step.

Nucleon emission via electromagnetic excitation in relativistic nucleus-nucleus collisions: Re-analysis of the Weizsacker-Williams method

NASA Technical Reports Server (NTRS)

Norbury, John W.

1989-01-01

Previous analyses of the comparison of Weizsacker-Williams (WW) theory to experiment for nucleon emission via electromagnetic (EM) excitations in nucleus-nucleus collisions were not definitive because of different assumptions concerning the value of the minimum impact parameter. This situation is corrected by providing criteria that allows definitive statements to be made concerning agreement or disagreement between WW theory and experiment.

Differential Dopamine Release Dynamics in the Nucleus Accumbens Core and Shell Reveal Complementary Signals for Error Prediction and Incentive Motivation

PubMed Central

Cacciapaglia, Fabio; Wightman, R. Mark; Carelli, Regina M.

2015-01-01

Mesolimbic dopamine (DA) is phasically released during appetitive behaviors, though there is substantive disagreement about the specific purpose of these DA signals. For example, prediction error (PE) models suggest a role of learning, while incentive salience (IS) models argue that the DA signal imbues stimuli with value and thereby stimulates motivated behavior. However, within the nucleus accumbens (NAc) patterns of DA release can strikingly differ between subregions, and as such, it is possible that these patterns differentially contribute to aspects of PE and IS. To assess this, we measured DA release in subregions of the NAc during a behavioral task that spatiotemporally separated sequential goal-directed stimuli. Electrochemical methods were used to measure subsecond NAc dopamine release in the core and shell during a well learned instrumental chain schedule in which rats were trained to press one lever (seeking; SL) to gain access to a second lever (taking; TL) linked with food delivery, and again during extinction. In the core, phasic DA release was greatest following initial SL presentation, but minimal for the subsequent TL and reward events. In contrast, phasic shell DA showed robust release at all task events. Signaling decreased between the beginning and end of sessions in the shell, but not core. During extinction, peak DA release in the core showed a graded decrease for the SL and pauses in release during omitted expected rewards, whereas shell DA release decreased predominantly during the TL. These release dynamics suggest parallel DA signals capable of supporting distinct theories of appetitive behavior. SIGNIFICANCE STATEMENT Dopamine signaling in the brain is important for a variety of cognitive functions, such as learning and motivation. Typically, it is assumed that a single dopamine signal is sufficient to support these cognitive functions, though competing theories disagree on how dopamine contributes to reward-based behaviors. Here, we have found that real-time dopamine release within the nucleus accumbens (a primary target of midbrain dopamine neurons) strikingly varies between core and shell subregions. In the core, dopamine dynamics are consistent with learning-based theories (such as reward prediction error) whereas in the shell, dopamine is consistent with motivation-based theories (e.g., incentive salience). These findings demonstrate that dopamine plays multiple and complementary roles based on discrete circuits that help animals optimize rewarding behaviors. PMID:26290234

Poly(lactide-co-glycolide) nanocapsules containing benzocaine: influence of the composition of the oily nucleus on physico-chemical properties and anesthetic activity.

PubMed

de Melo, Nathalie Ferreira Silva; Grillo, Renato; Guilherme, Viviane Aparecida; de Araujo, Daniele Ribeiro; de Paula, Eneida; Rosa, André Henrique; Fraceto, Leonardo Fernandes

2011-08-01

The aim of this work was to investigate the influence of the oily nucleus composition on physico-chemical properties and anesthetic activity of poly (lactide-co-glycolide) nanocapsules with benzocaine. Nanocapsules containing benzocaine were prepared with three different oily nucleus composition and characterized by mean diameter, polydispersivity, zeta potential, pH and stability were investigated as a function of time. In vitro release kinetics were performed in a system with two compartments separated by a cellulose membrane. Intensity and duration of analgesia were evaluated in rats by sciatic nerve blockade. The greatest stability, slower release profile and improvement in the local anesthetic activity of BZC were obtained with the formulation using USP mineral oil as component. Results from our study provide useful perspectives on selection of the primary materials needed to produce suspensions of polymeric nanocapsules able to act as carriers of BZC, with potential future application in the treatment of pain.

GHRELIN ACTIVATES HYPOPHYSIOTROPIC CORTICOTROPIN-RELEASING FACTOR NEURONS INDEPENDENTLY OF THE ARCUATE NUCLEUS

PubMed Central

Cabral, Agustina; Portiansky, Enrique; Sánchez-Jaramillo, Edith; Zigman, Jeffrey M.; Perello, Mario

2016-01-01

Previous work has established that the hormone ghrelin engages the hypothalamic-pituitary-adrenal neuroendocrine axis via activation of corticotropin-releasing factor (CRF) neurons of the hypothalamic paraventricular nucleus (PVN). The neuronal circuitry that mediates this effect of ghrelin is currently unknown. Here, we show that ghrelin-induced activation of PVN CRF neurons involved inhibition of γ-aminobutyric acid (GABA) inputs, likely via ghrelin binding sites that were localized at GABAergic terminals within the PVN. While ghrelin activated PVN CRF neurons in the presence of neuropeptide Y (NPY) receptor antagonists or in arcuate nucleus (ARC)-ablated mice, it failed to do it so in mice with ghrelin receptor expression limited to ARC agouti gene related protein (AgRP)/NPY neurons. These data support the notion that ghrelin activates PVN CRF neurons via inhibition of local GABAergic tone, in an ARC-independent manner. Furthermore, these data suggest that the neuronal circuits mediating ghrelin’s orexigenic action vs. its role as a stress signal are anatomically dissociated. PMID:26874559

Axial deformed solution of the Skyrme-Hartree-Fock-Bogolyubov equations using the transformed harmonic oscillator Basis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Perez, R. Navarro; Schunck, N.; Lasseri, R.

2017-03-09

HFBTHO is a physics computer code that is used to model the structure of the nucleus. It is an implementation of the nuclear energy Density Functional Theory (DFT), where the energy of the nucleus is obtained by integration over space of some phenomenological energy density, which is itself a functional of the neutron and proton densities. In HFBTHO, the energy density derives either from the zero-range Dkyrme or the finite-range Gogny effective two-body interaction between nucleons. Nuclear superfluidity is treated at the Hartree-Fock-Bogoliubov (HFB) approximation, and axial-symmetry of the nuclear shape is assumed. This version is the 3rd release ofmore » the program; the two previous versions were published in Computer Physics Communications [1,2]. The previous version was released at LLNL under GPL 3 Open Source License and was given release code LLNL-CODE-573953.« less

The hypothalamic paraventricular nucleus has a pivotal role in regulation of prolactin release in lactating rats.

PubMed

Kiss, J Z; Kanyicska, B; Nagy, G Y

1986-08-01

The affect of paraventricular nucleus (PVN) lesions on PRL secretory response to suckling was studied in adult female rats. Basal levels of PRL were similar in the control and lesioned groups. Substantial decreases in PRL levels occurred after separation of pups from their mothers in the control as well as lesioned animals. When mothers and pups were reunited, the circulating PRL concentrations of the control groups rose immediately from basal values of 50-100 micrograms/liter to reach peaks of 450-550 micrograms/liter. PVN lesions significantly decreased the suckling-induced rise of PRL levels. Furthermore, PVN lesions abolished the high amplitude, episodic pattern of PRL release in continuously lactating rats. These findings are consistent with the view that PVN neurons produce PRL releasing factor(s), which is (are) required for normal secretory patterns of PRL in lactating rats.

Articulatory Closure Proficiency in Patients with Parkinson's Disease Following Deep Brain Stimulation of the Subthalamic Nucleus and Caudal Zona Incerta

ERIC Educational Resources Information Center

Karlsson, Fredrik; Olofsson, Katarina; Blomstedt, Patric; Linder, Jan; Nordh, Erik; van Doorn, Jan

2014-01-01

Purpose: The present study aimed at comparing the effects of deep brain stimulation (DBS) treatment of the subthalamic nucleus (STN) and the caudal zona incerta (cZi) on the proficiency in achieving oral closure and release during plosive production of people with Parkinson's disease. Method: Nineteen patients participated preoperatively and…

Folate-targeted single-wall metal-organic nanotubes used as multifunctional drug carriers

NASA Astrophysics Data System (ADS)

Yang, Linyan; Liu, Min; Huang, Kebin; Ai, Xia; Li, Cun; Ma, Jifei; Jin, Tianming; Liu, Xin

2017-01-01

Doxorubicin (DOX) is a member of the anthracycline class of chemotherapeutic agents that are used for the treatment of many common human cancers. A self-assembled functionalized metal-organic nanotubes, SWMONTs could be loaded with the anticancer drug DOX. Via the modification of SWMONTs, DOX/SWMONTs-SiO2, DOX/SWMONTs-SiO2-NH2, DOX/SWMONTs-SiO2-NH2-FA samples could be obtained. The SEM characterization of the samples indicated that the particle size of DOX/SWMONTs-SiO2NH2 samples were smaller than 200 nm. Drug-release experiments implied that DOX from the DOX/SWMONTs-SiO2-NH2-FA samples could be released faster at acidic tumor tissue than at normal body fluid (pH7.4). DOX has strong cytotoxicity, and at 20 μg/mL dosage of DOX large amount of apoptotic cells could be seen. Cellular uptaking experiments were used to study the apoptotic mechanism, while for DOX/SWMONTs-SiO2-NH2-FA samples, the strong drug fluorescence was found in the cytoplasm rather than in the nucleus.

The γ-aminobutyric acid type B (GABAB) receptor agonist baclofen inhibits morphine sensitization by decreasing the dopamine level in rat nucleus accumbens.

PubMed

Fu, Zhenyu; Yang, Hongfa; Xiao, Yuqiang; Zhao, Gang; Huang, Haiyan

2012-07-10

Repeated morphine exposure can induce behavioral sensitization. There are evidences have shown that central gamma-aminobutyric acid (GABA) system is involved in morphine dependence. However, the effect of a GABAB receptor agonist baclofen on morphine-induced behavioral sensitization in rats is unclear. We used morphine-induced behavioral sensitization model in rat to investigate the effects of baclofen on behavioral sensitization. Moreover, dopamine release in the shell of the nucleus accumbens was evaluated using microdialysis assay in vivo. The present study demonstrated that morphine challenge (3 mg/kg, s.c.) obviously enhanced the locomotor activity following 4-day consecutive morphine administration and 3-day withdrawal period, which indicated the expression of morphine sensitization. In addition, chronic treatment with baclofen (2.5, 5 mg/kg) significantly inhibited the development of morphine sensitization. It was also found that morphine challenge 3 days after repeated morphine administration produced a significant increase of extracellular dopamine release in nucleus accumbens. Furthermore, chronic treatment with baclofen decreased the dopamine release induced by morphine challenge. Our results indicated that gamma-aminobutyric acid system plays an important role in the morphine sensitization in rat and suggested that behavioral sensitization is a promising model to study the mechanism underlying drug abuse.

Supersensitive Kappa Opioid Receptors Promotes Ethanol Withdrawal-Related Behaviors and Reduce Dopamine Signaling in the Nucleus Accumbens.

PubMed

Rose, Jamie H; Karkhanis, Anushree N; Chen, Rong; Gioia, Dominic; Lopez, Marcelo F; Becker, Howard C; McCool, Brian A; Jones, Sara R

2016-05-01

Chronic ethanol exposure reduces dopamine transmission in the nucleus accumbens, which may contribute to the negative affective symptoms associated with ethanol withdrawal. Kappa opioid receptors have been implicated in withdrawal-induced excessive drinking and anxiety-like behaviors and are known to inhibit dopamine release in the nucleus accumbens. The effects of chronic ethanol exposure on kappa opioid receptor-mediated changes in dopamine transmission at the level of the dopamine terminal and withdrawal-related behaviors were examined. Five weeks of chronic intermittent ethanol exposure in male C57BL/6 mice were used to examine the role of kappa opioid receptors in chronic ethanol-induced increases in ethanol intake and marble burying, a measure of anxiety/compulsive-like behavior. Drinking and marble burying were evaluated before and after chronic intermittent ethanol exposure, with and without kappa opioid receptor blockade by nor-binaltorphimine (10mg/kg i.p.). Functional alterations in kappa opioid receptors were assessed using fast scan cyclic voltammetry in brain slices containing the nucleus accumbens. Chronic intermittent ethanol-exposed mice showed increased ethanol drinking and marble burying compared with controls, which was attenuated with kappa opioid receptor blockade. Chronic intermittent ethanol-induced increases in behavior were replicated with kappa opioid receptor activation in naïve mice. Fast scan cyclic voltammetry revealed that chronic intermittent ethanol reduced accumbal dopamine release and increased uptake rates, promoting a hypodopaminergic state of this region. Kappa opioid receptor activation with U50,488H concentration-dependently decreased dopamine release in both groups; however, this effect was greater in chronic intermittent ethanol-treated mice, indicating kappa opioid receptor supersensitivity in this group. These data suggest that the chronic intermittent ethanol-induced increase in ethanol intake and anxiety/compulsive-like behaviors may be driven by greater kappa opioid receptor sensitivity and a hypodopaminergic state of the nucleus accumbens. © The Author 2015. Published by Oxford University Press on behalf of CINP.

The Decline in Pulsatile GnRH Release, as Reflected by Circulating LH Concentrations, During the Infant-Juvenile Transition in the Agonadal Male Rhesus Monkey (Macaca mulatta) Is Associated With a Reduction in Kisspeptin Content of KNDy Neurons of the Arcuate Nucleus in the Hypothalamus

PubMed Central

Ramaswamy, Suresh; Dwarki, Karthik; Ali, Barkat; Gibbs, Robert B.

2013-01-01

Puberty in primates is timed by 2 hypothalamic events: during late infancy a decline in pulsatile GnRH release occurs, leading to a hypogonadotropic state that maintains quiescence of the prepubertal gonad; and in late juvenile development, pulsatile GnRH release is reactivated and puberty initiated, a phase of development that is dependent on kisspeptin signaling. In the present study, we determined whether the arrest of GnRH pulsatility in infancy was associated with a change in kisspeptin expression in the mediobasal hypothalamus (MBH). Kisspeptin was determined using immunohistochemistry in coronal hypothalamic sections from agonadal male rhesus monkeys during early infancy when GnRH release as reflected by circulating LH concentrations was robust and compared with that in juveniles in which GnRH pulsatility was arrested. The distribution of immunopositive kisspeptin neurons in the arcuate nucleus of the MBH of infants was similar to that previously reported for adults. Kisspeptin cell body number was greater in infants compared with juveniles, and at the middle to posterior level of the arcuate nucleus, this developmental difference was statistically significant. Neurokinin B in the MBH exhibited a similar distribution to that of kisspeptin and was colocalized with kisspeptin in approximately 60% of kisspeptin perikarya at both developmental stages. Intensity of GnRH fiber staining in the median eminence was robust at both stages. These findings indicate that the switch that shuts off pulsatile GnRH release during infancy and that guarantees the subsequent quiescence of the prepubertal gonad involves a reduction in a stimulatory kisspeptin tone to the GnRH neuronal network. PMID:23525220

Differences in response to corticotropin-releasing factor after short- and long-term consumption of a high-fat diet.

PubMed

Legendre, Ariadne; Papakonstantinou, Emilia; Roy, Marie-Claude; Richard, Denis; Harris, Ruth B S

2007-09-01

We previously reported an exaggerated endocrine and weight loss response to stress in rats fed a high-fat (HF) diet for 5 days. Others report blunted stress-induced anxiety in rats made obese on a HF diet. Experiments described here tested whether sensitivity to stress-related peptides was changed in obese and nonobese HF-fed rats. Third ventricle infusion of corticotropin-releasing factor (CRF) in rats made obese on HF diet (40% kcal fat) produced an exaggerated hypophagia, which is thought to be mediated by CRF(2) receptors. Obese rats responded to a lower dose of CRF for a longer time than rats fed a low-fat (LF) diet (12% kcal fat). CRF-induced release of corticosterone, which is thought to be mediated by CRF(1) receptors, was not exaggerated in obese HF-fed rats. In contrast, rats fed HF diet for 5 days showed the same food intake and corticosterone response to CRF as LF-fed rats. CRF mRNA expression in the paraventricular nucleus of the hypothalamus was stimulated by mild stress (ip saline injection and placement in a novel cage) in LF-fed rats but not in rats fed HF diet for 5 days because of a nonsignificant increase in expression in nonstressed HF-fed rats. In addition, nonstressed levels of urocortin (UCN) I mRNA expression in the Edinger-Westphal nucleus were significantly inhibited in HF-fed rats. These data suggest that rats that have become obese on a HF diet show a change in responsiveness to stress peptides, whereas the increased stress response in nonobese HF-fed rats may be associated with changes in basal CRF and UCN I mRNA expression.

Aldosterone increases cardiac vagal tone via G protein-coupled oestrogen receptor activation

PubMed Central

Brailoiu, G Cristina; Benamar, Khalid; Arterburn, Jeffrey B; Gao, Erhe; Rabinowitz, Joseph E; Koch, Walter J; Brailoiu, Eugen

2013-01-01

In addition to acting on mineralocorticoid receptors, aldosterone has been recently shown to activate the G protein-coupled oestrogen receptor (GPER) in vascular cells. In light of the newly identified role for GPER in vagal cardiac control, we examined whether or not aldosterone activates GPER in rat nucleus ambiguus. Aldosterone produced a dose-dependent increase in cytosolic Ca2+ concentration in retrogradely labelled cardiac vagal neurons of nucleus ambiguus; the response was abolished by pretreatment with the GPER antagonist G-36, but was not affected by the mineralocorticoid receptor antagonists, spironolactone and eplerenone. In Ca2+-free saline, the response to aldosterone was insensitive to blockade of the Ca2+ release from lysosomes, while it was reduced by blocking the Ca2+ release via ryanodine receptors and abolished by blocking the IP3 receptors. Aldosterone induced Ca2+ influx via P/Q-type Ca2+ channels, but not via L-type and N-type Ca2+ channels. Aldosterone induced depolarization of cardiac vagal neurons of nucleus ambiguus that was sensitive to antagonism of GPER but not of mineralocorticoid receptor. in vivo studies, using telemetric measurement of heart rate, indicate that microinjection of aldosterone into the nucleus ambiguus produced a dose-dependent bradycardia in conscious, freely moving rats. Aldosterone-induced bradycardia was blocked by the GPER antagonist, but not by the mineralocorticoid receptor antagonists. In summary, we report for the first time that aldosterone decreases heart rate by activating GPER in cardiac vagal neurons of nucleus ambiguus. PMID:23878371

Effect of novel atypical antipsychotic, blonanserin, on extracellular neurotransmitter level in rat prefrontal cortex.

PubMed

Ohoyama, Keiko; Yamamura, Satoshi; Hamaguchi, Tatsuya; Nakagawa, Masanori; Motomura, Eishi; Shiroyama, Takashi; Tanii, Hisashi; Okada, Motohiro

2011-02-25

To clarify the mechanisms of action of blonanserin, an atypical antipsychotic drug, we studied the effects of systemic administration of blonanserin and risperidone on extracellular levels of norepinephrine, dopamine, serotonin, GABA and glutamate in the medial prefrontal cortex using microdialysis, and neuronal firing in the ventral tegmental area, locus coeruleus, dorsal raphe nucleus and mediodorsal thalamic nucleus using radiotelemetry. The binding affinities of blonanserin to D(2) and 5-HT(2A) receptors in the rat brain were confirmed and found to be similar. Blonanserin transiently increased neuronal firing in locus coeruleus and ventral tegmental area but not in dorsal raphe nucleus or mediodorsal thalamic nucleus, whereas risperidone increased the firing in locus coeruleus, ventral tegmental area and dorsal raphe nucleus but not in mediodorsal thalamic nucleus. Blonanserin persistently increased frontal extracellular levels of norepinephrine and dopamine but not serotonin, GABA or glutamate, whereas risperidone persistently increased those of norepinephrine, dopamine and serotonin but not GABA or glutamate. These results suggest a pharmacological correlation between the stimulatory effects of these antipsychotics on frontal monoamine release and neuronal activity in monoaminergic nuclei. Inhibition of the α(2) adrenoceptor increased extracellular monoamine levels and enhanced blonanserin-induced increase in extracellular serotonin level. These results indicated that the combination of antagonism of D(2) and 5-HT(2A) receptors contribute to the rise in extracellular levels of norepinephrine and dopamine, and that α(2) adrenoceptors play important roles in frontal serotonin release. They also suggest that blonanserin-induced activation of monoaminergic transmission could be, at least partially, involved in atypical antipsychotic properties of blonanserin. Copyright © 2010 Elsevier B.V. All rights reserved.

Tracking the intracellular drug release from graphene oxide using surface-enhanced Raman spectroscopy

NASA Astrophysics Data System (ADS)

Huang, Jie; Zong, Cheng; Shen, He; Cao, Yuhua; Ren, Bin; Zhang, Zhijun

2013-10-01

We have developed a graphene oxide (GO)-based nanoplatform simultaneously loaded with a chemical drug and Ag nanoparticles (NPs), and employed it to study the drug release from GO in living cells by surface-enhanced Raman spectroscopy (SERS). In our strategy, doxorubicin (DOX), a typical model anticancer drug, was loaded onto chemically prepared GO by means of π-π stacking, while the Ag NPs were covalently modified onto GO. After incubation of the DOX- and Ag NPs-loaded GO with Ca Ski cells for several hours, DOX will detach from the GO in an acidic environment due to the pH-dependent π-π interaction between DOX and GO. Real-time measurement of SERS signals of DOX using the GO loaded with Ag NPs as a SERS-active substrate allows us to monitor the process of the drug release inside the living cell. The SERS results reveal that DOX is initially released from the GO surface inside the lysosomes, then escapes into the cytoplasm, and finally enters the nucleus, while GO, the nanocarrier, remains within the cytoplasm, without entering the nucleus.We have developed a graphene oxide (GO)-based nanoplatform simultaneously loaded with a chemical drug and Ag nanoparticles (NPs), and employed it to study the drug release from GO in living cells by surface-enhanced Raman spectroscopy (SERS). In our strategy, doxorubicin (DOX), a typical model anticancer drug, was loaded onto chemically prepared GO by means of π-π stacking, while the Ag NPs were covalently modified onto GO. After incubation of the DOX- and Ag NPs-loaded GO with Ca Ski cells for several hours, DOX will detach from the GO in an acidic environment due to the pH-dependent π-π interaction between DOX and GO. Real-time measurement of SERS signals of DOX using the GO loaded with Ag NPs as a SERS-active substrate allows us to monitor the process of the drug release inside the living cell. The SERS results reveal that DOX is initially released from the GO surface inside the lysosomes, then escapes into the cytoplasm, and finally enters the nucleus, while GO, the nanocarrier, remains within the cytoplasm, without entering the nucleus. Electronic supplementary information (ESI) available: Cytotoxicity of Ag-GO SERS image after the cell incubated with Ag-GO for 2 h fluorescence images of Ca Ski cells. See DOI: 10.1039/c3nr03264g

Sex, drugs and gluttony: how the brain controls motivated behaviors.

PubMed

Hull, Elaine M

2011-07-25

Bart Hoebel has forged a view of an integrated neural network that mediates both natural rewards and drug use. He pioneered the use of microdialysis, and also effectively used electrical stimulation, lesions, microinjections, and immunohistochemistry. He found that feeding, stimulant drug administration, and electrical stimulation of the lateral hypothalamus (LH) all increased dopamine (DA) release in the nucleus accumbens (NAc). However, whereas DA in the NAc enhanced motivation, DA in the LH inhibited motivated behaviors. The Hull lab has pursued some of those ideas. We have suggested that serotonin (5-HT) in the perifornical LH inhibits sexual behavior by inhibiting orexin/hypocretin neurons (OX/HCRT), which would otherwise excite neurons in the mesocorticolimbic DA tract. We have shown that DA release in the medial preoptic area (MPOA) is very important for male sexual behavior, and that testosterone, glutamate, nitric oxide (NO) and previous sexual experience promote MPOA DA release and mating. Future research should follow Bart Hoebel's emphasis on neural systems and interactions among brain areas and neurotransmitters. Copyright © 2011 Elsevier Inc. All rights reserved.

Vasopressin and the Regulation of Thirst.

PubMed

Bichet, Daniel G

2018-01-01

Recent experiments using optogenetic tools allow the identification and functional analysis of thirst neurons and vasopressin producing neurons. Two major advances provide a detailed anatomy of taste for water and arginine-vasopressin (AVP) release: (1) thirst and AVP release are regulated not only by the classical homeostatic, intero-sensory plasma osmolality negative feedback, but also by novel, extero-sensory, anticipatory signals. These anticipatory signals for thirst and vasopressin release converge on the same homeostatic neurons of circumventricular organs that monitor the composition of the blood; (2) acid-sensing taste receptor cells (which express polycystic kidney disease 2-like 1 protein) on the tongue that were previously suggested as the sour taste sensors also mediate taste responses to water. The tongue has a taste for water. The median preoptic nucleus (MnPO) of the hypothalamus could integrate multiple thirst-generating stimuli including cardiopulmonary signals, osmolality, angiotensin II, oropharyngeal and gastric signals, the latter possibly representing anticipatory signals. Dehydration is aversive and MnPO neuron activity is proportional to the intensity of this aversive state. © 2018 The Author(s) Published by S. Karger AG, Basel.

Fission Fragment Mass Distributions and Total Kinetic Energy Release of 235-Uranium and 238-Uranium in Neutron-Induced Fission at Intermediate and Fast Neutron Energies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Duke, Dana Lynn

2015-11-12

This Ph.D. dissertation describes a measurement of the change in mass distributions and average total kinetic energy (TKE) release with increasing incident neutron energy for fission of 235U and 238U. Although fission was discovered over seventy-five years ago, open questions remain about the physics of the fission process. The energy of the incident neutron, En, changes the division of energy release in the resulting fission fragments, however, the details of energy partitioning remain ambiguous because the nucleus is a many-body quantum system. Creating a full theoretical model is difficult and experimental data to validate existing models are lacking. Additional fissionmore » measurements will lead to higher-quality models of the fission process, therefore improving applications such as the development of next-generation nuclear reactors and defense. This work also paves the way for precision experiments such as the Time Projection Chamber (TPC) for fission cross section measurements and the Spectrometer for Ion Determination in Fission (SPIDER) for precision mass yields.« less

Fluorescent protein-tagged Vpr dissociates from HIV-1 core after viral fusion and rapidly enters the cell nucleus.

PubMed

Desai, Tanay M; Marin, Mariana; Sood, Chetan; Shi, Jiong; Nawaz, Fatima; Aiken, Christopher; Melikyan, Gregory B

2015-10-29

HIV-1 Vpr is recruited into virions during assembly and appears to remain associated with the viral core after the reverse transcription and uncoating steps of entry. This feature has prompted the use of fluorescently labeled Vpr to visualize viral particles and to follow trafficking of post-fusion HIV-1 cores in the cytoplasm. Here, we tracked single pseudovirus entry and fusion and observed that fluorescently tagged Vpr gradually dissociates from post-fusion viral cores over the course of several minutes and accumulates in the nucleus. Kinetics measurements showed that fluorescent Vpr released from the cores very rapidly entered the cell nucleus. More than 10,000 Vpr molecules can be delivered into the cell nucleus within 45 min of infection by HIV-1 particles pseudotyped with the avian sarcoma and leukosis virus envelope glycoprotein. The fraction of Vpr from cell-bound viruses that accumulated in the nucleus was proportional to the extent of virus-cell fusion and was fully blocked by viral fusion inhibitors. Entry of virus-derived Vpr into the nucleus occurred independently of envelope glycoproteins or target cells. Fluorescence correlation spectroscopy revealed two forms of nuclear Vpr-monomers and very large complexes, likely involving host factors. The kinetics of viral Vpr entering the nucleus after fusion was not affected by point mutations in the capsid protein that alter the stability of the viral core. The independence of Vpr shedding of capsid stability and its relatively rapid dissociation from post-fusion cores suggest that this process may precede capsid uncoating, which appears to occur on a slower time scale. Our results thus demonstrate that a bulk of fluorescently labeled Vpr incorporated into HIV-1 particles is released shortly after fusion. Future studies will address the question whether the quick and efficient nuclear delivery of Vpr derived from incoming viruses can regulate subsequent steps of HIV-1 infection.

Subcollicular projections to the auditory thalamus and collateral projections to the inferior colliculus.

PubMed

Schofield, Brett R; Mellott, Jeffrey G; Motts, Susan D

2014-01-01

Experiments in several species have identified direct projections to the medial geniculate nucleus (MG) from cells in subcollicular auditory nuclei. Moreover, many cochlear nucleus cells that project to the MG send collateral projections to the inferior colliculus (IC) (Schofield et al., 2014). We conducted three experiments to characterize projections to the MG from the superior olivary and the lateral lemniscal regions in guinea pigs. For experiment 1, we made large injections of retrograde tracer into the MG. Labeled cells were most numerous in the superior paraolivary nucleus, ventral nucleus of the trapezoid body, lateral superior olivary nucleus, ventral nucleus of the lateral lemniscus, ventrolateral tegmental nucleus, paralemniscal region and sagulum. Additional sources include other periolivary nuclei and the medial superior olivary nucleus. The projections are bilateral with an ipsilateral dominance (66%). For experiment 2, we injected tracer into individual MG subdivisions. The results show that the subcollicular projections terminate primarily in the medial MG, with the dorsal MG a secondary target. The variety of projecting nuclei suggest a range of functions, including monaural and binaural aspects of hearing. These direct projections could provide the thalamus with some of the earliest (i.e., fastest) information regarding acoustic stimuli. For experiment 3, we made large injections of different retrograde tracers into one MG and the homolateral IC to identify cells that project to both targets. Such cells were numerous and distributed across many of the nuclei listed above, mostly ipsilateral to the injections. The prominence of the collateral projections suggests that the same information is delivered to both the IC and the MG, or perhaps that a common signal is being delivered as a preparatory indicator or temporal reference point. The results are discussed from functional and evolutionary perspectives.

Subcollicular projections to the auditory thalamus and collateral projections to the inferior colliculus

PubMed Central

Schofield, Brett R.; Mellott, Jeffrey G.; Motts, Susan D.

2014-01-01

Experiments in several species have identified direct projections to the medial geniculate nucleus (MG) from cells in subcollicular auditory nuclei. Moreover, many cochlear nucleus cells that project to the MG send collateral projections to the inferior colliculus (IC) (Schofield et al., 2014). We conducted three experiments to characterize projections to the MG from the superior olivary and the lateral lemniscal regions in guinea pigs. For experiment 1, we made large injections of retrograde tracer into the MG. Labeled cells were most numerous in the superior paraolivary nucleus, ventral nucleus of the trapezoid body, lateral superior olivary nucleus, ventral nucleus of the lateral lemniscus, ventrolateral tegmental nucleus, paralemniscal region and sagulum. Additional sources include other periolivary nuclei and the medial superior olivary nucleus. The projections are bilateral with an ipsilateral dominance (66%). For experiment 2, we injected tracer into individual MG subdivisions. The results show that the subcollicular projections terminate primarily in the medial MG, with the dorsal MG a secondary target. The variety of projecting nuclei suggest a range of functions, including monaural and binaural aspects of hearing. These direct projections could provide the thalamus with some of the earliest (i.e., fastest) information regarding acoustic stimuli. For experiment 3, we made large injections of different retrograde tracers into one MG and the homolateral IC to identify cells that project to both targets. Such cells were numerous and distributed across many of the nuclei listed above, mostly ipsilateral to the injections. The prominence of the collateral projections suggests that the same information is delivered to both the IC and the MG, or perhaps that a common signal is being delivered as a preparatory indicator or temporal reference point. The results are discussed from functional and evolutionary perspectives. PMID:25100950

Large area emulsion chamber experiments for the Space Shuttle

NASA Technical Reports Server (NTRS)

Parnell, T. A.

1985-01-01

Emulsion-chamber experiments employing nuclear-track emulsions, etchable plastic detectors, metal plates, and X-ray films continue to demonstrate high productivity and potential in the study of cosmic-ray primaries and their interactions. Emulsions, with unsurpassed track-recording capability, provide an appropriate medium for the study of nucleus-nucleus interactions at high energy, which will likely produce observations of a phase change in nuclear matter. The many advantages of emulsion chambers (excellent multitrack recording capability, large geometry factor, low apparatus cost, simplicity of design and construction) are complemented by the major advantages of the Space Shuttle as an experiment carrier. A Shuttle experiment which could make a significant advance in both cosmic-ray primary and nucleus-nucleus interaction studies is described. Such an experiment would serve as a guide for use of emulsions during the Space Station era. Some practical factors that must be considered in planning a Shuttle exposure of emulsion chambers are discussed.

Developmental changes in NMDA receptor expression in the platyfish brain

NASA Technical Reports Server (NTRS)

Flynn, K. M.; Schreibman, M. P.; Magliulo-Cepriano, L.

1997-01-01

We have examined the distribution of the N-methyl-D-aspartate (NMDA) receptor in the brain of a freshwater teleost using an antibody against the R1 subunit of the receptor (NMDAR1). The primary site of localization was the nucleus olfactoretinalis (NOR), a significant gonadotropin releasing hormone (GnRH)-containing brain nucleus. The number of cells expressing NMDAR1 in this nucleus was dependent upon developmental stage, with pubescent and mature animals displaying significantly more stained cells than immature and senescent animals. This is the first reported observation of age- and maturity-related NMDA receptor association with GnRH-containing brain areas.

Mechanisms of Kappa Opioid Receptor Potentiation of Dopamine D2 Receptor Function in Quinpirole-Induced Locomotor Sensitization in Rats.

PubMed

Escobar, Angélica P; González, Marcela P; Meza, Rodrigo C; Noches, Verónica; Henny, Pablo; Gysling, Katia; España, Rodrigo A; Fuentealba, José A; Andrés, María E

2017-08-01

Increased locomotor activity in response to the same stimulus is an index of behavioral sensitization observed in preclinical models of drug addiction and compulsive behaviors. Repeated administration of quinpirole, a D2/D3 dopamine agonist, induces locomotor sensitization. This effect is potentiated and accelerated by co-administration of U69593, a kappa opioid receptor agonist. The mechanism underlying kappa opioid receptor potentiation of quinpirole-induced locomotor sensitization remains to be elucidated. Immunofluorescence anatomical studies were undertaken in mice brain slices and rat presynaptic synaptosomes to reveal kappa opioid receptor and D2R pre- and postsynaptic colocalization in the nucleus accumbens. Tonic and phasic dopamine release in the nucleus accumbens of rats repeatedly treated with U69593 and quinpirole was assessed by microdialysis and fast scan cyclic voltammetry. Anatomical data show that kappa opioid receptor and D2R colocalize postsynaptically in medium spiny neurons of the nucleus accumbens and the highest presynaptic colocalization occurs on the same dopamine terminals. Significantly reduced dopamine levels were observed in quinpirole, and U69593-quinpirole treated rats, explaining sensitization of D2R. Presynaptic inhibition induced by kappa opioid receptor and D2R of electrically evoked dopamine release was faster in U69593-quinpirole compared with quinpirole-repeatedly treated rats. Pre- and postsynaptic colocalization of kappa opioid receptor and D2R supports a role for kappa opioid receptor potentiating both the D2R inhibitory autoreceptor function and the inhibitory action of D2R on efferent medium spiny neurons. Kappa opioid receptor co-activation accelerates D2R sensitization by contributing to decrease dopamine release in the nucleus accumbens. © The Author 2017. Published by Oxford University Press on behalf of CINP.

Cloning of corticotropin-releasing hormone (CRH) precursor cDNA and immunohistochemical detection of CRH peptide in the brain of the Japanese eel, paying special attention to gonadotropin-releasing hormone.

PubMed

Amano, Masafumi; Mizusawa, Nanami; Okubo, Kataaki; Amiya, Noriko; Mizusawa, Kanta; Chiba, Hiroaki; Yamamoto, Naoyuki; Takahashi, Akiyoshi

2014-04-01

The stress-related corticotropin-releasing hormone (CRH) was first identified by isolation of its cDNA from the brain of the Japanese eel Anguilla japonica. CRH cDNA encodes a signal peptide, a cryptic peptide and CRH (41 amino acids). The sequence homology to mammalian CRH is high. Next, the distribution of CRH-immunoreactive (ir) cell bodies and fibers in the brain and pituitary were examined by immunohistochemistry. CRH-ir cell bodies were detected in several brain regions, e.g., nucleus preopticus pars magnocellularis, nucleus preopticus pars gigantocellularis and formatio reticularis superius. In the brain, CRH-ir fibers were distributed not only in the hypothalamus but also in various regions. Some CRH-ir fibers projected to adrenocorticotropic hormone (ACTH) cells in the rostral pars distalis of the pituitary and also the α-melanocyte-stimulating hormone (α-MSH) cells in the pars intermedia of the pituitary. Finally, the neuroanatomical relationship between the CRH neurons and gonadotropin-releasing hormone (GnRH) neurons was examined by dual-label immunohistochemistry. CRH-ir fibers were found to be in close contact with GnRH-ir cell bodies in the hypothalamus and in the midbrain tegmentum and GnRH-ir fibers were in close contact with CRH-ir cell bodies in the nucleus preopticus pars magnocellularis. These results suggest that CRH has some physiological functions other than the stimulation of ACTH and α-MSH secretion and that reciprocal connections may exist between the CRH neurons and GnRH neurons in the brain of the Japanese eel.

The Arcuate Nucleus: A Site of Fast Negative Feedback for Corticosterone Secretion in Male Rats

PubMed Central

Kawata, Mitsuhiro; Escobar, Carolina

2017-01-01

Abstract Variations in circulating corticosterone (Cort) are driven by the paraventricular nucleus of the hypothalamus (PVN), mainly via the sympathetic autonomic nervous system (ANS) directly stimulating Cort release from the adrenal gland and via corticotropin-releasing hormone targeting the adenohypophysis to release adrenocorticotropic hormone (ACTH). Cort feeds back through glucocorticoid receptors (GRs). Here we show in male Wistar rats that PVN neurons projecting to the adrenal gland do not express GRs, leaving the question of how the ANS in the PVN gets information about circulating Cort levels to control the adrenal. Since the arcuate nucleus (ARC) shows a less restrictive blood–brain barrier, expresses GRs, and projects to the PVN, we investigated whether the ARC can detect and produce fast adjustments of circulating Cort. In low Cort conditions (morning), local microdialysis in the ARC with type I GR antagonist produced a fast and sustained increase of Cort. This was not observed with a type II antagonist. At the circadian peak levels of Cort (afternoon), a type II GR antagonist, but not a type I antagonist, increased Cort levels but not ACTH levels. Antagonist infusions in the PVN did not modify circulating Cort levels, demonstrating the specificity of the ARC to give Cort negative feedback. Furthermore, type I and II GR agonists in the ARC prevented the increase of Cort after stress, demonstrating the role of the ARC as sensor to modulate Cort release. Our findings show that the ARC may be essential to sense blood levels of Cort and adapt Cort secretion depending on such conditions as stress or time of day. PMID:28275717

Differential Dopamine Release Dynamics in the Nucleus Accumbens Core and Shell Reveal Complementary Signals for Error Prediction and Incentive Motivation.

PubMed

Saddoris, Michael P; Cacciapaglia, Fabio; Wightman, R Mark; Carelli, Regina M

2015-08-19

Mesolimbic dopamine (DA) is phasically released during appetitive behaviors, though there is substantive disagreement about the specific purpose of these DA signals. For example, prediction error (PE) models suggest a role of learning, while incentive salience (IS) models argue that the DA signal imbues stimuli with value and thereby stimulates motivated behavior. However, within the nucleus accumbens (NAc) patterns of DA release can strikingly differ between subregions, and as such, it is possible that these patterns differentially contribute to aspects of PE and IS. To assess this, we measured DA release in subregions of the NAc during a behavioral task that spatiotemporally separated sequential goal-directed stimuli. Electrochemical methods were used to measure subsecond NAc dopamine release in the core and shell during a well learned instrumental chain schedule in which rats were trained to press one lever (seeking; SL) to gain access to a second lever (taking; TL) linked with food delivery, and again during extinction. In the core, phasic DA release was greatest following initial SL presentation, but minimal for the subsequent TL and reward events. In contrast, phasic shell DA showed robust release at all task events. Signaling decreased between the beginning and end of sessions in the shell, but not core. During extinction, peak DA release in the core showed a graded decrease for the SL and pauses in release during omitted expected rewards, whereas shell DA release decreased predominantly during the TL. These release dynamics suggest parallel DA signals capable of supporting distinct theories of appetitive behavior. Dopamine signaling in the brain is important for a variety of cognitive functions, such as learning and motivation. Typically, it is assumed that a single dopamine signal is sufficient to support these cognitive functions, though competing theories disagree on how dopamine contributes to reward-based behaviors. Here, we have found that real-time dopamine release within the nucleus accumbens (a primary target of midbrain dopamine neurons) strikingly varies between core and shell subregions. In the core, dopamine dynamics are consistent with learning-based theories (such as reward prediction error) whereas in the shell, dopamine is consistent with motivation-based theories (e.g., incentive salience). These findings demonstrate that dopamine plays multiple and complementary roles based on discrete circuits that help animals optimize rewarding behaviors. Copyright © 2015 the authors 0270-6474/15/3511572-11$15.00/0.

Nesfatin-1-regulated oxytocinergic signaling in the paraventricular nucleus causes anorexia through a leptin-independent melanocortin pathway.

PubMed

Maejima, Yuko; Sedbazar, Udval; Suyama, Shigetomo; Kohno, Daisuke; Onaka, Tatsushi; Takano, Eisuke; Yoshida, Natsu; Koike, Masato; Uchiyama, Yasuo; Fujiwara, Ken; Yashiro, Takashi; Horvath, Tamas L; Dietrich, Marcelo O; Tanaka, Shigeyasu; Dezaki, Katsuya; Oh-I, Shinsuke; Hashimoto, Koushi; Shimizu, Hiroyuki; Nakata, Masanori; Mori, Masatomo; Yada, Toshihiko

2009-11-01

The hypothalamic paraventricular nucleus (PVN) functions as a center to integrate various neuronal activities for regulating feeding behavior. Nesfatin-1, a recently discovered anorectic molecule, is localized in the PVN. However, the anorectic neural pathway of nesfatin-1 remains unknown. Here we show that central injection of nesfatin-1 activates the PVN and brain stem nucleus tractus solitarius (NTS). In the PVN, nesfatin-1 targets both magnocellular and parvocellular oxytocin neurons and nesfatin-1 neurons themselves and stimulates oxytocin release. Immunoelectron micrographs reveal nesfatin-1 specifically in the secretory vesicles of PVN neurons, and immunoneutralization against endogenous nesfatin-1 suppresses oxytocin release in the PVN, suggesting paracrine/autocrine actions of nesfatin-1. Nesfatin-1-induced anorexia is abolished by an oxytocin receptor antagonist. Moreover, oxytocin terminals are closely associated with and oxytocin activates pro-opiomelanocortin neurons in the NTS. Oxytocin induces melanocortin-dependent anorexia in leptin-resistant Zucker-fatty rats. The present results reveal the nesfatin-1-operative oxytocinergic signaling in the PVN that triggers leptin-independent melanocortin-mediated anorexia.

Trajectory analysis for the nucleus and dust of comet C/2013 A1 (Siding Spring)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Farnocchia, Davide; Chesley, Steven R.; Chodas, Paul W.

Comet C/2013 A1 (Siding Spring) will experience a high velocity encounter with Mars on 2014 October 19 at a distance of 135,000 km ± 5000 km from the planet center. We present a comprehensive analysis of the trajectory of both the comet nucleus and the dust tail. The nucleus of C/2013 A1 cannot impact on Mars even in the case of unexpectedly large nongravitational perturbations. Furthermore, we compute the required ejection velocities for the dust grains of the tail to reach Mars as a function of particle radius and density and heliocentric distance of the ejection. A comparison between ourmore » results and the most current modeling of the ejection velocities suggests that impacts are possible only for millimeter to centimeter size particles released more than 13 AU from the Sun. However, this level of cometary activity that far from the Sun is considered extremely unlikely. The arrival time of these particles spans a 20-minute time interval centered at 2014 October 19 at 20:09 TDB, i.e., around the time that Mars crosses the orbital plane of C/2013 A1. Ejection velocities larger than currently estimated by a factor >2 would allow impacts for smaller particles ejected as close as 3 AU from the Sun. These particles would reach Mars from 19:13 TDB to 20:40 TDB.« less

Glucokinase activity in the arcuate nucleus regulates glucose intake

PubMed Central

Hussain, Syed; Richardson, Errol; Ma, Yue; Holton, Christopher; De Backer, Ivan; Buckley, Niki; Dhillo, Waljit; Bewick, Gavin; Zhang, Shuai; Carling, David; Bloom, Steve; Gardiner, James

2014-01-01

The brain relies on a constant supply of glucose, its primary fuel, for optimal function. A taste-independent mechanism within the CNS that promotes glucose delivery to the brain has been postulated to maintain glucose homeostasis; however, evidence for such a mechanism is lacking. Here, we determined that glucokinase activity within the hypothalamic arcuate nucleus is involved in regulation of dietary glucose intake. In fasted rats, glucokinase activity was specifically increased in the arcuate nucleus but not other regions of the hypothalamus. Moreover, pharmacologic and genetic activation of glucokinase in the arcuate nucleus of rodent models increased glucose ingestion, while decreased arcuate nucleus glucokinase activity reduced glucose intake. Pharmacologic targeting of potential downstream glucokinase effectors revealed that ATP-sensitive potassium channel and P/Q calcium channel activity are required for glucokinase-mediated glucose intake. Additionally, altered glucokinase activity affected release of the orexigenic neurotransmitter neuropeptide Y in response to glucose. Together, our results suggest that glucokinase activity in the arcuate nucleus specifically regulates glucose intake and that appetite for glucose is an important driver of overall food intake. Arcuate nucleus glucokinase activation may represent a CNS mechanism that underlies the oft-described phenomena of the “sweet tooth” and carbohydrate craving. PMID:25485685

Effect of subthalamic nucleus stimulation during exercise on the mesolimbocortical dopaminergic region in Parkinson's disease: a positron emission tomography study.

PubMed

Nozaki, Takao; Sugiyama, Kenji; Yagi, Shunsuke; Yoshikawa, Etsuji; Kanno, Toshihiko; Asakawa, Tetsuya; Ito, Tae; Terada, Tatsuhiro; Namba, Hiroki; Ouchi, Yasuomi

2013-03-01

To elucidate the dynamic effects of deep brain stimulation (DBS) in the subthalamic nucleus (STN) during activity on the dopaminergic system, 12 PD patients who had STN-DBS operations at least 1 month prior, underwent two positron emission tomography scans during right-foot movement in DBS-off and DBS-on conditions. To quantify motor performance changes, the motion speed and mobility angle of the foot at the ankle were measured twice. Estimations of the binding potential of [(11)C]raclopride (BP(ND)) were based on the Logan plot method. Significant motor recovery was found in the DBS-on condition. The STN-DBS during exercise significantly reduced the [(11)C]raclopride BP(ND) in the caudate and the nucleus accumbens (NA), but not in the dorsal or ventral putamen. The magnitude of dopamine release in the NA correlated negatively with the magnitude of motor load, indicating that STN-DBS facilitated motor behavior more smoothly and at less expense to dopamine neurons in the region. The lack of dopamine release in the putamen and the significant dopamine release in the ventromedial striatum by STN-DBS during exercise indicated dopaminergic activation occurring in the motivational circuit during action, suggesting a compensatory functional activation of the motor loop from the nonmotor to the motor loop system.

The gamma-aminobutyric acid type B (GABAB) receptor agonist baclofen inhibits morphine sensitization by decreasing the dopamine level in rat nucleus accumbens

PubMed Central

2012-01-01

Background Repeated morphine exposure can induce behavioral sensitization. There are evidences have shown that central gamma-aminobutyric acid (GABA) system is involved in morphine dependence. However, the effect of a GABAB receptor agonist baclofen on morphine-induced behavioral sensitization in rats is unclear. Methods We used morphine-induced behavioral sensitization model in rat to investigate the effects of baclofen on behavioral sensitization. Moreover, dopamine release in the shell of the nucleus accumbens was evaluated using microdialysis assay in vivo. Results The present study demonstrated that morphine challenge (3 mg/kg, s.c.) obviously enhanced the locomotor activity following 4-day consecutive morphine administration and 3-day withdrawal period, which indicated the expression of morphine sensitization. In addition, chronic treatment with baclofen (2.5, 5 mg/kg) significantly inhibited the development of morphine sensitization. It was also found that morphine challenge 3 days after repeated morphine administration produced a significant increase of extracellular dopamine release in nucleus accumbens. Furthermore, chronic treatment with baclofen decreased the dopamine release induced by morphine challenge. Conclusions Our results indicated that gamma-aminobutyric acid system plays an important role in the morphine sensitization in rat and suggested that behavioral sensitization is a promising model to study the mechanism underlying drug abuse. PMID:22559224

The response of a scintillation counter below an emulsion chamber to heavy nucleus interactions in the chamber

NASA Technical Reports Server (NTRS)

Burnett, T. H.; Dake, S.; Derrickson, J. H.; Fountain, W. F.; Fuki, M.; Gregory, J. C.; Hayashi, T.; Hayashi, T.; Holynski, R.; Iwai, J.;

Microinjection of urocortin 2 into the dorsal raphe nucleus activates serotonergic neurons and increases extracellular serotonin in the basolateral amygdala.

PubMed

Amat, J; Tamblyn, J P; Paul, E D; Bland, S T; Amat, P; Foster, A C; Watkins, L R; Maier, S F

2004-01-01

The intra dorsal raphe nucleus (DRN) administration of corticotropin releasing hormone (CRF) inhibits serotonergic (5-HT) activity in this structure, an effect blocked by antagonists selective for the type 1 CRF receptor (CRF1). The DRN has a high density of the type 2 receptor (CRF2), and so the present experiments explored the impact of CRF2 activation within the DRN on 5-HT function. The intra-DRN administration of the selective CRF2 agonist urocortin 2 (Ucn 2) dose dependently increased 5-HT efflux in the basolateral amygdala, a projection region of the DRN. Intra-DRN Ucn 2 also increased c-fos expression in labeled 5-HT neurons. Both of these effects of Ucn 2 were completely blocked by intra-DRN antisauvagine-30 (ASV-30), a relatively selective CRF2 antagonist. These data suggest that CRF1 and CRF2 activation within the DRN affect 5-HT neurons in opponent fashion. Implications of these results for understanding the behavioral effects of CRF and other CRF-like ligands are discussed.

Glutamatergic Receptor Activation in the Commisural Nucleus Tractus Solitarii (cNTS) Mediates Brain Glucose Retention (BGR) Response to Anoxic Carotid Chemoreceptor (CChr) Stimulation in Rats.

PubMed

Cuéllar, R; Montero, S; Luquín, S; García-Estrada, J; Dobrovinskaya, O; Melnikov, V; Lemus, M; de Álvarez-Buylla, E Roces

2015-01-01

Glutamate, released from central terminals of glossopharyngeal nerve, is a major excitatory neurotransmitter of commissural nucleus tractus solitarii (cNTS) afferent terminals, and brain derived neurotrophic factor (BDNF) has been shown to attenuate glutamatergic AMPA currents in NTS neurons. To test the hypothesis that AMPA contributes to glucose regulation in vivo modulating the hyperglycemic reflex with brain glucose retention (BGR), we microinjected AMPA and NBQX (AMPA antagonist) into the cNTS before carotid chemoreceptor stimulation in anesthetized normal Wistar rats, while hyperglycemic reflex an brain glucose retention (BGR) were analyzed. To investigate the underlying mechanisms, GluR2/3 receptor and c-Fos protein expressions in cNTS neurons were determined. We showed that AMPA in the cNTS before CChr stimulation inhibited BGR observed in aCSF group. In contrast, NBQX in similar conditions, did not modify the effects on glucose variables observed in aCSF control group. These experiments suggest that glutamatergic pathways, via AMPA receptors, in the cNTS may play a role in glucose homeostasis.

Response contingency directs long-term cocaine-induced neuroplasticity in prefrontal and striatal dopamine terminals.

PubMed

Wiskerke, Joost; Schoffelmeer, Anton N M; De Vries, Taco J

2016-10-01

Exposure to addictive substances such as cocaine is well-known to alter brain organisation. Cocaine-induced neuroadaptations depend on several factors, including drug administration paradigm. To date, studies addressing the consequences of cocaine exposure on dopamine transmission have either not been designed to investigate the role of response contingency or focused only on short-term neuroplasticity. We demonstrate a key role of response contingency in directing long-term cocaine-induced neuroplasticity throughout projection areas of the mesocorticolimbic dopamine system. We found enhanced electrically-evoked [(3)H]dopamine release from superfused brain slices of nucleus accumbens shell and core, dorsal striatum and medial prefrontal cortex three weeks after cessation of cocaine self-administration. In yoked cocaine rats receiving the same amount of cocaine passively, sensitised dopamine terminal reactivity was only observed in the nucleus accumbens core. Control sucrose self-administration experiments demonstrated that the observed neuroadaptations were not the result of instrumental learning per se. Thus, long-term withdrawal from cocaine self-administration is associated with widespread sensitisation of dopamine terminals throughout frontostriatal circuitries. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

Influence of Volatile Anesthesia on the Release of Glutamate and other Amino Acids in the Nucleus Accumbens in a Rat Model of Alcohol Withdrawal: A Pilot Study

PubMed Central

Seidemann, Thomas; Spies, Claudia; Morgenstern, Rudolf; Wernecke, Klaus-Dieter; Netzhammer, Nicolai

2017-01-01

Background Alcohol withdrawal syndrome is a potentially life-threatening condition, which can occur when patients with alcohol use disorders undergo general anesthesia. Excitatory amino acids, such as glutamate, act as neurotransmitters and are known to play a key role in alcohol withdrawal syndrome. To understand this process better, we investigated the influence of isoflurane, sevoflurane, and desflurane anesthesia on the profile of excitatory and inhibitory amino acids in the nucleus accumbens (NAcc) of alcohol-withdrawn rats (AWR). Methods Eighty Wistar rats were randomized into two groups of 40, pair-fed with alcoholic or non-alcoholic nutrition. Nutrition was withdrawn and microdialysis was performed to measure the activity of amino acids in the NAcc. The onset time of the withdrawal syndrome was first determined in an experiment with 20 rats. Sixty rats then received isoflurane, sevoflurane, or desflurane anesthesia for three hours during the withdrawal period, followed by one hour of elimination. Amino acid concentrations were measured using chromatography and results were compared to baseline levels measured prior to induction of anesthesia. Results Glutamate release increased in the alcohol group at five hours after the last alcohol intake (p = 0.002). After 140 min, desflurane anesthesia led to a lower release of glutamate (p < 0.001) and aspartate (p = 0.0007) in AWR compared to controls. GABA release under and after desflurane anesthesia was also significantly lower in AWR than controls (p = 0.023). Over the course of isoflurane anesthesia, arginine release decreased in AWR compared to controls (p < 0.001), and aspartate release increased after induction relative to controls (p20min = 0.015 and p40min = 0.006). However, amino acid levels did not differ between the groups as a result of sevoflurane anesthesia. Conclusions Each of three volatile anesthetics we studied showed different effects on excitatory and inhibitory amino acid concentrations. Under desflurane anesthesia, both glutamate and aspartate showed a tendency to be lower in AWR than controls over the whole timecourse. The inhibitory amino acid arginine increased in AWR compared to controls, whereas GABA levels decreased. However, there were no significant differences in amino acid concentrations under or after sevoflurane anesthesia. Under isoflurane, aspartate release increased in AWR following induction, and from 40 min to 140 min arginine release in controls was elevated. The precise mechanisms through which each of the volatile anesthetics affected amino acid concentrations are still unclear and further experimental research is required to draw reliable conclusions. PMID:28045949

Influence of Volatile Anesthesia on the Release of Glutamate and other Amino Acids in the Nucleus Accumbens in a Rat Model of Alcohol Withdrawal: A Pilot Study.

PubMed

Seidemann, Thomas; Spies, Claudia; Morgenstern, Rudolf; Wernecke, Klaus-Dieter; Netzhammer, Nicolai

2017-01-01

Alcohol withdrawal syndrome is a potentially life-threatening condition, which can occur when patients with alcohol use disorders undergo general anesthesia. Excitatory amino acids, such as glutamate, act as neurotransmitters and are known to play a key role in alcohol withdrawal syndrome. To understand this process better, we investigated the influence of isoflurane, sevoflurane, and desflurane anesthesia on the profile of excitatory and inhibitory amino acids in the nucleus accumbens (NAcc) of alcohol-withdrawn rats (AWR). Eighty Wistar rats were randomized into two groups of 40, pair-fed with alcoholic or non-alcoholic nutrition. Nutrition was withdrawn and microdialysis was performed to measure the activity of amino acids in the NAcc. The onset time of the withdrawal syndrome was first determined in an experiment with 20 rats. Sixty rats then received isoflurane, sevoflurane, or desflurane anesthesia for three hours during the withdrawal period, followed by one hour of elimination. Amino acid concentrations were measured using chromatography and results were compared to baseline levels measured prior to induction of anesthesia. Glutamate release increased in the alcohol group at five hours after the last alcohol intake (p = 0.002). After 140 min, desflurane anesthesia led to a lower release of glutamate (p < 0.001) and aspartate (p = 0.0007) in AWR compared to controls. GABA release under and after desflurane anesthesia was also significantly lower in AWR than controls (p = 0.023). Over the course of isoflurane anesthesia, arginine release decreased in AWR compared to controls (p < 0.001), and aspartate release increased after induction relative to controls (p20min = 0.015 and p40min = 0.006). However, amino acid levels did not differ between the groups as a result of sevoflurane anesthesia. Each of three volatile anesthetics we studied showed different effects on excitatory and inhibitory amino acid concentrations. Under desflurane anesthesia, both glutamate and aspartate showed a tendency to be lower in AWR than controls over the whole timecourse. The inhibitory amino acid arginine increased in AWR compared to controls, whereas GABA levels decreased. However, there were no significant differences in amino acid concentrations under or after sevoflurane anesthesia. Under isoflurane, aspartate release increased in AWR following induction, and from 40 min to 140 min arginine release in controls was elevated. The precise mechanisms through which each of the volatile anesthetics affected amino acid concentrations are still unclear and further experimental research is required to draw reliable conclusions.

Internal pallidum and substantia nigra control different parts of the mesopontine reticular formation in primate.

PubMed

Rolland, Anne-Sophie; Karachi, Carine; Muriel, Marie-Paule; Hirsch, Etienne C; François, Chantal

2011-08-01

The locomotor area has recently emerged as a target for deep brain stimulation to lessen gait disturbances in advanced parkinsonian patients. An important step in choosing this target is to define anatomical limits of its 2 components, the pedunculopontine nucleus and the cuneiform nucleus, their connections with the basal ganglia, and their output descending pathway. Based on the hypothesis that pedunculopontine nucleus controls locomotion whereas cuneiform nucleus controls axial posture, we analyzed whether both nuclei receive inputs from the internal pallidum and substantia nigra using anterograde and retrograde tract tracing in monkeys. We also examined whether these nuclei convey descending projections to the reticulospinal pathway. Pallidal terminals were densely distributed and restricted to the pedunculopontine nucleus, whereas nigral terminals were diffusely observed in the whole extent of both the pedunculopontine nucleus and the cuneiform nucleus. Moreover, nigral terminals formed symmetric synapses with pedunculopontine nucleus and cuneiform nucleus dendrites. Retrograde tracing experiments confirmed these results because labeled cell bodies were observed in both the internal pallidum and substantia nigra after pedunculopontine nucleus injection, but only in the substantia nigra after cuneiform nucleus injection. Furthermore, anterograde tracing experiments revealed that the pedunculopontine nucleus and cuneiform nucleus project to large portions of the pontomedullary reticular formation. This is the first anatomical evidence that the internal pallidum and the substantia nigra control different parts of the brain stem and can modulate the descending reticulospinal pathway in primates. These findings support the functional hypothesis that the nigro-cuneiform nucleus pathway could control axial posture whereas the pallido-pedunculopontine nucleus pathway could modulate locomotion. Copyright © 2011 Movement Disorder Society.

The role of reactive oxygen species in methamphetamine self-administration and dopamine release in the nucleus accumbens.

PubMed

Jang, Eun Young; Yang, Chae Ha; Hedges, David M; Kim, Soo Phil; Lee, Jun Yeon; Ekins, Tyler G; Garcia, Brandon T; Kim, Hee Young; Nelson, Ashley C; Kim, Nam Jun; Steffensen, Scott C

2017-09-01

Methamphetamine (METH) markedly increases dopamine (DA) release in the mesolimbic DA system, which plays an important role in mediating the reinforcing effects of METH. METH-induced DA release results in the formation of reactive oxygen species (ROS), leading to oxidative damage. We have recently reported that ROS are implicated in behavior changes and DA release in the nucleus accumbens (NAc) following cocaine administration. The aim of this study was to evaluate the involvement of ROS in METH-induced locomotor activity, self-administration and enhancement of DA release in the NAc. Systemic administration of a non-specific ROS scavenger, N-tert-butyl-α-phenylnitrone (PBN; 0, 50 and 75 mg/kg, IP) or a superoxide-selective scavenger, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL; 0, 50 and 100 mg/kg, IP), attenuated METH-induced locomotor activity without affecting generalized behavior in METH-naïve rats. PBN and TEMPOL significantly attenuated METH self-administration without affecting food intake. Increased oxidative stress was found in neurons, but not astrocytes, microglia or oligodendrocytes, in the NAc of METH self-administering rats. In addition, TEMPOL significantly decreased METH enhancement of DA release in the NAc. Taken together, these results suggest that enhancement of ROS in the NAc contributes to the reinforcing effect of METH. © 2016 Society for the Study of Addiction.

Noradrenergic innervation of the hypothalamus of rhesus monkeys: distribution of dopamine-beta-hydroxylase immunoreactive fibers and quantitative analysis of varicosities in the paraventricular nucleus.

PubMed

Ginsberg, S D; Hof, P R; Young, W G; Morrison, J H

1993-01-22

The distribution of noradrenergic processes within the hypothalamus of rhesus monkeys (Macaca mulatta) was examined by immunohistochemistry with an antibody against dopamine-beta-hydroxylase. The results revealed that the pattern of dopamine-beta-hydroxylase immunoreactivity varied systematically throughout the rhesus monkey hypothalamus. Extremely high densities of dopamine-beta-hydroxylase-immunoreactive processes were observed in the paraventricular and supraoptic nuclei, while relatively lower levels were found in the arcuate and dorsomedial nuclei and in the medial preoptic, perifornical, and suprachiasmatic areas. Moderate levels of dopamine-beta-hydroxylase immunoreactivity were found throughout the lateral hypothalamic area and in the internal lamina of the median eminence. Very few immunoreactive processes were found in the ventromedial nucleus or in the mammillary complex. Other midline diencephalic structures were found to have high densities of dopamine-beta-hydroxylase immunoreactivity, including the paraventricular nucleus of the thalamus and a discrete subregion of nucleus reuniens, the magnocellular subfascicular nucleus. A moderate density of dopamine-beta-hydroxylase immunoreactive processes were found in the rhomboid nucleus and zona incerta whereas little dopamine-beta-hydroxylase immunoreactivity was found in the fields of Forel, nucleus reuniens, or subthalamic nucleus. The differential distribution of dopamine-beta-hydroxylase-immunoreactive processes may reflect a potential role of norepinephrine as a regulator of a variety of functions associated with the nuclei that are most heavily innervated, e.g., neuroendocrine release from the paraventricular and supraoptic nuclei, and gonadotropin release from the medial preoptic area and mediobasal hypothalamus. Additionally, quantitative analysis of dopamine-beta-hydroxylase-immunoreactive varicosities was performed on a laser scanning microscope in both magnocellular and parvicellular regions of the paraventricular nucleus of the hypothalamus. The methodology employed in this study allowed for the high resolution of immunoreactive profiles through the volume of tissue being analyzed, and was more accurate than conventional light microscopy in terms of varicosity quantification. Quantitatively, a significant difference in the density of dopamine-beta-hydroxylase-immunoreactive varicosities was found between magnocellular and parvicellular regions, suggesting that parvicellular neurons received a denser noradrenergic input. These differential patterns may reflect an important functional role for norepinephrine in the regulation of anterior pituitary secretion through the hypothalamic-pituitary-adrenal stress axis.

Striatal dopaminergic modulation of reinforcement learning predicts reward-oriented behavior in daily life.

PubMed

Kasanova, Zuzana; Ceccarini, Jenny; Frank, Michael J; Amelsvoort, Thérèse van; Booij, Jan; Heinzel, Alexander; Mottaghy, Felix; Myin-Germeys, Inez

2017-07-01

Much human behavior is driven by rewards. Preclinical neurophysiological and clinical positron emission tomography (PET) studies have implicated striatal phasic dopamine (DA) release as a primary modulator of reward processing. However, the relationship between experimental reward-induced striatal DA release and responsiveness to naturalistic rewards, and therefore functional relevance of these findings, has been elusive. We therefore combined, for the first time, a DA D 2/3 receptor [ 18 F]fallypride PET during a probabilistic reinforcement learning (RL) task with a six day ecological momentary assessments (EMA) of reward-related behavior in the everyday life of 16 healthy volunteers. We detected significant reward-induced DA release in the bilateral putamen, caudate nucleus and ventral striatum, the extent of which was associated with better behavioral performance on the RL task across all regions. Furthermore, individual variability in the extent of reward-induced DA release in the right caudate nucleus and ventral striatum modulated the tendency to be actively engaged in a behavior if the active engagement was previously deemed enjoyable. This study suggests a link between striatal reward-related DA release and ecologically relevant reward-oriented behavior, suggesting an avenue for the inquiry into the DAergic basis of optimal and impaired motivational drive. Copyright © 2017 Elsevier B.V. All rights reserved.

Co-release of noradrenaline and dopamine in the cerebral cortex elicited by single train and repeated train stimulation of the locus coeruleus

PubMed Central

Devoto, Paola; Flore, Giovanna; Saba, Pierluigi; Fà, Mauro; Gessa, Gian Luigi

2005-01-01

Background Previous studies by our group suggest that extracellular dopamine (DA) and noradrenaline (NA) may be co-released from noradrenergic nerve terminals in the cerebral cortex. We recently demonstrated that the concomitant release of DA and NA could be elicited in the cerebral cortex by electrical stimulation of the locus coeruleus (LC). This study analyses the effect of both single train and repeated electrical stimulation of LC on NA and DA release in the medial prefrontal cortex (mPFC), occipital cortex (Occ), and caudate nucleus. To rule out possible stressful effects of electrical stimulation, experiments were performed on chloral hydrate anaesthetised rats. Results Twenty min electrical stimulation of the LC, with burst type pattern of pulses, increased NA and DA both in the mPFC and in the Occ. NA in both cortices and DA in the mPFC returned to baseline within 20 min after the end of the stimulation period, while DA in the Occ reached a maximum increase during 20 min post-stimulation and remained higher than baseline values at 220 min post-stimulation. Local perfusion with tetrodotoxin (TTX, 10 μM) markedly reduced baseline NA and DA in the mPFC and Occ and totally suppressed the effect of electrical stimulation in both areas. A sequence of five 20 min stimulations at 20 min intervals were delivered to the LC. Each stimulus increased NA to the same extent and duration as the first stimulus, whereas DA remained elevated at the time next stimulus was delivered, so that baseline DA progressively increased in the mPFC and Occ to reach about 130 and 200% the initial level, respectively. In the presence of the NA transport (NAT) blocker desipramine (DMI, 100 μM), multiple LC stimulation still increased extracellular NA and DA levels. Electrical stimulation of the LC increased NA levels in the homolateral caudate nucleus, but failed to modify DA level. Conclusion The results confirm and extend that LC stimulation induces a concomitant release of DA and NA in the mPFC and Occ. The different time-course of LC-induced elevation of DA and NA suggests that their co-release may be differentially controlled. PMID:15865626

Contrasting expressions of aggressive behavior released by lesions of the central nucleus of the amygdala during wakefulness and rapid eye movement sleep without atonia in cats.

PubMed

Zagrodzka, J; Hedberg, C E; Mann, G L; Morrison, A R

1998-06-01

Whether damage to the central nucleus of the amygdala (Ace) contributes to the predatorylike attack sometimes observed in rapid eye movement sleep without atonia (REM-A), created in cats by bilateral pontine lesions, was examined. Such lesions eliminate REM sleep skeletal muscle atonia and release elaborate behavior. Unilateral damage to the Ace alone increased affective defensive aggressive behavior toward humans and conspecifics without altering predatory behavior in wakefulness. Pontine lesions added at loci normally not leading to aggression induced predatorylike attacks in REM-A as well as the waking affective defense. Alterations of autonomic activity, the absence of relevant environmental stimuli in REM-A, or both may explain the state-related differences.

N-Methyl-d-aspartate Modulation of Nucleus Accumbens Dopamine Release by Metabotropic Glutamate Receptors: Fast Cyclic Voltammetry Studies in Rat Brain Slices in Vitro.

PubMed

Yavas, Ersin; Young, Andrew M J

2017-02-15

The N-methyl-d-aspartate (NMDA) receptor antagonist, phencyclidine, induces behavioral changes in rodents mimicking symptoms of schizophrenia, possibly mediated through dysregulation of glutamatergic control of mesolimbic dopamine release. We tested the hypothesis that NMDA receptor activation modulates accumbens dopamine release, and that phencyclidine pretreatment altered this modulation. NMDA caused a receptor-specific, dose-dependent decrease in electrically stimulated dopamine release in nucleus accumbens brain slices. This decrease was unaffected by picrotoxin, making it unlikely to be mediated through GABAergic neurones, but was decreased by the metabotropic glutamate receptor antagonist, (RS)-α-methyl-4-sulfonophenylglycine, indicating that NMDA activates mechanisms controlled by these receptors to decrease stimulated dopamine release. The effect of NMDA was unchanged by in vivo pretreatment with phencyclidine (twice daily for 5 days), with a washout period of at least 7 days before experimentation, which supports the hypothesis that there is no enduring direct effect of PCP at NMDA receptors after this pretreatment procedure. We propose that NMDA depression of accumbal dopamine release is mediated by metabotropic glutamate receptors located pre- or perisynaptically, and suggest that NMDA evoked increased extrasynaptic spillover of glutamate is sufficient to activate these receptors that, in turn, inhibit dopamine release. Furthermore, we suggest that enduring functional changes brought about by subchronic phencyclidine pretreatment, modeling deficits in schizophrenia, are downstream effects consequent on chronic blockade of NMDA receptors, rather than direct effects on NMDA receptors themselves.

Amphetamine regulation of acetylcholine and gamma-aminobutyric acid in nucleus accumbens.

PubMed

Lindefors, N; Hurd, Y L; O'Connor, W T; Brené, S; Persson, H; Ungerstedt, U

1992-01-01

In situ hybridization histochemistry and in vivo microdialysis were combined to study the effect of amphetamine on the expression of choline acetyltransferase and glutamate decarboxylase67 mRNA and in vivo release of acetylcholine and GABA in rat medial nucleus accumbens. Differential effects on acetylcholine and GABA neurons by a single challenge injection of amphetamine (1.5 mg/kg, s.c.) were apparent in saline-pretreated and amphetamine-pretreated (same dose, twice daily for the previous seven days) rats. Extracellular acetylcholine levels were increased up to 50% over a prolonged period following both single and repeated amphetamine. In contrast, extracellular concentrations of GABA were gradually decreased to half the control values, but only in rats receiving repeated amphetamine. Although the increase of acetylcholine release was not associated with any change in choline acetyltransferase mRNA levels, the number of neurons expressing high levels of glutamate decarboxylase67 mRNA was decreased (28%) following repeated injections. Thus we suggest that amphetamine decreases extracellular GABA levels by a slow mechanism, associated with the decreased expression of glutamate decarboxylase67 mRNA in a subpopulation of densely labeled neurons in the medial nucleus accumbens. The delayed response by GABA to amphetamine may reflect supersensitivity in the activity of postsynaptic gamma-aminobutyric acid-containing neurons in nucleus accumbens as a consequence of the repeated amphetamine treatment.

Effects of input processing and type of personal frequency modulation system on speech-recognition performance of adults with cochlear implants.

PubMed

Wolfe, Jace; Schafer, Erin; Parkinson, Aaron; John, Andrew; Hudson, Mary; Wheeler, Julie; Mucci, Angie

2013-01-01

The objective of this study was to compare speech recognition in quiet and in noise for cochlear implant recipients using two different types of personal frequency modulation (FM) systems (directly coupled [direct auditory input] versus induction neckloop) with each of two sound processors (Cochlear Nucleus Freedom versus Cochlear Nucleus 5). Two different experiments were conducted within this study. In both these experiments, mixing of the FM signal within the Freedom processor was implemented via the same scheme used clinically for the Freedom sound processor. In Experiment 1, the aforementioned comparisons were conducted with the Nucleus 5 programmed so that the microphone and FM signals were mixed and then the mixed signals were subjected to autosensitivity control (ASC). In Experiment 2, comparisons between the two FM systems and processors were conducted again with the Nucleus 5 programmed to provide a more complex multistage implementation of ASC during the preprocessing stage. This study was a within-subject, repeated-measures design. Subjects were recruited from the patient population at the Hearts for Hearing Foundation in Oklahoma City, OK. Fifteen subjects participated in Experiment 1, and 16 subjects participated in Experiment 2. Subjects were adults who had used either unilateral or bilateral cochlear implants for at least 1 year. In this experiment, no differences were found in speech recognition in quiet obtained with the two different FM systems or the various sound-processor conditions. With each sound processor, speech recognition in noise was better with the directly coupled direct auditory input system relative to the neckloop system. The multistage ASC processing of the Nucleus 5 sound processor provided better performance than the single-stage approach for the Nucleus 5 and the Nucleus Freedom sound processor. Speech recognition in noise is substantially affected by the type of sound processor, FM system, and implementation of ASC used by a Cochlear implant recipient.

Dynamic, mechanical integration between nucleus and cell- where physics meets biology.

PubMed

Dickinson, Richard B; Neelam, Srujana; Lele, Tanmay P

2015-01-01

Nuclear motions like rotation, translation and deformation suggest that the nucleus is acted upon by mechanical forces. Molecular linkages with the cytoskeleton are thought to transfer forces to the nuclear surface. We developed an approach to apply reproducible, known mechanical forces to the nucleus in spread adherent cells and quantified the elastic response of the mechanically integrated nucleus-cell. The method is sensitive to molecular perturbations and revealed new insight into the function of the LINC complex. While these experiments revealed elastic behaviors, turnover of the cytoskeleton by assembly/disassembly and binding/unbinding of linkages are expected to dissipate any stored mechanical energy in the nucleus or the cytoskeleton. Experiments investigating nuclear forces over longer time scales demonstrated the mechanical principle that expansive/compressive stresses on the nuclear surface arise from the movement of the cell boundaries to shape and position the nucleus. Such forces can shape the nucleus to conform to cell shapes during cell movements with or without myosin activity.

Dynamic, mechanical integration between nucleus and cell- where physics meets biology

PubMed Central

Dickinson, Richard B; Neelam, Srujana; Lele, Tanmay P

2015-01-01

Nuclear motions like rotation, translation and deformation suggest that the nucleus is acted upon by mechanical forces. Molecular linkages with the cytoskeleton are thought to transfer forces to the nuclear surface. We developed an approach to apply reproducible, known mechanical forces to the nucleus in spread adherent cells and quantified the elastic response of the mechanically integrated nucleus-cell. The method is sensitive to molecular perturbations and revealed new insight into the function of the LINC complex. While these experiments revealed elastic behaviors, turnover of the cytoskeleton by assembly/disassembly and binding/unbinding of linkages are expected to dissipate any stored mechanical energy in the nucleus or the cytoskeleton. Experiments investigating nuclear forces over longer time scales demonstrated the mechanical principle that expansive/compressive stresses on the nuclear surface arise from the movement of the cell boundaries to shape and position the nucleus. Such forces can shape the nucleus to conform to cell shapes during cell movements with or without myosin activity. PMID:26338356

Direct observation of nanoparticle-cancer cell nucleus interactions.

PubMed

Dam, Duncan Hieu M; Lee, Jung Heon; Sisco, Patrick N; Co, Dick T; Zhang, Ming; Wasielewski, Michael R; Odom, Teri W

2012-04-24

We report the direct visualization of interactions between drug-loaded nanoparticles and the cancer cell nucleus. Nanoconstructs composed of nucleolin-specific aptamers and gold nanostars were actively transported to the nucleus and induced major changes to the nuclear phenotype via nuclear envelope invaginations near the site of the construct. The number of local deformations could be increased by ultrafast, light-triggered release of the aptamers from the surface of the gold nanostars. Cancer cells with more nuclear envelope folding showed increased caspase 3 and 7 activity (apoptosis) as well as decreased cell viability. This newly revealed correlation between drug-induced changes in nuclear phenotype and increased therapeutic efficacy could provide new insight for nuclear-targeted cancer therapy.

Role of fructose and fructokinase in acute dehydration-induced vasopressin gene expression and secretion in mice

PubMed Central

Roncal-Jimenez, Carlos A.; Lanaspa-Garcia, Miguel A.; Oppelt, Sarah A.; Kuwabara, Masanari; Jensen, Thomas; Milagres, Tamara; Andres-Hernando, Ana; Ishimoto, Takuji; Garcia, Gabriela E.; Johnson, Ginger; MacLean, Paul S.; Sanchez-Lozada, Laura-Gabriela; Tolan, Dean R.; Johnson, Richard J.

2016-01-01

Fructose stimulates vasopressin in humans and can be generated endogenously by activation of the polyol pathway with hyperosmolarity. We hypothesized that fructose metabolism in the hypothalamus might partly control vasopressin responses after acute dehydration. Wild-type and fructokinase-knockout mice were deprived of water for 24 h. The supraoptic nucleus was evaluated for vasopressin and markers of the aldose reductase-fructokinase pathway. The posterior pituitary vasopressin and serum copeptin levels were examined. Hypothalamic explants were evaluated for vasopressin secretion in response to exogenous fructose. Water restriction increased serum and urine osmolality and serum copeptin in both groups of mice, although the increase in copeptin in wild-type mice was larger than that in fructokinase-knockout mice. Water-restricted, wild-type mice showed an increase in vasopressin and aldose reductase mRNA, sorbitol, fructose and uric acid in the supraoptic nucleus. In contrast, fructokinase-knockout mice showed no change in vasopressin or aldose reductase mRNA, and no changes in sorbitol or uric acid, although fructose levels increased. With water restriction, vasopressin in the pituitary of wild-type mice was significantly less than that of fructokinase-knockout mice, indicating that fructokinase-driven vasopressin secretion overrode synthesis. Fructose increased vasopressin release in hypothalamic explants that was not observed in fructokinase-knockout mice. In situ hybridization documented fructokinase mRNA in the supraoptic nucleus, paraventricular nucleus and suprachiasmatic nucleus. Acute dehydration activates the aldose reductase-fructokinase pathway in the hypothalamus and partly drives the vasopressin response. Exogenous fructose increases vasopressin release in hypothalamic explants dependent on fructokinase. Nevertheless, circulating vasopressin is maintained and urinary concentrating is not impaired. NEW & NOTEWORTHY This study increases our understanding of the mechanisms leading to vasopressin release under conditions of water restriction (acute dehydration). Specifically, these studies suggest that the aldose reductase-fructokinase pathways may be involved in vasopressin synthesis in the hypothalamus and secretion by the pituitary in response to acute dehydration. Nevertheless, mice undergoing water restriction remain capable of maintaining sufficient vasopressin (copeptin) levels to allow normal urinary concentration. Further studies of the aldose reductase-fructokinase system in vasopressin regulation appear indicated. PMID:27852737

Role of fructose and fructokinase in acute dehydration-induced vasopressin gene expression and secretion in mice.

PubMed

Song 宋志林, Zhilin; Roncal-Jimenez, Carlos A; Lanaspa-Garcia, Miguel A; Oppelt, Sarah A; Kuwabara, Masanari; Jensen, Thomas; Milagres, Tamara; Andres-Hernando, Ana; Ishimoto, Takuji; Garcia, Gabriela E; Johnson, Ginger; MacLean, Paul S; Sanchez-Lozada, Laura-Gabriela; Tolan, Dean R; Johnson, Richard J

2017-02-01

Fructose stimulates vasopressin in humans and can be generated endogenously by activation of the polyol pathway with hyperosmolarity. We hypothesized that fructose metabolism in the hypothalamus might partly control vasopressin responses after acute dehydration. Wild-type and fructokinase-knockout mice were deprived of water for 24 h. The supraoptic nucleus was evaluated for vasopressin and markers of the aldose reductase-fructokinase pathway. The posterior pituitary vasopressin and serum copeptin levels were examined. Hypothalamic explants were evaluated for vasopressin secretion in response to exogenous fructose. Water restriction increased serum and urine osmolality and serum copeptin in both groups of mice, although the increase in copeptin in wild-type mice was larger than that in fructokinase-knockout mice. Water-restricted, wild-type mice showed an increase in vasopressin and aldose reductase mRNA, sorbitol, fructose and uric acid in the supraoptic nucleus. In contrast, fructokinase-knockout mice showed no change in vasopressin or aldose reductase mRNA, and no changes in sorbitol or uric acid, although fructose levels increased. With water restriction, vasopressin in the pituitary of wild-type mice was significantly less than that of fructokinase-knockout mice, indicating that fructokinase-driven vasopressin secretion overrode synthesis. Fructose increased vasopressin release in hypothalamic explants that was not observed in fructokinase-knockout mice. In situ hybridization documented fructokinase mRNA in the supraoptic nucleus, paraventricular nucleus and suprachiasmatic nucleus. Acute dehydration activates the aldose reductase-fructokinase pathway in the hypothalamus and partly drives the vasopressin response. Exogenous fructose increases vasopressin release in hypothalamic explants dependent on fructokinase. Nevertheless, circulating vasopressin is maintained and urinary concentrating is not impaired. This study increases our understanding of the mechanisms leading to vasopressin release under conditions of water restriction (acute dehydration). Specifically, these studies suggest that the aldose reductase-fructokinase pathways may be involved in vasopressin synthesis in the hypothalamus and secretion by the pituitary in response to acute dehydration. Nevertheless, mice undergoing water restriction remain capable of maintaining sufficient vasopressin (copeptin) levels to allow normal urinary concentration. Further studies of the aldose reductase-fructokinase system in vasopressin regulation appear indicated. Copyright © 2017 the American Physiological Society.

Nucleus accumbens hyperpolarization-activated cyclic nucleotide-gated channels modulate methamphetamine self-administration in rats.

PubMed

Cao, Dan-Ni; Song, Rui; Zhang, Shu-Zhuo; Wu, Ning; Li, Jin

2016-08-01

Methamphetamine addiction is believed to primarily result from increased dopamine release and the inhibition of dopamine uptake. Some evidence suggests that hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play important roles in the functional modulation of dopaminergic neurons and the pathophysiology of related diseases. However, little is known about the effects of HCN channels on methamphetamine addiction. The present study investigated the role of brain HCN channels in methamphetamine addiction. Acute intracerebroventricular (i.c.v.) injection or bilateral intra-accumbens microinjections of non-selective HCN channel blocker ZD7288 (0.3125 and 0.625 μg) significantly reduced both methamphetamine (0.0125 or 0.05 mg/kg/infusion)-induced self-administration under fixed ratio 2 reinforcement and the breakpoint of methamphetamine (0.05 mg/kg/infusion) under progressive ratio reinforcement in rats. Moreover, compared with i.c.v. injection, bilateral intra-accumbens microinjections of ZD7288 exerted stronger inhibitory effects, suggesting that blockade of HCN channels in the nucleus accumbens reduced the reinforcing effects of and motivation for methamphetamine. We also found that ZD7288 (0.625 and 1.25 μg, i.c.v.) significantly decreased methamphetamine (1 mg/kg, intraperitoneal (i.p.))-induced hyperactivity with no effect on the spontaneous activity in rats. Finally, in vivo microdialysis experiments showed that the HCN channel blockade using ZD7288 (0.625 and 1.25 μg, i.c.v.) decreased methamphetamine (1 mg/kg, i.p.)-induced elevation of extracellular dopamine levels in the nucleus accumbens. These results indicate that HCN channels in the nucleus accumbens are involved in the reinforcing properties of methamphetamine and highlight the importance of HCN channels in the regulation of dopamine neurotransmission underlying methamphetamine addiction.

Suckling induced activation pattern in the brain of rat pups.

PubMed

Barna, János; Renner, Eva; Arszovszki, Antónia; Cservenák, Melinda; Kovács, Zsolt; Palkovits, Miklós; Dobolyi, Arpád

2018-06-01

The aim of the study was to understand the effects of suckling on the brain of the pups by mapping their brain activation pattern in response to suckling. The c-fos method was applied to identify activated neurons. Fasted rat pups were returned to their mothers for suckling and sacrificed 2 hours later for Fos immunohistochemistry. Double labeling was also performed to characterize some of the activated neurons. For comparison, another group of fasted pups were given dry food before Fos mapping. After suckling, we found an increase in the number of Fos-immunoreactive neurons in the insular and somatosensory cortices, central amygdaloid nucleus (CAm), paraventricular (PVN) and supraoptic hypothalamic nuclei, lateral parabrachial nucleus (LPB), nucleus of the solitary tract (NTS), and the area postrema. Double labeling experiments demonstrated the activation of calcitonin gene-related peptide-ir (CGRP-ir) neurons in the LPB, corticotropin-releasing hormone-ir (CRH-ir) but not oxytocin-ir neurons in the PVN, and noradrenergic neurons in the NTS. In the CAm, Fos-ir neurons did not contain CRH but were apposed to CGRP-ir fiber terminals. Refeeding with dry food-induced Fos activation in all brain areas activated by suckling. The degree of activation was higher following dry food consumption than suckling in the insular cortex, and lower in the supraoptic nucleus and the NTS. Furthermore, the accumbens, arcuate, and dorsomedial hypothalamic nuclei, and the lateral hypothalamic area, which were not activated by suckling, showed activation by dry food. Neurons in a number of brain areas are activated during suckling, and may participate in the signaling of satiety, taste perception, reward, food, and salt balance regulation.

A mechanistic hypothesis of the factors that enhance vulnerability to nicotine use in females

PubMed Central

O'Dell, Laura E.; Torres, Oscar V.

2013-01-01

Women are particularly more vulnerable to tobacco use than men. This review proposes a unifying hypothesis that females experience greater rewarding effects of nicotine and more intense stress produced by withdrawal than males. We also provide a neural framework whereby estrogen promotes greater rewarding effects of nicotine in females via enhanced dopamine release in the nucleus accumbens (NAcc). During withdrawal, we suggest that corticotropin-releasing factor (CRF) stress systems are sensitized and promote a greater suppression of dopamine release in the NAcc of females versus males. Taken together, females display enhanced nicotine reward via estrogen and amplified effects of withdrawal via stress systems. Although this framework focuses on sex differences in adult rats, it is also applied to adolescent females who display enhanced rewarding effects of nicotine, but reduced effects of withdrawal from this drug. Since females experience strong rewarding effects of nicotine, a clinical implication of our hypothesis is that specific strategies to prevent smoking initiation among females are critical. Also, anxiolytic medications may be more effective in females that experience intense stress during withdrawal. Furthermore, medications that target withdrawal should not be applied in a unilateral manner across age and sex, given that nicotine withdrawal is lower during adolescence. This review highlights key factors that promote nicotine use in females, and future studies on sex-dependent interactions of stress and reward systems are needed to test our mechanistic hypotheses. Future studies in this area will have important translational value toward reducing health disparities produced by nicotine use in females. PMID:23684991

Characterization of In Vitro Release of Neurochemicals from the Intermediate Area of the Rat Thoracic Spinal Cord: Regulation by Coexisting Neurochemical and Presynaptic Autoreceptors

DTIC Science & Technology

1995-06-16

university of the Health Sciences ABSTRACT serotonin (5-HT), substance P (SP), neurokinin A (NKA) and thyrotropin-releasing hormone (TRH) coexist in the...intermediolateral cell column IML pars funiculars IML pars principal is immunoreactivity mean arterial pressure neurokinin A neurokinin B nucleus tractus...thyrotropin-releasing hormone (TRH) and neurokinin A (NKA) coexist in these IML-projecting neurons. We propose that each of these colocalized

Prenatal glucocorticoid programming of brain corticosteroid receptors and corticotrophin-releasing hormone: possible implications for behaviour.

PubMed

Welberg, L A; Seckl, J R; Holmes, M C

2001-01-01

Glucocorticoids may underlie the association between low birth weight and adult disorders such as hypertension, type 2 diabetes and affective dysfunction. We investigated the behavioural and molecular consequences of two paradigms of prenatal dexamethasone administration in rats. Rats received dexamethasone (100 microg/kg per day) throughout pregnancy (DEX1-3), in the last third of pregnancy only (DEX3) or vehicle. Both dexamethasone treatments reduced birth weight, only DEX1-3 offspring had reduced body weight in adulthood. In adult offspring, both prenatal dexamethasone paradigms reduced exploratory behaviour in an open field. In contrast, only DEX3 reduced exploration in an elevated plus-maze and impaired behavioural responses and learning in a forced-swim test. This behavioural inhibition may reflect increased baseline corticotrophin-releasing hormone mRNA levels (30% higher) in the central nucleus of the amygdala in both dexamethasone-exposed groups. Adult DEX3 offspring also showed increased corticotrophin-releasing hormone mRNA with unaltered glucocorticoid receptor mRNA in the hypothalamic paraventricular nucleus and reduced hippocampal glucocorticoid- and mineralocorticoid receptor mRNA expression, suggesting reduced hippocampal sensitivity to glucocorticoid suppression of the stress axis. In contrast, DEX1-3 rats had no changes in hippocampal corticosteroid receptors, but showed increased mRNA levels for both receptors in the basolateral nucleus of the amygdala. From this data we suggest that prenatal glucocorticoid exposure programs behavioural inhibition perhaps via increased amygdalar corticotrophin-releasing hormone levels, while DEX3 also impairs coping and learning in aversive situations, possibly via altered hippocampal corticosteroid receptor levels. Overexposure to glucocorticoids, especially late in gestation, may explain the link between reduced early growth and adult affective dysfunction.

METHAMPHETAMINE-INDUCED DOPAMINE TERMINAL DEFICITS IN THE NUCLEUS ACCUMBENS ARE EXACERBATED BY REWARD-ASSOCIATED CUES AND ATTENUATED BY CB1 RECEPTOR ANTAGONISM

PubMed Central

Loewinger, Gabriel C.; Beckert, Michael V.; Tejeda, Hugo A.; Cheer, Joseph F.

2012-01-01

Methamphetamine (METH) exposure is primarily associated with deleterious effects to dopaminergic neurons. While several studies have implicated the endocannabinoid system in METH’s locomotor, rewarding and neurochemical effects, a role for this signaling system in METH’s effects on dopamine terminal dynamics has not been elucidated. Given that CB1 receptor blockade reduces the acute potentiation of phasic extracellular dopamine release from other psychomotor stimulant drugs and that the degree of acute METH-induced increases in extracellular dopamine levels is related to the severity of dopamine depletion, we predicted that pretreatment with the CB1 receptor antagonist rimonabant would reduce METH-induced alterations at dopamine terminals. Furthermore, we hypothesized that administration of METH in environments where reward associated-cues were present would potentiate METH’s acute effects on dopamine release in the nucleus accumbens and exacerbate changes in dopamine terminal activity. Fast-scan cyclic voltammetry was used to measure electrically-evoked dopamine release in the nucleus accumbens and revealed markers of compromised dopamine terminal integrity nine days after a single dose of METH. These were exacerbated in animals that received METH in the presence of reward-associated cues, and attenuated in rimonabant-pretreated animals. While these deficits in dopamine dynamics were associated with reduced operant responding on days following METH administration in animals treated with only METH, rimonabant-pretreated animals exhibited levels of operant responding comparable to control. Moreover, dopamine release correlated significantly with changes in lever pressing behavior that occurred on days following METH administration. Together these data suggest that the endocannabinoid system is involved in the subsecond dopaminergic response to METH. PMID:22306525

The distribution of substance P and kisspeptin in the mediobasal hypothalamus of the male rhesus monkey and a comparison of intravenous administration of these peptides to release GnRH as reflected by LH secretion

PubMed Central

Kalil, Bruna; Ramaswamy, Suresh; Plant, Tony M.

2016-01-01

Substance P (SP) was recently reported to be expressed in human KNDy neurons and to enhance KNDy neuron excitability in the mouse hypothalamus. We therefore examined 1) interactions of SP and kisspeptin in the mediobasal hypothalamus of adult male rhesus monkeys using immunofluorescence, and 2) the ability of SP to induce LH release in GnRH primed, agonadal juvenile male monkeys. SP cell bodies were observed only occasionally in the arcuate nucleus (Arc), but more frequently dorsal to the Arc in the region of the pre-mammilary nucleus. Castration resulted in an increase in the number of SP cell bodies in the Arc but not in the other nuclei. SP fibers innervated the Arc where they were found in close apposition with kisspeptin perikarya in the periphery of this nucleus. Beaded SP axons projected to the median eminence where they terminated in the external layer and intermingled with beaded kisspeptin axons. Colocalization of the two peptides, however, was not observed. Although close apposition between SP fibers and kisspeptin neurons suggest a role for SP in modulating GnRH pulse generator activity, iv injections of SP failed to elicit release of GnRH (as reflected by LH) in the juvenile monkey. Although the finding of structural interactions between SP and kisspeptin neurons are consistent with the notion that this tachykinin may be involved in regulating pulsatile GnRH release, the apparent absence of expression of SP in KNDy neurons suggests that this peptide is unlikely to be a fundamental component of the primate GnRH pulse generator. PMID:26580201

Presence of corticotrophin-releasing factor and/or tyrosine hydroxylase in cells of a neural brain-testicular pathway that are labelled by a transganglionic tracer.

PubMed

James, P; Rivier, C; Lee, S

2008-02-01

Our laboratory has shown that male testosterone levels are not solely controlled by the release of hypothalamic gonadotrophin-releasing hormone and pituitary luteinising hormone, but are also regulated by a multisynaptic pathway connecting the brain and the testis that interferes with the testosterone response to gonadotrophins. This pathway, which is independent of the pituitary gland, is activated by an i.c.v. injection of either the stress-related peptide corticotrophin-releasing factor (CRF) or of beta-adrenoceptor agonists, both of which alter androgen release and decrease levels of the peripheral-type benzodiazepine receptor and the steroidogenic acute regulatory protein within Leydig cells. Our original studies used the retrograde transganglionic tracer pseudorabies virus (PRV) to map progression of the virus from the testes to upper brain levels. The present study aimed to extend this work by identifying the regions where CRF and catecholamine neurones represented components of the stress-activated, brain-testicular pathway that prevents testosterone increases. To this end, anaesthetised adult male rats received an intra-testicular injection of PRV. Using immunofluorescence, we identified co-labelling of PRV and either CRF or tyrosine hydroxylase (TH), the enzyme responsible for biogenic amine synthesis. Co-labelling of PRV and CRF was found in the bed nucleus of the stria terminalis, the paraventricular nucleus of the hypothalamus (PVN) and the central amygdala. Co-labelling of PRV and TH was found in the PVN, substantia nigra, A7/Kölliker-Fuse area, area of A5, locus coeruleus, nucleus of solitary tract, area of C3, area of C2 and the area of C1/A1. These results indicate that most cell groups of the ventral noradrenergic pathway have neurones that are a part of the brain-testicular pathway. This suggests that the stress hormones CRF and catecholamines may act as neurotransmitters that signal the pathway to inhibit increases in plasma testosterone levels.

Leptin inhibits and ghrelin augments hypothalamic noradrenaline release after stress.

PubMed

Kawakami, Akio; Okada, Nobukazu; Rokkaku, Kumiko; Honda, Kazufumi; Ishibashi, Shun; Onaka, Tatsushi

2008-09-01

Metabolic conditions affect hypothalamo-pituitary-adrenal responses to stressful stimuli. Here we examined effects of food deprivation, leptin and ghrelin upon noradrenaline release in the hypothalamic paraventricular nucleus (PVN) and plasma adrenocorticotropic hormone (ACTH) concentrations after stressful stimuli. Food deprivation augmented both noradrenaline release in the PVN and the increase in plasma ACTH concentration following electrical footshocks (FSs). An intracerebroventricular injection of leptin attenuated the increases in hypothalamic noradrenaline release and plasma ACTH concentrations after FSs, while ghrelin augmented these responses. These data suggest that leptin inhibits and ghrelin facilitates neuroendocrine stress responses via noradrenaline release and indicate that a decrease in leptin and an increase in ghrelin release after food deprivation might contribute to augmentation of stress-induced ACTH release in a fasting state.

Continuous nucleus extraction by optically-induced cell lysis on a batch-type microfluidic platform.

PubMed

Huang, Shih-Hsuan; Hung, Lien-Yu; Lee, Gwo-Bin

2016-04-21

The extraction of a cell's nucleus is an essential technique required for a number of procedures, such as disease diagnosis, genetic replication, and animal cloning. However, existing nucleus extraction techniques are relatively inefficient and labor-intensive. Therefore, this study presents an innovative, microfluidics-based approach featuring optically-induced cell lysis (OICL) for nucleus extraction and collection in an automatic format. In comparison to previous micro-devices designed for nucleus extraction, the new OICL device designed herein is superior in terms of flexibility, selectivity, and efficiency. To facilitate this OICL module for continuous nucleus extraction, we further integrated an optically-induced dielectrophoresis (ODEP) module with the OICL device within the microfluidic chip. This on-chip integration circumvents the need for highly trained personnel and expensive, cumbersome equipment. Specifically, this microfluidic system automates four steps by 1) automatically focusing and transporting cells, 2) releasing the nuclei on the OICL module, 3) isolating the nuclei on the ODEP module, and 4) collecting the nuclei in the outlet chamber. The efficiency of cell membrane lysis and the ODEP nucleus separation was measured to be 78.04 ± 5.70% and 80.90 ± 5.98%, respectively, leading to an overall nucleus extraction efficiency of 58.21 ± 2.21%. These results demonstrate that this microfluidics-based system can successfully perform nucleus extraction, and the integrated platform is therefore promising in cell fusion technology with the goal of achieving genetic replication, or even animal cloning, in the near future.

Urocortin 3 modulates social discrimination abilities via corticotropin-releasing hormone receptor type 2.

PubMed

Deussing, Jan M; Breu, Johannes; Kühne, Claudia; Kallnik, Magdalena; Bunck, Mirjam; Glasl, Lisa; Yen, Yi-Chun; Schmidt, Mathias V; Zurmühlen, Regine; Vogl, Annette M; Gailus-Durner, Valérie; Fuchs, Helmut; Hölter, Sabine M; Wotjak, Carsten T; Landgraf, Rainer; de Angelis, Martin Hrabé; Holsboer, Florian; Wurst, Wolfgang

2010-07-07

Urocortin 3 (UCN3) is strongly expressed in specific nuclei of the rodent brain, at sites distinct from those expressing urocortin 1 and urocortin 2, the other endogenous ligands of corticotropin-releasing hormone receptor type 2 (CRH-R2). To determine the physiological role of UCN3, we generated UCN3-deficient mice, in which the UCN3 open reading frame was replaced by a tau-lacZ reporter gene. By means of this reporter gene, the nucleus parabrachialis and the premammillary nucleus were identified as previously unknown sites of UCN3 expression. Additionally, the introduced reporter gene enabled the visualization of axonal projections of UCN3-expressing neurons from the superior paraolivary nucleus to the inferior colliculus and from the posterodorsal part of the medial amygdala to the principal nucleus of the bed nucleus of the stria terminalis, respectively. The examination of tau-lacZ reporter gene activity throughout the brain underscored a predominant expression of UCN3 in nuclei functionally connected to the accessory olfactory system. Male and female mice were comprehensively phenotyped but none of the applied tests provided indications for a role of UCN3 in the context of hypothalamic-pituitary-adrenocortical axis regulation, anxiety- or depression-related behavior. However, inspired by the prevalent expression throughout the accessory olfactory system, we identified alterations in social discrimination abilities of male and female UCN3 knock-out mice that were also present in male CRH-R2 knock-out mice. In conclusion, our results suggest a novel role for UCN3 and CRH-R2 related to the processing of social cues and to the establishment of social memories.

Bubbling cell death: A hot air balloon released from the nucleus in the cold.

PubMed

Chang, Nan-Shan

2016-06-01

Cell death emanating from the nucleus is largely unknown. In our recent study, we determined that when temperature is lowered in the surrounding environment, apoptosis stops and bubbling cell death (BCD) occurs. The study concerns the severity of frostbite. When exposed to severe cold and strong ultraviolet (UV) irradiation, people may suffer serious damages to the skin and internal organs. This ultimately leads to limb amputations, organ failure, and death. BCD is defined as "formation of a single bubble from the nucleus per cell and release of this swelling bubble from the cell surface to extracellular space that causes cell death." When cells are subjected to UV irradiation and/or brief cold shock (4℃ for 5 min) and then incubated at room temperature or 4℃ for time-lapse microscopy, each cell releases an enlarging nuclear gas bubble containing nitric oxide. Certain cells may simultaneously eject hundreds or thousands of exosome-like particles. Unlike apoptosis, no phosphatidylserine flip-over, mitochondrial apoptosis, damage to Golgi complex, and chromosomal DNA fragmentation are shown in BCD. When the temperature is increased back at 37℃, bubble formation stops and apoptosis restarts. Mechanistically, proapoptotic WW domain-containing oxidoreductase and p53 block the protective TNF receptor adaptor factor 2 that allows nitric oxide synthase 2 to synthesize nitric oxide and bubble formation. In this mini-review, updated knowledge in cell death and the proposed molecular mechanism for BCD are provided. © 2016 by the Society for Experimental Biology and Medicine.

Bubbling cell death: A hot air balloon released from the nucleus in the cold

PubMed Central

2016-01-01

Cell death emanating from the nucleus is largely unknown. In our recent study, we determined that when temperature is lowered in the surrounding environment, apoptosis stops and bubbling cell death (BCD) occurs. The study concerns the severity of frostbite. When exposed to severe cold and strong ultraviolet (UV) irradiation, people may suffer serious damages to the skin and internal organs. This ultimately leads to limb amputations, organ failure, and death. BCD is defined as “formation of a single bubble from the nucleus per cell and release of this swelling bubble from the cell surface to extracellular space that causes cell death.” When cells are subjected to UV irradiation and/or brief cold shock (4℃ for 5 min) and then incubated at room temperature or 4℃ for time-lapse microscopy, each cell releases an enlarging nuclear gas bubble containing nitric oxide. Certain cells may simultaneously eject hundreds or thousands of exosome-like particles. Unlike apoptosis, no phosphatidylserine flip-over, mitochondrial apoptosis, damage to Golgi complex, and chromosomal DNA fragmentation are shown in BCD. When the temperature is increased back at 37℃, bubble formation stops and apoptosis restarts. Mechanistically, proapoptotic WW domain-containing oxidoreductase and p53 block the protective TNF receptor adaptor factor 2 that allows nitric oxide synthase 2 to synthesize nitric oxide and bubble formation. In this mini-review, updated knowledge in cell death and the proposed molecular mechanism for BCD are provided. PMID:27075929

Utility of a tripolar stimulating electrode for eliciting dopamine release in the rat striatum.

PubMed

Bergstrom, B P; Garris, P A

1999-03-01

The present study evaluated tripolar stimulating electrodes for eliciting dopamine release in the rat brain in vivo. Stimulating electrodes were placed either in the medial forebrain bundle or in the ventral mesencephalon associated with the ventral tegmental area and substantia nigra. The concentration of extracellular dopamine was monitored in dopamine terminal fields at 100-ms intervals using fast-scan cyclic voltammetry at carbon-fiber microelectrodes. To characterize the stimulated area, recordings were collected in several striatal regions including the caudate putamen and the core and shell of the nucleus accumbens. The tripolar electrode was equally effective in stimulating dopamine release in medial and lateral regions of the striatum. In contrast, responses evoked by a bipolar electrode were typically greater in one mediolateral edge versus the other. The added size of the tripolar electrode did not appear to cause complications as signals were stable over the course of the experiment (3 h). Subsets of mesostriatal dopamine neurons could also be selectively activated using the tripolar electrode in excellent agreement with previously described topography. Taken together, these results suggested that the tripolar stimulating electrode is well suited for studying the regulation of midbrain dopamine neurons in vivo.

Relativistic Hydrodynamics for Heavy-Ion Collisions

ERIC Educational Resources Information Center

Ollitrault, Jean-Yves

2008-01-01

Relativistic hydrodynamics is essential to our current understanding of nucleus-nucleus collisions at ultrarelativistic energies (current experiments at the Relativistic Heavy Ion Collider, forthcoming experiments at the CERN Large Hadron Collider). This is an introduction to relativistic hydrodynamics for graduate students. It includes a detailed…

Interactions of Stress and CRF in Ethanol-Withdrawal Induced Anxiety in Adolescent and Adult Rats

PubMed Central

Wills, Tiffany A.; Knapp, Darin J.; Overstreet, David H.; Breese, George R.

2010-01-01

Background Repeated stress or administration of corticotropin-releasing factor (CRF) prior to ethanol exposure sensitizes anxiety-like behavior in adult rats. Current experiments determined whether adolescent rats were more sensitive to these challenges in sensitizing ethanol withdrawal-induced anxiety and altering CRF levels in brain during withdrawal. Methods Male adult and adolescent Sprague–Dawley rats were restraint stressed (1 hour) twice 1 week apart prior to a single 5-day cycle of ethanol diet (ED; stress/withdrawal paradigm). Other rats received control diet (CD) and three 1-hour restraint stress sessions. Rats were then tested 5, 24, or 48 hours after the final withdrawal for anxiety-like behavior in the social interaction (SI) test. In other experiments, adolescent rats were given two microinjections of CRF icv 1 week apart followed by 5-days of either CD or ED and tested in social interaction 5 hours into withdrawal. Finally, CRF immunoreactivity was measured in the central nucleus of the amygdala (CeA) and paraventricular nucleus (PVN) after rats experienced control diet, repeated ethanol withdrawals, or stress/withdrawal. Results Rats of both ages had reduced SI following the stress/withdrawal paradigm, and this effect recovered within 24 hours. Higher CRF doses were required to reduce SI in adolescents than previously reported in adults. CRF immunohistochemical levels were higher in the PVN and CeA of CD-exposed adolescents. In adolescent rats, repeated ethanol withdrawals decreased CRF in the CeA but was not associated with decreased CRF cell number. There was no change in CRF from adult treatments. Conclusions In the production of anxiety-like behavior, adolescent rats have equal sensitivity with stress and lower sensitivity with CRF compared to adults. Further, adolescents had higher basal levels of CRF within the PVN and CeA and reduced CRF levels following repeated ethanol withdrawals. This reduced CRF within the CeA could indicate increased release of CRF, and future work will determine how this change relates to behavior. PMID:20586753

Visualization of Oxytocin Release that Mediates Paired Pulse Facilitation in Hypothalamic Pathways to Brainstem Autonomic Neurons

PubMed Central

Piñol, Ramón A.; Jameson, Heather; Popratiloff, Anastas; Lee, Norman H.; Mendelowitz, David

2014-01-01

Recent work has shown that oxytocin is involved in more than lactation and uterine contraction. The paraventricular nucleus of the hypothalamus (PVN) contains neuroendocrine neurons that control the release of hormones, including vasopressin and oxytocin. Other populations of PVN neurons do not release hormones, but rather project to and release neurotransmitters onto other neurons in the CNS involved in fluid retention, thermoregulation, sexual behavior and responses to stress. Activation of oxytocin receptors can be cardioprotective and reduces the adverse cardiovascular consequences of anxiety and stress, yet how oxytocin can affect heart rate and cardiac function is unknown. While anatomical work has shown the presence of peptides, including oxytocin, in the projections from the PVN to parasympathetic nuclei, electrophysiological studies to date have only demonstrated release of glutamate and activation of fast ligand gated receptors in these pathways. In this study, using rats, we directly show, using sniffer CHO cells that express oxytocin receptors and the Ca2+ indicator R-GECO, that optogenetic activation of channelrhodopsin-2 (ChR2) expressing PVN fibers in the brainstem activates oxytocin receptors in the dorsomotor nucleus of the vagus (DMNV). We also demonstrate that while a single photoactivation of PVN terminals only activates glutamatergic receptors in brainstem cardiac vagal neurons (CVNs), neurons that dominate the neural control of heart rate, both the paired pulse facilitation, and sustained enhancement of glutamate release in this pathway is mediated by activation of oxytocin receptors. Our results provide direct evidence that a pathway from the PVN likely releases oxytocin and enhances short-term plasticity of this critical autonomic connection. PMID:25379676

Fluoxetine Alleviates Behavioral Depression while Decreasing Acetylcholine Release in the Nucleus Accumbens Shell

PubMed Central

Chau, David T; Rada, Pedro V; Kim, Kay; Kosloff, Rebecca A; Hoebel, Bartley G

2011-01-01

Selective serotonin reuptake inhibitors, such as fluoxetine, have demonstrated the ability to alleviate behavioral depression in the forced swim test; however, the sites and mechanisms of their actions remain to be further elucidated. Previous studies have suggested that behavioral depression in the swim test is mediated in part by acetylcholine (ACh) stimulating the cholinergic M1 receptors in the nucleus accumbens (NAc) shell. The current study tested whether acute, local, and chronic, subcutaneous fluoxetine treatments increase escape motivation during the swim test while simultaneously lowering extracellular ACh in the NAc shell. Experiment 1: Fluoxetine (1.0 mM) infused unilaterally in the NAc shell for 40 min reduced extracellular ACh while simultaneously increasing swimming time. Experiment 2: Fluoxetine (0.2, 0.5, and 0.75 mM) infused bilaterally in the NAc shell on day 3 dose-dependently decreased immobility and increased the total escape attempts (swimming and climbing) compared with Ringer given on day 2. Experiment 3: Fluoxetine (0.5 mM) infused bilaterally in the NAc for 40 min did not affect activities in an open field. Experiment 4: Chronic systemic fluoxetine treatment decreased immobility scores and increased total escape attempt scores compared with control saline treatment. In all, 14 days after the initial swim test, basal extracellular ACh in the shell was still elevated in the saline-treated group, but not in the fluoxetine-treated group. In summary, these data suggest that one of the potential mechanisms by which fluoxetine alleviates behavioral depression in the forced swim test may be to suppress cholinergic activities in the NAc shell. PMID:21525864

Direct Observation of Nanoparticle-Cancer Cell Nucleus Interactions

PubMed Central

Dam, Duncan Hieu M.; Lee, Jung Heon; Sisco, Patrick N.; Co, Dick T.; Zhang, Ming; Wasielewski, Michael R.; Odom, Teri W.

2012-01-01

We report the direct visualization of interactions between drug-loaded nanoparticles and the cancer cell nucleus. Nanoconstructs composed of nucleolin-specific aptamers and gold nanostars were actively transported to the nucleus and induced major changes to the nuclear phenotype via nuclear envelope invaginations near the site of the construct. The number of local deformations could be increased by ultra-fast, light-triggered release of the aptamers from the surface of the gold nanostars. Cancer cells with more nuclear envelope folding showed increased caspase 3 and 7 activity (apoptosis) as well as decreased cell viability. This newly revealed correlation between drug-induced changes in nuclear phenotype and increased therapeutic efficacy could provide new insight for nuclear-targeted cancer therapy. PMID:22424173

Neuronal calcium sensor-1 deletion in the mouse decreases motivation and dopamine release in the nucleus accumbens.

PubMed

Ng, Enoch; Varaschin, Rafael K; Su, Ping; Browne, Caleb J; Hermainski, Joanna; Le Foll, Bernard; Pongs, Olaf; Liu, Fang; Trudeau, Louis-Eric; Roder, John C; Wong, Albert H C

2016-03-15

Calcium sensors detect intracellular calcium changes and interact with downstream targets to regulate many functions. Neuronal Calcium Sensor-1 (NCS-1) or Frequenin is widely expressed in the nervous system, and involved in neurotransmission, synaptic plasticity and learning. NCS-1 interacts with and regulates dopamine D2 receptor (D2R) internalization and is implicated in disorders like schizophrenia and substance abuse. However, the role of NCS-1 in behaviors dependent on dopamine signaling in the striatum, where D2R is most highly expressed, is unknown. We show that Ncs-1 deletion in the mouse decreases willingness to work for food. Moreover, Ncs-1 knockout mice have significantly lower activity-dependent dopamine release in the nucleus accumbens core in acute slice recordings. In contrast, food preference, responding for conditioned reinforcement, ability to represent changes in reward value, and locomotor response to amphetamine are not impaired. These studies identify novel roles for NCS-1 in regulating activity-dependent striatal dopamine release and aspects of motivated behavior. Copyright © 2015 Elsevier B.V. All rights reserved.

Dynamics of neuromodulatory feedback determines frequency modulation in a reduced respiratory network: a computational study.

PubMed

Toporikova, Natalia; Butera, Robert J

2013-02-01

Neuromodulators, such as amines and neuropeptides, alter the activity of neurons and neuronal networks. In this work, we investigate how neuromodulators, which activate G(q)-protein second messenger systems, can modulate the bursting frequency of neurons in a critical portion of the respiratory neural network, the pre-Bötzinger complex (preBötC). These neurons are a vital part of the ponto-medullary neuronal network, which generates a stable respiratory rhythm whose frequency is regulated by neuromodulator release from the nearby Raphe nucleus. Using a simulated 50-cell network of excitatory preBötC neurons with a heterogeneous distribution of persistent sodium conductance and Ca(2+), we determined conditions for frequency modulation in such a network by simulating interaction between Raphe and preBötC nuclei. We found that the positive feedback between the Raphe excitability and preBötC activity induces frequency modulation in the preBötC neurons. In addition, the frequency of the respiratory rhythm can be regulated via phasic release of excitatory neuromodulators from the Raphe nucleus. We predict that the application of a G(q) antagonist will eliminate this frequency modulation by the Raphe and keep the network frequency constant and low. In contrast, application of a G(q) agonist will result in a high frequency for all levels of Raphe stimulation. Our modeling results also suggest that high [K(+)] requirement in respiratory brain slice experiments may serve as a compensatory mechanism for low neuromodulatory tone. Copyright © 2012 Elsevier B.V. All rights reserved.

Proton Therapy

MedlinePlus

... matter is made up of tiny particles called atoms. At the center of every atom is a nucleus, which holds two types of ... which is a nuclear reactor that can smash atoms to release proton, neutron, and helium ion beams. ...

Regulation of /sup 3/H-dopamine release by presynaptic GABA and glutamate heteroreceptors in rat brain nucleus accumbens synaptosomes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kovalev, G.I.; Hetey, L.

1987-06-01

The aim of this investigation was a neurochemical study of the effect of agonists of different types of GABA receptors - muscimol (type A receptor), baclofen (type B receptor), delta-aminolevulinic acid (DALA; GABA autoreceptor), and also of GABA itself - on tritium-labelled dopamine release, stimulated by potassium cations, from synaptosomes of the nuclei accumbenes of the rat brain.

Angiotensin II in the paraventricular nucleus stimulates sympathetic outflow to the cardiovascular system and make vasopressin release in rat.

PubMed

Khanmoradi, Mehrangiz; Nasimi, Ali

2016-10-06

The hypothalamic paraventricular nucleus (PVN) plays essential roles in neuroendocrine and autonomic functions, including cardiovascular regulation. It was shown that microinjection of angiotensin II (AngII) into the PVN produced a pressor response. In this study, we explored the probable mechanisms of this pressor response. AngII was microinjected into the PVN and cardiovascular responses were recorded. Then, the responses were re-tested after systemic injection of a ganglionic blocker, Hexamethonium, or a vasopressin V1 receptor blocker. Hexamethonium pretreatment (i.v.) greatly and significantly attenuated the pressor response to AngII, with no significant effect on heart rate, indicating that the sympathetic system is involved in the cardiovascular effect of AngII in the PVN. Systemic pretreatment (i.v.) with V1 antagonist greatly and significantly attenuated the pressor response to AngII, with no significant effect on heart rate, indicating that vasopressin release is involved in the cardiovascular effect of AngII in the PVN. Overall, we found that AngII microinjected into the PVN produced a pressor response mediated by the sympathetic system and vasopressin release, indicating that other than circulating AngII, endogenous AngII of the PVN increases the vasopressin release from the PVN. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Ion bombardment experiments suggesting an origin for organic particles in pre-cometary and cometary ices

NASA Technical Reports Server (NTRS)

Wdowiak, Thomas J.; Robinson, Edward L.; Flickinger, Gregory C.; Boyd, David A.

1989-01-01

During the Giotto and Vega encounters with Comet Halley both organic particles called CHON and energetic ions were detected. The acceleration of ions to hundreds of keV in the vicinity of the bow shock and near the nucleus may be a demonstration of a situation occurring in the early solar system (perhaps during the T Tauri stage) that led to the formation of organic particles only now released. Utilizing a Van de Graaff accelerator and a target chamber having cryogenic and mass spectrometer capabilities, frozen gases were bombarded at 10 K with 175 keV protons with the result that fluffy solid material remains after sublimation of the ice. Initial experiments were carried out with a gas mixture in parts of 170 carbon monoxide, 170 argon, 25 water, 20 nitrogen, and 15 methane formulated to reflect an interstellar composition in experiments involving the freezing out of the products of a plasma. The plasma experiments resulted in a varnish-like film residue that exhibited luminescence when excited with ultraviolet radiation, while the ion bombardment created particulate material that was not luminescent.

Spinodal assisted growing dynamics of critical nucleus in polymer blends

NASA Astrophysics Data System (ADS)

Zhang, Xinghua; Qi, Shuanhu; Yan, Dadong

2012-11-01

In metastable polymer blends, nonclassical critical nucleus is not a drop of stable phase in core wrapped with a sharp interface, but a diffuse structure depending on the metastability. Thus, forming a critical nucleus does not mean the birth of a new phase. In the present work, the nonclassical growing dynamics of the critical nucleus is addressed in the metastable polymer blends by incorporating self-consistent field theory and external potential dynamics theory, which leads to an intuitionistic description for the scattering experiments. The results suggest that the growth of nonclassical critical nucleus is controlled by the spinodal-decomposition which happens in the region surrounding the nucleus. This leads to forming the shell structures around the nucleus.

IL-5 Induces Suspended Eosinophils to Undergo Unique Global Reorganization Associated with Priming

PubMed Central

Han, Shih-Tsung

2014-01-01

The experiments described herein define a unique program of polarization of suspended human eosinophils stimulated with IL-5 family cytokines. We found that eosinophil granules and the nucleus move in opposite directions to form, respectively, a granular compartment and the nucleopod, a specialized uropod occupied by the nucleus and covered with adhesion receptors, including P-selectin glycoprotein ligand-1, CD44, and activated αMβ2 integrin. Ligated IL-5 family receptors localize specifically at the tip of the nucleopod in proximity to downstream signaling partners Janus tyrosine kinase 2, signal transducer and activator of transcription-1 and -5, and extracellular signal–regulated kinase. Microscopy and effects of cytochalasin B and nocodazole indicate that remodeling of filamentous actin and reorientation of the microtubule network are required for eosinophil polarization and nucleopod formation. IL-5 induces persistent polarization and extracellular signal–regulated kinase redistribution that are associated with eosinophil priming, a robust response on subsequent stimulation with N-formyl-methionyl-leucyl-phenylalanine. Global reorganization of cytoskeleton, organelles, adhesion receptors, and signaling molecules likely facilitates vascular arrest, extravasation, migration, granule release, and survival of eosinophils entering inflamed tissues from the bloodstream. PMID:24156300

The dynamics of GABA signaling: Revelations from the circadian pacemaker in the suprachiasmatic nucleus

PubMed Central

Albers, H. Elliott; Walton, James C.; Gamble, Karen L.; McNeill, John K.; Hummer, Daniel L.

2016-01-01

Virtually every neuron within the suprachiasmatic nucleus (SCN) communicates via GABAergic signaling. The extracellular levels of GABA within the SCN are determined by a complex interaction of synthesis and transport, as well as synaptic and non-synaptic release. The response to GABA is mediated by GABAA receptors that respond to both phasic and tonic GABA release and that can produce excitatory as well as inhibitory cellular responses. GABA also influences circadian control through the exclusively inhibitory effects of GABAB receptors. Both GABA and neuropeptide signaling occur within the SCN, although the functional consequences of the interactions of these signals are not well understood. This review considers the role of GABA in the circadian pacemaker, in the mechanisms responsible for the generation of circadian rhythms, in the ability of non-photic stimuli to reset the phase of the pacemaker, and in the ability of the day-night cycle to entrain the pacemaker. PMID:27894927

Steroid Receptor Coactivator-interacting Protein (SIP) Inhibits Caspase-independent Apoptosis by Preventing Apoptosis-inducing Factor (AIF) from Being Released from Mitochondria*

PubMed Central

Wang, Dandan; Liang, Jing; Zhang, Yu; Gui, Bin; Wang, Feng; Yi, Xia; Sun, Luyang; Yao, Zhi; Shang, Yongfeng

2012-01-01

Apoptosis-inducing factor (AIF) is a caspase-independent death effector. Normally residing in the mitochondrial intermembrane space, AIF is released and translocated to the nucleus in response to proapoptotic stimuli. Nuclear AIF binds to DNA and induces chromatin condensation and DNA fragmentation, characteristics of apoptosis. Until now, it remained to be clarified how the mitochondrial-nuclear translocation of AIF is regulated. Here we report that steroid receptor coactivator-interacting protein (SIP) interacts directly with AIF in mitochondria and specifically inhibits caspase-independent and AIF-dependent apoptosis. Challenging cells with apoptotic stimuli leads to rapid degradation of SIP, and subsequently AIF is liberated from mitochondria and translocated to the nucleus to induce apoptosis. Together, our data demonstrate that SIP is a novel regulator in caspase-independent and AIF-mediated apoptosis. PMID:22371500

Reanalysis of the preoptic afferents and efferents involved in the surge of LH, FSH and prolactin release in the proestrous rat.

PubMed

Kimura, F; Kawakami, M

1978-01-01

In order to elucidate neural pathways concerned with the proestrous surge of LH, FSH and prolactin (Prl) release, brain transection or lesion was made acutely under ether anesthesia between 12.00 and 14.00 h of proestrus, and electrochemical stimulation was done under anesthesia with pentobarbital sodium (31.5 mg/kg b.w.) injected at 13.45 h. Transection which interrupted the connection of septum (SEPT), diagonal band of Broca (DBB) and bed nucleus of stria terminalis (BST) with the preoptic-suprachiasmatic area interfered with ovulation and surge of release of all 3 hormones. Isolation of the basal part of the suprachiasmatic area, including the suprachiasmatic nucleus (SCH), blocked ovulation also. Bilateral lesions in the medial preoptic area (MPO) with platinium-iridium electrode blocked ovulation and the surge of LH and Prl release, but not of FSH. Lesions in the SCH blocked ovulation and the surge of LH, but not of FSH and Prl. In the rat with acute isolation of the basal part of the suprachiasmatic area and SCH, stimulation of the MPO failed to induce ovulation and LH release, but was followed by FSH release. Prl release was not inhibited as in the intact rat. When the rat had the antero-SCH cut, stimulation of the SCH induced LH release but not FSH, and the inhibition on Prl release was pronounced. These findings offer evidence that the limbic-forebrain inputs are necessary for the preoptic integration in order to stimulate the proestrous surge of LH, FSH and Prl release. Furthermore, it is possible that separate pathways from the preoptic area to the medial basal hypothalamus are concerned in the stimulation of individual hormones--a restricted route for LH which may pass through the SCH, a diffuse one for FSH which may pass through either the SCH or anterior hypothalamic area, and a relatively diffuse one for Prl which may pass outside the SCH.

PAC1 receptor antagonism in the bed nucleus of the stria terminalis (BNST) attenuates the endocrine and behavioral consequences of chronic stress

PubMed Central

Roman, Carolyn W.; Lezak, Kim R.; Hartsock, Matthew J.; Falls, William A.; Braas, Karen M.; Howard, Alan B.; Hammack, Sayamwong E.; May, Victor

2015-01-01

Summary Chronic or repeated stressor exposure can induce a number of maladaptive behavioral and physiological consequences and among limbic structures, the bed nucleus of the stria terminalis (BNST) has been implicated in the integration and interpretation of stress responses. Previous work has demonstrated that chronic variate stress (CVS) exposure in rodents increases BNST pituitary adenylate cyclase activating polypeptide (PACAP, Adcyap1) and PAC1 receptor (Adcyap1r1) transcript expression, and that acute BNST PACAP injections can stimulate anxiety-like behavior. Here we show that chronic stress increases PACAP expression selectively in the oval nucleus of the dorsolateral BNST in patterns distinct from those for corticotropin releasing hormone (CRH). Among receptor subtypes, BNST PACAP signaling through PAC1 receptors not only heightened anxiety responses as measured by different behavioral parameters but also induced anorexic-like behavior to mimic the consequences of stress. Conversely, chronic inhibition of BNST PACAP signaling by continuous infusion with the PAC1 receptor antagonist PACAP(6-38) during the week of CVS attenuated these stress-induced behavioral responses and changes in weight gain. BNST PACAP signaling stimulated the hypothalamic-pituitary-adrenal (HPA) axis and heightened corticosterone release; further, BNST PACAP(6-38) administration blocked corticosterone release in a sensitized stress model. In aggregate with recent associations of PACAP/PAC1 receptor dysregulation with altered stress responses including post-traumatic stress disorder, these data suggest that BNST PACAP/PAC1 receptor signaling mechanisms may coordinate the behavioral and endocrine consequences of stress. PMID:25001965

The role of the mesolimbic dopamine system in the formation of blood-oxygen-level dependent responses in the medial prefrontal/anterior cingulate cortex during high-frequency stimulation of the rat perforant pathway.

PubMed

Helbing, Cornelia; Brocka, Marta; Scherf, Thomas; Lippert, Michael T; Angenstein, Frank

2016-12-01

Several human functional magnetic resonance imaging studies point to an activation of the mesolimbic dopamine system during reward, addiction and learning. We previously found activation of the mesolimbic system in response to continuous but not to discontinuous perforant pathway stimulation in an experimental model that we now used to investigate the role of dopamine release for the formation of functional magnetic resonance imaging responses. The two stimulation protocols elicited blood-oxygen-level dependent responses in the medial prefrontal/anterior cingulate cortex and nucleus accumbens. Inhibition of dopamine D 1/5 receptors abolished the formation of functional magnetic resonance imaging responses in the medial prefrontal/anterior cingulate cortex during continuous but not during discontinuous pulse stimulations, i.e. only when the mesolimbic system was activated. Direct electrical or optogenetic stimulation of the ventral tegmental area caused strong dopamine release but only electrical stimulation triggered significant blood-oxygen level-dependent responses in the medial prefrontal/anterior cingulate cortex and nucleus accumbens. These functional magnetic resonance imaging responses were not affected by the D 1/5 receptor antagonist SCH23390 but reduced by the N-methyl-D-aspartate receptor antagonist MK801. Therefore, glutamatergic ventral tegmental area neurons are already sufficient to trigger blood-oxygen-level dependent responses in the medial prefrontal/anterior cingulate cortex and nucleus accumbens. Although dopamine release alone does not affect blood-oxygen-level dependent responses it can act as a switch, permitting the formation of blood-oxygen-level dependent responses. © The Author(s) 2015.

Pre- and Post-perihelion Observations of C/2009 P1 (Garradd): Evidence for an Oxygen-rich Heritage?

NASA Technical Reports Server (NTRS)

Disanti, Michael Antonio; Villanueva, Geronimo Luis; Paganini, Lucas; Bonev, Boncho P.; Keane, Jacqueline V.; Meech, Karen J.; Mumma, Michael Jon

2013-01-01

We conducted pre- and post-perihelion observations of Comet C/2009 P1 (Garradd) on UT 2011 October 13 and 2012 January 8, at heliocentric distances of 1.83 and 1.57 AU, respectively, using the high-resolution infrared spectrometer (NIRSPEC) at the Keck II 10-m telescope on Mauna Kea, HI. Pre-perihelion, we obtained production rates for nine primary volatiles (native ices): H2O, CO, CH3OH, CH4, C2H6, HCN, C2H2, H2CO, and NH3. Post-perihelion, we obtained production rates for three of these (H2O, CH4, and HCN) and sensitive upper limits for three others (C2H2, H2CO, and NH3). CO was enriched and C2H2 was depleted, yet C2H6 and CH3OH were close to their currentmean values asmeasured in a dominant group of Oort cloud comets. This may indicate processing of its pre-cometary ices in a relatively oxygen-rich environment. Our measurements indicate consistent pre- and post-perihelion abundance ratios relative to H2O, suggesting we were measuring compositional homogeneity among measured species to the depths in the nucleus sampled. However, the overall gas production was lower post-perihelion despite its smaller heliocentric distance on January 8. This is qualitatively consistent with other studies of C/2009 P1, perhaps due to seasonal differences in the heating of one or more active regions on the nucleus. On October 13, the water profile showed a pronounced excess towards the Sun-facing hemisphere that was not seen in other molecules, including H2O on January 8, nor in the dust continuum. Inter-comparison of profiles from October 13 permitted us to quantify contributions due to release of H2O from the nucleus, and fromits release in the coma. This resulted in the latter source contributing 25-30% of the total observed water within our slit, which covered roughly +/-300 km by +/-4500 km from the nucleus. We attribute this excess H2O, which peaked at a mean projected distance of 1300-1500 km from the nucleus, to release from water-rich, relatively pure icy grains

Aversive and appetitive events evoke the release of corticotropin-releasing hormone and bombesin-like peptides at the central nucleus of the amygdala.

PubMed

Merali, Z; McIntosh, J; Kent, P; Michaud, D; Anisman, H

1998-06-15

There is wide agreement that corticotropin-releasing hormone (CRH) systems within the brain are activated by stressful stimuli. There is also mounting evidence for the role of bombesin (BN)-like peptides in the mediation of the stress response. To date, however, the extent to which other stimuli increase the activity of these peptidergic systems has received little attention. In the present investigation we validated and used in vivo microdialysis sampling followed by ex vivo radioimmunoassays to monitor the release of CRH and BN-like peptides during appetitive (food intake) and stressful (restraint) events. It is demonstrated for the first time that the in vivo release of CRH and BN-like peptides at the central nucleus of the amygdala was markedly increased by both stressor exposure and food ingestion. In fact, the meal-elicited rise of CRH release was as great as that associated with 20 min of restraint stress. Paralleling these findings, circulating ACTH and corticosterone levels were also increased in response to both food intake and restraint. Contrary to the current views, these results indicate that either food ingestion is interpreted as a "stressful" event by certain neural circuits involving the central amygdala or that the CRH- and BN-related peptidergic systems may serve a much broader role than previously envisioned. Rather than evoking feelings of fear and anxiety, these systems may serve to draw attention to events or cues of biological significance, such as those associated with food availability as well as those posing a threat to survival.

Glutamate input in the dorsal raphe nucleus as a determinant of escalated aggression in male mice.

PubMed

Takahashi, Aki; Lee, Ray X; Iwasato, Takuji; Itohara, Shigeyoshi; Arima, Hiroshi; Bettler, Bernhard; Miczek, Klaus A; Koide, Tsuyoshi

2015-04-22

Although the dorsal raphe nucleus (DRN) has long been linked to neural control of aggression, little is known about the regulatory influences of the DRN when an animal engages in either adaptive species-typical aggressive behavior or escalated aggression. Therefore it is important to explore which neurotransmitter inputs into the DRN determine the escalation of aggression in male mice. Previously, we observed that microinjection of the GABAB receptor agonist baclofen into the DRN escalates aggressive behavior in male mice. Here, we used a serotonin (5-HT) neuron-specific GABAB receptor knock-out mouse to demonstrate that baclofen acts on nonserotonergic neurons to escalate aggression. Intra-DRN baclofen administration increased glutamate release, but did not alter GABA release, within the DRN. Microinjection of l-glutamate into the DRN escalated dose-dependently attack bites toward an intruder. In vivo microdialysis showed that glutamate release increased in the DRN during an aggressive encounter, and the level of glutamate was further increased when the animal was engaged in escalated aggressive behavior after social instigation. Finally, 5-HT release was increased within the DRN and also in the medial prefrontal cortex when animals were provoked by social instigation, and during escalated aggression after social instigation, but this increase in 5-HT release was not observed when animals were engaged in species-typical aggression. In summary, glutamate input into the DRN is enhanced during escalated aggression, which causes a phasic increase of 5-HT release from the DRN 5-HT neurons. Copyright © 2015 the authors 0270-6474/15/356452-12$15.00/0.

Nucleus Accumbens Shell Dopamine Preferentially Tracks Information Related to Outcome Value of Reward.

PubMed

Sackett, Deirdre A; Saddoris, Michael P; Carelli, Regina M

2017-01-01

Effective decision-making requires organisms to predict reward values and bias behavior toward the best available option. The mesolimbic dopamine system, including the nucleus accumbens (NAc) shell and core, is involved in this process. Although studies support a role of the shell and core in specific aspects of decision-making (e.g., risk, effort, delay), no studies have directly compared dopamine release dynamics in these subregions to cues exclusively signaling the availability of different reward magnitudes. Here, fast-scan cyclic voltammetry was used to compare rapid dopamine release dynamics in the NAc subregions during a magnitude-based decision-making task. Rats learned that distinct cues signaled the availability of either a small or large reward (one or two sugar pellets), and then were given an opportunity to choose their preferred option. We found that peak dopamine release tracked the more preferred (higher-magnitude) option in both core and shell subregions. Critically, however, overall (i.e., global) dopamine release was significantly higher and longer lasting in the shell and tracked the preferred magnitude during the entire cue period. Further, in the shell (not core), dopamine signaling significantly declined immediately at the lever press for reward but increased during the period of reward consumption. Collectively, the results indicate that although dopamine release in both the core and shell are activated by cues signaling the opportunity to respond for rewards of different magnitudes, dopamine release in the shell plays a differential and unique role in tracking information related to the outcome value of reward.

Beer self-administration provokes lateralized nucleus accumbens dopamine release in male heavy drinkers.

PubMed

Oberlin, Brandon G; Dzemidzic, Mario; Tran, Stella M; Soeurt, Christina M; O'Connor, Sean J; Yoder, Karmen K; Kareken, David A

2015-03-01

Although striatal dopamine (DA) is important in alcohol abuse, the nature of DA release during actual alcohol drinking is unclear, since drinking includes self-administration of both conditioned flavor stimuli (CS) of the alcoholic beverage and subsequent intoxication, the unconditioned stimulus (US). Here, we used a novel self-administration analog to distinguish nucleus accumbens (NAcc) DA responses specific to the CS and US. Right-handed male heavy drinkers (n = 26) received three positron emission tomography (PET) scans with the D2/D3 radioligand [(11)C]raclopride (RAC) and performed a pseudo self-administration task that separately administered a flavor CS of either a habitually consumed beer or the appetitive control Gatorade®, concomitant with the US of ethanol intoxication (0.06 g/dL intravenous (IV) administration) or IV saline. Scan conditions were Gatorade flavor + saline (Gat&Sal), Gatorade flavor + ethanol (Gat&Eth), and beer flavor + ethanol (Beer&Eth). Ethanol (US) reduced RAC binding (inferring DA release) in the left (L) NAcc [Gat&Sal > Gat&Eth]. Beer flavor (CS) increased DA in the right (R) NAcc [Gat&Eth > Beer&Eth]. The combination of beer flavor and ethanol (CS + US), [Gat&Sal > Beer&Eth], induced DA release in bilateral NAcc. Self-reported intoxication during scanning correlated with L NAcc DA release. Relative to saline, infusion of ethanol increased alcoholic drink wanting. Our findings suggest lateralized DA function in the NAcc, with L NAcc DA release most reflecting intoxication, R NAcc DA release most reflecting the flavor CS, and the conjoint CS + US producing a bilateral NAcc response.

The Integrated Hypothalamic Tachykinin-Kisspeptin System as a Central Coordinator for Reproduction

PubMed Central

Bosch, Martha A.; León, Silvia; Simavli, Serap; True, Cadence; Pinilla, Leonor; Carroll, Rona S.; Seminara, Stephanie B.; Tena-Sempere, Manuel; Rønnekleiv, Oline K.; Kaiser, Ursula B.

2015-01-01

Tachykinins are comprised of the family of related peptides, substance P (SP), neurokinin A (NKA), and neurokinin B (NKB). NKB has emerged as regulator of kisspeptin release in the arcuate nucleus (ARC), whereas the roles of SP and NKA in reproduction remain unknown. This work explores the roles of SP and NKA in the central regulation of GnRH release. First, central infusion of specific agonists for the receptors of SP (neurokinin receptor 1, NK1R), NKA (NK2R) and NKB (NK3R) each induced gonadotropin release in adult male and ovariectomized, estradiol-replaced female mice, which was absent in Kiss1r−/− mice, indicating a kisspeptin-dependent action. The NK2R agonist, however, decreased LH release in ovariectomized-sham replaced females, as documented for NK3R agonists but in contrast to the NK1R agonist, which further increased LH release. Second, Tac1 (encoding SP and NKA) expression in the ARC and ventromedial nucleus was inhibited by circulating estradiol but did not colocalize with Kiss1 mRNA. Third, about half of isolated ARC Kiss1 neurons expressed Tacr1 (NK1R) and 100% Tacr3 (NK3R); for anteroventral-periventricular Kiss1 neurons and GnRH neurons, approximately one-fourth expressed Tacr1 and one-tenth Tacr3; Tacr2 (NK2R) expression was absent in all cases. Overall, these results identify a potent regulation of gonadotropin release by the SP/NK1R and NKA/NK2R systems in the presence of kisspeptin-Kiss1r signaling, indicating that they may, along with NKB/NK3R, control GnRH release, at least in part through actions on Kiss1 neurons. PMID:25422875

The integrated hypothalamic tachykinin-kisspeptin system as a central coordinator for reproduction.

PubMed

Navarro, Víctor M; Bosch, Martha A; León, Silvia; Simavli, Serap; True, Cadence; Pinilla, Leonor; Carroll, Rona S; Seminara, Stephanie B; Tena-Sempere, Manuel; Rønnekleiv, Oline K; Kaiser, Ursula B

2015-02-01

Tachykinins are comprised of the family of related peptides, substance P (SP), neurokinin A (NKA), and neurokinin B (NKB). NKB has emerged as regulator of kisspeptin release in the arcuate nucleus (ARC), whereas the roles of SP and NKA in reproduction remain unknown. This work explores the roles of SP and NKA in the central regulation of GnRH release. First, central infusion of specific agonists for the receptors of SP (neurokinin receptor 1, NK1R), NKA (NK2R) and NKB (NK3R) each induced gonadotropin release in adult male and ovariectomized, estradiol-replaced female mice, which was absent in Kiss1r(-/-) mice, indicating a kisspeptin-dependent action. The NK2R agonist, however, decreased LH release in ovariectomized-sham replaced females, as documented for NK3R agonists but in contrast to the NK1R agonist, which further increased LH release. Second, Tac1 (encoding SP and NKA) expression in the ARC and ventromedial nucleus was inhibited by circulating estradiol but did not colocalize with Kiss1 mRNA. Third, about half of isolated ARC Kiss1 neurons expressed Tacr1 (NK1R) and 100% Tacr3 (NK3R); for anteroventral-periventricular Kiss1 neurons and GnRH neurons, approximately one-fourth expressed Tacr1 and one-tenth Tacr3; Tacr2 (NK2R) expression was absent in all cases. Overall, these results identify a potent regulation of gonadotropin release by the SP/NK1R and NKA/NK2R systems in the presence of kisspeptin-Kiss1r signaling, indicating that they may, along with NKB/NK3R, control GnRH release, at least in part through actions on Kiss1 neurons.

Electromagnetic Nucleus - Nucleus Cross Sections Using Energy Dependent Branching Ratios

NASA Astrophysics Data System (ADS)

Adamczyk, Anne; Norbury, John

2009-11-01

Energy dependent branching ratios, derived from Weisskopf-Ewing theory, are presented and compared to an energy independent formalism, developed by Norbury, Townsend, and Westfall. The energy dependent branching ratio formalism is more versatile since it allows for not only neutron and proton emission, but also alpha particle, deuteron, helion, and triton emission. A new theoretical method for calculating electromagnetic dissociation (EMD) nucleus - nucleus cross sections, with energy dependent branching ratios, is introduced. Comparisons of photonuclear and nucleus - nucleus cross sections, using energy dependent and independent branching ratios, to experiment are presented. Experimental efforts, by various groups, have focused on measuring cross sections for proton and neutron emission, because proton and neutron emission is generally more probable than heavier particle emission. Consequently, comparisons of energy dependent and independent branching ratios to experiment are made for photoneutron and photoproton cross sections. EMD cross sections for single neutron, proton, and alpha particle removal are calculated and compared to experimental data for a variety of projectile, target, and energy combinations. Results indicate that using energy dependent branching ratios yields better estimates.

Heavy-flavour and quarkonium production in the LHC era: from proton-proton to heavy-ion collisions

DOE PAGES

Andronic, A.; Arleo, F.; Arnaldi, R.; ...

2016-02-29

This report reviews the study of open heavy-flavour and quarkonium production in high-energy hadronic collisions, as tools to investigate fundamental aspects of Quantum Chromodynamics, from the proton and nucleus structure at high energy to deconfinement and the properties of the Quark-Gluon Plasma. Emphasis is given to the lessons learnt from LHC Run 1 results, which are reviewed in a global picture with the results from SPS and RHIC at lower energies, as well as to the questions to be addressed in the future. The report covers heavy flavour and quarkonium production in proton-proton, proton-nucleus and nucleus-nucleus collisions. This includes discussionmore » of the effects of hot and cold strongly interacting matter, quarkonium photo-production in nucleus-nucleus collisions and perspectives on the study of heavy flavour and quarkonium with upgrades of existing experiments and new experiments. The report results from the activity of the SaporeGravis network of the I3 Hadron Physics programme of the European Union 7th Framework Programme.« less

Rasgrf2 controls dopaminergic adaptations to alcohol in mice.

PubMed

Easton, Alanna C; Rotter, Andrea; Lourdusamy, Anbarasu; Desrivières, Sylvane; Fernández-Medarde, Alberto; Biermann, Teresa; Fernandes, Cathy; Santos, Eugenio; Kornhuber, Johannes; Schumann, Gunter; Müller, Christian P

2014-10-01

Alcohol abuse leads to serious health problems with no effective treatment available. Recent evidence suggests a role for ras-specific guanine-nucleotide releasing factor 2 (RASGRF2) in alcoholism. Rasgrf2 is a calcium sensor and MAPK/ERK activating protein, which has been linked to neurotransmitter release and monoaminergic receptor adaptations. Rasgrf2 knock out (KO) mice do not develop a dopamine response in the nucleus accumbens after an alcohol challenge and show a reduced consumption of alcohol. The present study aims to further characterise the role of Rasgrf2 in dopaminergic activation beyond the nucleus accumbens following alcohol treatment. Using in vivo microdialysis we found that alcohol induces alterations in dopamine levels in the dorsal striatum between wildtype (WT) and Rasgrf2 KO mice. There was no difference in the expression of dopamine transporter (DAT), dopamine receptor regulating factor (DRRF), or dopamine D2 receptor (DRD2) mRNA in the brain between Rasgrf2 KO and WT mice. After sub-chronic alcohol treatment, DAT and DRRF, but not DRD2 mRNA expression differed between WT and Rasgrf2 KO mice. Brain adaptations were positively correlated with splenic expression levels. These data suggest that Rasgrf2 controls dopaminergic signalling and adaptations to alcohol also in other brain regions, beyond the nucleus accumbens. Copyright © 2014 Elsevier Inc. All rights reserved.

ON THE ORIGIN OF INNER COMA STRUCTURES OBSERVED BY ROSETTA DURING A DIURNAL ROTATION OF COMET 67P/CHURYUMOV–GERASIMENKO

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kramer, Tobias; Noack, Matthias

2016-05-20

The Rosetta probe around comet 67P/Churyumov–Gerasimenko (67P) reveals an anisotropic dust distribution of the inner coma with jet-like structures. The physical processes leading to jet formation are under debate, with most models for cometary activity focusing on localized emission sources, such as cliffs or terraced regions. Here we suggest, by correlating high-resolution simulations of the dust environment around 67P with observations, that the anisotropy and the background dust density of 67P originate from dust released across the entire sunlit surface of the nucleus rather than from few isolated sources. We trace back trajectories from coma regions with high local dustmore » density in space to the non-spherical nucleus and identify two mechanisms of jet formation: areas with local concavity in either two dimensions or only one. Pits and craters are examples of the first case; the neck region of the bi-lobed nucleus of 67P is an example of the latter case. The conjunction of multiple sources, in addition to dust released from all other sunlit areas, results in a high correlation coefficient (∼0.8) of the predictions with observations during a complete diurnal rotation period of 67P.« less

The amalgamation stage of fusion reactions

NASA Astrophysics Data System (ADS)

Mouze, Genevieve

2005-04-01

There is no need of a repulsive potential in the amalgamation stage for explaining the small fusion cross sections. The repulsive potential proposed by A. Adamian et al.(1) can advantageously be replaced by the affinity of the reaction of re-dissociation of the compound nucleus into its entrance-channel configuration. This reaction, which occurs after the penetration of the Coulomb barrier, is an equilibrium between dual and compact form of the compound nucleus, and the energy Q released in the dissociation is equal to the energy required for amalgamating. The total energy of the confined system being equal to the height B of the Coulomb barrier, the intrinsic excitation energy of the compact nucleus is equal to (B - Q). In the reaction 82Se+ 138Ba (2), the dissociation of 220Th releases 180.524 MeV, and B= 196.08 MeV. With an intrinsic excitation energy of 15.56 MeV, the confined compact 220Th has enough energy for emitting two neutrons ( S(2n) = 13.85 MeV). Thus the favored xn channel of fusion reactions can be precisely predicted. This new, mass-data-based model of fusion is completely parameter-free. 1 G.G. Adamian et al., PRC 69 (2004) 044601. 2 K. Satou et al. PRC C 65(2002) 054602.

BDNF and glucocorticoids regulate corticotrophin-releasing hormone (CRH) homeostasis in the hypothalamus.

PubMed

Jeanneteau, Freddy D; Lambert, W Marcus; Ismaili, Naima; Bath, Kevin G; Lee, Francis S; Garabedian, Michael J; Chao, Moses V

2012-01-24

Regulation of the hypothalamic-pituitary-adrenal (HPA) axis is critical for adaptation to environmental changes. The principle regulator of the HPA axis is corticotrophin-releasing hormone (CRH), which is made in the parventricular nucleus and is an important target of negative feedback by glucocorticoids. However, the molecular mechanisms that regulate CRH are not fully understood. Disruption of normal HPA axis activity is a major risk factor of neuropsychiatric disorders in which decreased expression of the glucocorticoid receptor (GR) has been documented. To investigate the role of the GR in CRH neurons, we have targeted the deletion of the GR, specifically in the parventricular nucleus. Impairment of GR function in the parventricular nucleus resulted in an enhancement of CRH expression and an up-regulation of hypothalamic levels of BDNF and disinhibition of the HPA axis. BDNF is a stress and activity-dependent factor involved in many activities modulated by the HPA axis. Significantly, ectopic expression of BDNF in vivo increased CRH, whereas reduced expression of BDNF, or its receptor TrkB, decreased CRH expression and normal HPA functions. We find the differential regulation of CRH relies upon the cAMP response-element binding protein coactivator CRTC2, which serves as a switch for BDNF and glucocorticoids to direct the expression of CRH.

Estradiol Membrane-Initiated Signaling and Female Reproduction.

PubMed

Micevych, Paul E; Wong, Angela May; Mittelman-Smith, Melinda Anne

2015-07-01

The discoveries of rapid, membrane-initiated steroid actions and central nervous system steroidogenesis have changed our understanding of the neuroendocrinology of reproduction. Classical nuclear actions of estradiol and progesterone steroids affecting transcription are essential. However, with the discoveries of membrane-associated steroid receptors, it is becoming clear that estradiol and progesterone have neurotransmitter-like actions activating intracellular events. Ultimately, membrane-initiated actions can influence transcription. Estradiol membrane-initiated signaling (EMS) modulates female sexual receptivity and estrogen feedback regulating the luteinizing hormone (LH) surge. In the arcuate nucleus, EMS activates a lordosis-regulating circuit that extends to the medial preoptic nucleus and subsequently to the ventromedial nucleus (VMH)--the output from the limbic and hypothalamic regions. Here, we discuss how EMS leads to an active inhibition of lordosis behavior. To stimulate ovulation, EMS facilitates astrocyte synthesis of progesterone (neuroP) in the hypothalamus. Regulation of GnRH release driving the LH surge is dependent on estradiol-sensitive kisspeptin (Kiss1) expression in the rostral periventricular nucleus of the third ventricle (RP3V). NeuroP activation of the LH surge depends on Kiss1, but the specifics of signaling have not been well elucidated. RP3V Kiss1 neurons appear to integrate estradiol and progesterone information which feeds back onto GnRH neurons to stimulate the LH surge. In a second population of Kiss1 neurons, estradiol suppresses the surge but maintains tonic LH release, another critical component of the estrous cycle. Together, evidence suggests that regulation of reproduction involves membrane action of steroids, some of which are synthesized in the brain. © 2015 American Physiological Society.

Heterogeneities of 67P nucleus seen by CONSERT in the vicinity of Abydos

NASA Astrophysics Data System (ADS)

Ciarletti, Valerie; Lasue, Jéremie; Hérique, Alain; Kofman, Wlodek; Levasseur-Regourd, Anny-Chantal; Lemmonier, Florentin; Guiffaut, Christophe; Plettemeier, Dirk

2016-04-01

Since their arrival at comet 67P in August 2014, a number of instruments onboard Rosetta's main spacecraft and Philae lander have been observing the surface of the nucleus and have revealed details of amazing structures. This information was complemented by information about the nucleus internal structure collected by the CONSERT (Comet Nucleus Sounding Experiment by Radiowave Transmission) experiment in order to constrain the nucleus formation and evolution. The CONSERT experiment is a bistatic radar with receivers and transmitters on-board both Rosetta's main spacecraft and Philae lander. The instrument makes use of electromagnetic waves at 90 MHz that propagated, during the First Science Sequence, between Philae and Rosetta through the small lobe of 67P over distances ranging from approximately 200 to 800 m depending on the spacecraft location. The data used here have been collected at depths that reach a maximum of about one hundred of meters nucleus in the vicinity of Abydos. The data collected by CONSERT provide an estimate of the permittivity mean value and information about its spatial variability inside the sounded volume. Thanks to the 10 MHz frequency bandwidth of the signal used by the instrument a spatial resolution around 10m is obtained inside the sounded volume of the nucleus. In this paper, we specifically focus on local variations in the nucleus subsurface permittivity. A number of electromagnetic simulations corresponding to the CONSERT operations have been performed for a variety of subsurface permittivity models. The effect of local vertical and horizontal large scale variations as well as smaller scale random fractal structure of the permittivity values around the landing site will be presented and discussed in comparison with CONSERT's experimental data collected in the same configurations. Possible interpretations of the results will be presented as well as potential consequences for the nucleus structure in connection with observations made available by other instruments.

Role of nesprin-1 in nuclear deformation in endothelial cells under static and uniaxial stretching conditions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Anno, Toshiro; Sakamoto, Naoya, E-mail: sakan@me.kawasaki-m.ac.jp; Sato, Masaaki

Highlights: Black-Right-Pointing-Pointer Nesprin-1 knockdown decreases widths of nuclei in ECs under static condition. Black-Right-Pointing-Pointer Nuclear strain caused by stretching is increased by nesprin-1 knockdown in ECs. Black-Right-Pointing-Pointer We model mechanical interactions of F-actin with the nucleus in stretched cells. Black-Right-Pointing-Pointer F-actin bound to nesprin-1 may cause sustainable force transmission to the nucleus. -- Abstract: The linker of nucleus and cytoskeleton (LINC) complex, including nesprin-1, has been suggested to be crucial for many biological processes. Previous studies have shown that mutations in nesprin-1 cause abnormal cellular functions and diseases, possibly because of insufficient force transmission to the nucleus through actin filamentsmore » (F-actin) bound to nesprin-1. However, little is known regarding the mechanical interaction between the nucleus and F-actin through nesprin-1. In this study, we examined nuclear deformation behavior in nesprin-1 knocked-down endothelial cells (ECs) subjected to uniaxial stretching by evaluating nuclear strain from lateral cross-sectional images. The widths of nuclei in nesprin-1 knocked-down ECs were smaller than those in wild-type cells. In addition, nuclear strain in nesprin-1 knocked-down cells, which is considered to be compressed by the actin cortical layer, increased compared with that in wild-type cells under stretching condition. These results indicate that nesprin-1 knockdown releases the nucleus from the tension of F-actin bound to the nucleus, thereby increasing allowance for deformation before stretching, and that F-actin bound to the nucleus through nesprin-1 causes sustainable force transmission to the nucleus.« less

PECULIAR NEAR-NUCLEUS OUTGASSING OF COMET 17P/HOLMES DURING ITS 2007 OUTBURST

DOE Office of Scientific and Technical Information (OSTI.GOV)

Qi, Chunhua; Gurwell, Mark A.; Wilner, David J.

2015-01-20

We present high angular resolution Submillimeter Array observations of the outbursting Jupiter family comet 17P/Holmes on 2007 October 26-29, achieving a spatial resolution of 2.''5, or ∼3000 km at the comet distance. The observations resulted in detections of the rotational lines CO 3-2, HCN 4-3, H{sup 13}CN 4-3, CS 7-6, H{sub 2}CO 3{sub 1,} {sub 2}-2{sub 1,} {sub 1}, H{sub 2}S 2{sub 2,} {sub 0}-2{sub 1,} {sub 1}, and multiple CH{sub 3}OH lines, along with the associated dust continuum at 221 and 349 GHz. The continuum has a spectral index of 2.7 ± 0.3, slightly steeper than blackbody emission from large dust particles.more » From the imaging data, we identify two components in the molecular emission. One component is characterized by a relatively broad line width (∼1 km s{sup –1} FWHM) exhibiting a symmetric outgassing pattern with respect to the nucleus position. The second component has a narrower line width (<0.5 km s{sup –1} FWHM) with the line center redshifted by 0.1-0.2 km s{sup –1} (cometocentric frame), and shows a velocity shift across the nucleus position with the position angle gradually changing from 66° to 30° within the four days of observations. We determine distinctly different CO/HCN ratios for each of the components. For the broad-line component we find CO/HCN < 7, while in the narrow-line component, CO/HCN = 40 ± 5. We hypothesize that the narrow-line component originates from the ice grain halo found in near-nucleus photometry, believed to be created by sublimating recently released ice grains around the nucleus during the outburst. In this interpretation, the high CO/HCN ratio of this component reflects the more pristine volatile composition of nucleus material released in the outburst.« less

Subcellular plasticity of the corticotropin-releasing factor receptor in dendrites of the mouse bed nucleus of the stria terminalis following chronic opiate exposure.

PubMed

Jaferi, A; Lane, D A; Pickel, V M

2009-09-29

Chronic opiate administration alters the expression levels of the stress-responsive peptide, corticotropin-releasing factor (CRF), in the bed nucleus of the stria terminalis (BNST). This brain region contains CRF receptors that drive drug-seeking behavior exacerbated by stress. We used electron microscopy to quantitatively compare immunolabeling of the corticotropin-releasing factor receptor (CRFr) and CRF in the anterolateral bed nucleus of the stria terminalis (BSTal) of mice injected with saline or morphine in escalating doses for 14 days. We also compared the results with those in non-injected control mice. The tissue was processed for CRFr immunogold and CRF immunoperoxidase labeling. The non-injected controls had a significantly lower plasmalemmal density of CRFr immunogold particles in dendrites compared with mice receiving saline, but not those receiving morphine, injections. Compared with saline, however, mice receiving chronic morphine showed a significantly lower plasmalemmal, and greater cytoplasmic, density of CRFr immunogold in dendrites. Within the cytoplasmic compartment of somata and dendrites of the BSTal, the proportion of CRFr gold particles associated with mitochondria was three times as great in mice receiving morphine compared with saline. This subcellular distribution is consistent with morphine,- and CRFr-associated modulation of intracellular calcium release or oxidative stress. The between-group changes occurred without effect on the total number of dendritic CRFr immunogold particles, suggesting that chronic morphine enhances internalization or decreases delivery of the CRFr to the plasma membrane, a trafficking effect that is also affected by the stress of daily injections. In contrast, saline and morphine treatment groups showed no significant differences in the total number of CRF-immunoreactive axon terminals, or the frequency with which these terminals contacted CRFr-containing dendrites. This suggests that morphine does not influence axonal availability of CRF in the BSTal. The results have important implications for drug-associated adaptations in brain stress systems that may contribute to the motivation to continue drug use during dependence.

Neural correlates underlying naloxone-induced amelioration of sexual behavior deterioration due to an alarm pheromone

PubMed Central

Kobayashi, Tatsuya; Kiyokawa, Yasushi; Takeuchi, Yukari; Mori, Yuji

2015-01-01

Sexual behavior is suppressed by various types of stressors. We previously demonstrated that an alarm pheromone released by stressed male Wistar rats is a stressor to other rats, increases the number of mounts needed for ejaculation, and decreases the hit rate (described as the number of intromissions/sum of the mounts and intromissions). This deterioration in sexual behavior was ameliorated by pretreatment with the opioid receptor antagonist naloxone. However, the neural mechanism underlying this remains to be elucidated. Here, we examined Fos expression in 31 brain regions of pheromone-exposed rats and naloxone-pretreated pheromone-exposed rats 60 min after 10 intromissions. As previously reported, the alarm pheromone increased the number of mounts and decreased the hit rate. In addition, Fos expression was increases in the anterior medial division (BNSTam), anterior lateral division (BNSTal) and posterior division (BNSTp) of the bed nucleus of the stria terminalis, parvocellular part of the paraventricular nucleus of the hypothalamus, arcuate nucleus, dorsolateral and ventrolateral periaqueductal gray, and nucleus paragigantocellularis (nPGi). Fos expression was decreased in the magnocellular part of the paraventricular nucleus of the hypothalamus. Pretreatment with naloxone blocked the pheromone-induced changes in Fos expression in the magnocellular part of the paraventricular nucleus of the hypothalamus, ventrolateral periaqueductal gray, and nPGi. Based on these results, we hypothesize that the alarm pheromone deteriorated sexual behavior by activating the ventrolateral periaqueductal gray-nucleus paragigantocellularis cluster and suppressing the magnocellular part of the paraventricular nucleus of the hypothalamus (PVN) via the opioidergic pathway. PMID:25755631

Episodic Social Stress-Escalated Cocaine Self-Administration: Role of Phasic and Tonic Corticotropin Releasing Factor in the Anterior and Posterior Ventral Tegmental Area.

PubMed

Holly, Elizabeth N; Boyson, Christopher O; Montagud-Romero, Sandra; Stein, Dirson J; Gobrogge, Kyle L; DeBold, Joseph F; Miczek, Klaus A

2016-04-06

Intermittent social defeat stress escalates later cocaine self-administration. Reward and stress both activate ventral tegmental area (VTA) dopamine neurons, increasing downstream extracellular dopamine concentration in the medial prefrontal cortex and nucleus accumbens. The stress neuropeptide corticotropin releasing factor (CRF) and its receptors (CRF-R1, CRF-R2) are located in the VTA and influence dopaminergic activity. These experiments explore how CRF release and the activation of its receptors within the VTA both during and after stress influence later cocaine self-administration in rats.In vivo microdialysis of CRF in the VTA demonstrated that CRF is phasically released in the posterior VTA (pVTA) during acute defeat, but, with repeated defeat, CRF is recruited into the anterior VTA (aVTA) and CRF tone is increased in both subregions. Intra-VTA antagonism of CRF-R1 in the pVTA and CRF-R2 in the aVTA during each social defeat prevented escalated cocaine self-administration in a 24 h "binge." VTA CRF continues to influence cocaine seeking in stressed animals long after social defeat exposure. Unlike nonstressed controls, previously stressed rats show significant cocaine seeking after 15 d of forced abstinence. Previously stressed rats continue to express elevated CRF tone within the VTA and antagonism of pVTA CRF-R1 or aVTA CRF-R2 reverses cocaine seeking. In conclusion, these experiments demonstrate neuroadaptive changes in tonic and phasic CRF with repeated stress, that CRF release during stress may contribute to later escalated cocaine taking, and that persistently elevated CRF tone in the VTA may drive later cocaine seeking through increased activation of pVTA CRF-R1 and aVTA CRF-R2. Corticotropin releasing factor (CRF) within the ventral tegmental area (VTA) has emerged as a likely candidate molecule underlying the fundamental link between stress history and escalated drug self-administration. However, the nature of CRF release in the VTA during acute and repeated stress, as well as its role in enduring neuroadaptations driving later drug taking and seeking, are poorly understood. These experiments explore how CRF is released and interacts with its receptors in specific regions of the VTA both during and after stress to fuel later escalated cocaine taking and seeking behavior. Understanding these acute and persistent changes to the VTA CRF system may lead to better therapeutic interventions for addiction. Copyright © 2016 the authors 0270-6474/16/364094-13$15.00/0.

Episodic Social Stress-Escalated Cocaine Self-Administration: Role of Phasic and Tonic Corticotropin Releasing Factor in the Anterior and Posterior Ventral Tegmental Area

PubMed Central

Boyson, Christopher O.; Montagud-Romero, Sandra; Stein, Dirson J.; Gobrogge, Kyle L.; DeBold, Joseph F.; Miczek, Klaus A.

2016-01-01

Intermittent social defeat stress escalates later cocaine self-administration. Reward and stress both activate ventral tegmental area (VTA) dopamine neurons, increasing downstream extracellular dopamine concentration in the medial prefrontal cortex and nucleus accumbens. The stress neuropeptide corticotropin releasing factor (CRF) and its receptors (CRF-R1, CRF-R2) are located in the VTA and influence dopaminergic activity. These experiments explore how CRF release and the activation of its receptors within the VTA both during and after stress influence later cocaine self-administration in rats. In vivo microdialysis of CRF in the VTA demonstrated that CRF is phasically released in the posterior VTA (pVTA) during acute defeat, but, with repeated defeat, CRF is recruited into the anterior VTA (aVTA) and CRF tone is increased in both subregions. Intra-VTA antagonism of CRF-R1 in the pVTA and CRF-R2 in the aVTA during each social defeat prevented escalated cocaine self-administration in a 24 h “binge.” VTA CRF continues to influence cocaine seeking in stressed animals long after social defeat exposure. Unlike nonstressed controls, previously stressed rats show significant cocaine seeking after 15 d of forced abstinence. Previously stressed rats continue to express elevated CRF tone within the VTA and antagonism of pVTA CRF-R1 or aVTA CRF-R2 reverses cocaine seeking. In conclusion, these experiments demonstrate neuroadaptive changes in tonic and phasic CRF with repeated stress, that CRF release during stress may contribute to later escalated cocaine taking, and that persistently elevated CRF tone in the VTA may drive later cocaine seeking through increased activation of pVTA CRF-R1 and aVTA CRF-R2. SIGNIFICANCE STATEMENT Corticotropin releasing factor (CRF) within the ventral tegmental area (VTA) has emerged as a likely candidate molecule underlying the fundamental link between stress history and escalated drug self-administration. However, the nature of CRF release in the VTA during acute and repeated stress, as well as its role in enduring neuroadaptations driving later drug taking and seeking, are poorly understood. These experiments explore how CRF is released and interacts with its receptors in specific regions of the VTA both during and after stress to fuel later escalated cocaine taking and seeking behavior. Understanding these acute and persistent changes to the VTA CRF system may lead to better therapeutic interventions for addiction. PMID:27053215

Determining the meson-nucleus potential - on the way to mesic states

NASA Astrophysics Data System (ADS)

Metag, Volker

2015-08-01

Experimental approaches to determine the real and imaginary part of the meson-nucleus potential are described. The experiments have been performed with the Crystal Barrel/TAPS detector at the electron accelerator ELSA (Bonn) and the Crystal Ball/TAPS detector at MAMI (Mainz). Measuring the transparency ratio as well as the excitation function and momentum distribution for photo production of ω and η' mesons, the imaginary part of the η'-nucleus potential is found to be smaller than the real part. In case of the ω meson the opposite is observed. This makes the η' meson a good candidate for the search for meson-nucleus bound states while no resolved ω mesic states can be expected. The results are discussed and compared to theoretical predictions. An outlook on future experiments is given.

Nucleus Accumbens Acetylcholine Receptors Modulate Dopamine and Motivation.

PubMed

Collins, Anne L; Aitken, Tara J; Greenfield, Venuz Y; Ostlund, Sean B; Wassum, Kate M

2016-11-01

Environmental reward-predictive cues can motivate reward-seeking behaviors. Although this influence is normally adaptive, it can become maladaptive in disordered states, such as addiction. Dopamine release in the nucleus accumbens core (NAc) is known to mediate the motivational impact of reward-predictive cues, but little is known about how other neuromodulatory systems contribute to cue-motivated behavior. Here, we examined the role of the NAc cholinergic receptor system in cue-motivated behavior using a Pavlovian-to-instrumental transfer task designed to assess the motivating influence of a reward-predictive cue over an independently-trained instrumental action. Disruption of NAc muscarinic acetylcholine receptor activity attenuated, whereas blockade of nicotinic receptors augmented cue-induced invigoration of reward seeking. We next examined a potential dopaminergic mechanism for this behavioral effect by combining fast-scan cyclic voltammetry with local pharmacological acetylcholine receptor manipulation. The data show evidence of opposing modulation of cue-evoked dopamine release, with muscarinic and nicotinic receptor antagonists causing suppression and augmentation, respectively, consistent with the behavioral effects of these manipulations. In addition to demonstrating cholinergic modulation of naturally-evoked and behaviorally-relevant dopamine signaling, these data suggest that NAc cholinergic receptors may gate the expression of cue-motivated behavior through modulation of phasic dopamine release.

Localization and characterization of angiotensin II receptor binding and angiotensin converting enzyme in the human medulla oblongata.

PubMed

Allen, A M; Chai, S Y; Clevers, J; McKinley, M J; Paxinos, G; Mendelsohn, F A

1988-03-08

Angiotensin II receptor and angiotensin converting enzyme distributions in the human medulla oblongata were localised by quantitative in vitro autoradiography. Angiotensin II receptors were labelled with the antagonist analogue 125I-[Sar1, Ile8] AII while angiotensin converting enzyme was labelled with 125I-351A, a derivative of the specific converting enzyme inhibitor, lisinopril. Angiotensin II receptor binding and angiotensin converting enzyme are present in high concentrations in the nucleus of the solitary tract, the dorsal motor nucleus of vagus, the rostral and caudal ventrolateral reticular nucleus, and in a band connecting the dorsal and ventral regions. In the rostral and caudal ventrolateral reticular nucleus, angiotensin II receptors are distributed in a punctate pattern that registers with neuronal cell bodies. The distribution and density of these cell bodies closely resemble those of catecholamine-containing neurones mapped by others. In view of the known interactions of angiotensin II with both central and peripheral catecholamine-containing neurons of laboratory animals, the current anatomical findings suggest similar interactions between these neuroactive compounds in the human central nervous system. The presence of angiotensin II receptors and angiotensin converting enzyme in the nucleus of the solitary tract, dorsal motor nucleus of vagus, and rostral and caudal ventrolateral reticular nucleus demonstrates sites for central angiotensin II to exert its known actions on vasopressin release and autonomic functions including blood pressure control. These data also suggest a possible interaction between angiotensin II and central catecholeminergic systems.

First Search for the EMC Effect and Nuclear Shadowing in Neutrino Nucleus Deep Inelastic Scattering at MINERvA

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mousseau, Joel A.

2015-01-01

Decades of research in electron-nucleus deep inelastic scattering (DIS) have provided a clear picture of nuclear physics at high momentum transfer. While these effects have been clearly demonstrated by experiment, the theoretical explanation of their origin in some kinematic regions has been lacking. Particularly, the effects in the intermediate regions of Bjorken-x, anti-shadowing and the EMC effect have no universally accepted quantum mechanical explanation. In addition, these effects have not been measured systematically with neutrino-nucleus deep inelastic scattering, due to experiments lacking multiple heavy targets.

Phenobarbital blockade of the preovulatory luteinizing hormone surge: association with phase-advanced circadian clock and altered suprachiasmatic nucleus Period1 gene expression

PubMed Central

Legan, Sandra J.; Donoghue, Kathleen M.; Franklin, Kathleen M.; Duncan, Marilyn J.

2009-01-01

The suprachiasmatic nucleus (SCN) controls the timing of the preovulatory luteinizing hormone (LH) surge in laboratory rodents. Barbiturate administration during a critical period on proestrus delays the surge and prolongs the estrous cycle 1 day. Because a nonphotic timing signal (zeitgeber) during the critical period that phase advances activity rhythms can also induce the latter effect, we hypothesized that barbiturates delay the LH surge by phase-advancing its circadian timing signal beyond the critical period. In experiment 1, locomotor rhythms and estrous cycles were monitored in hamsters for 2–3 wk preinjection and postinjection of vehicle or phenobarbital and after transfer to darkness at zeitgeber time (ZT) 6 on proestrus. Phenobarbital delayed estrous cycles in five of seven hamsters, which exhibited phase shifts that averaged twofold greater than those exhibited by vehicle controls or phenobarbital-injected hamsters with normal cycles. Experiment 2 used a similar protocol, but injections were at ZT 5, and blood samples for LH determination were collected from 1200 to 1800 on proestrus and the next day via jugular cannulae inserted the day before proestrus. Phenobarbital delayed the LH surge 1 day in all six hamsters, but it occurred at an earlier circadian time, supporting the above hypothesis. Experiment 3 investigated whether phenobarbital, like other nonphotic zeitgebers, suppresses SCN Period1 and Period2 transcription. Two hours postinjection, phenobarbital decreased SCN expression of only Period1 mRNA, as determined by in situ hybridization. These results suggest that phenobarbital advances the SCN pacemaker, governing activity rhythms and hormone release in part by decreasing its Period1 gene expression. PMID:19297538

Photoreceptive oscillators within neurons of the premammillary nucleus (PMM) and seasonal reproduction in temperate zone birds.

PubMed

Kosonsiriluk, Sunantha; Mauro, Laura J; Chaiworakul, Voravasa; Chaiseha, Yupaporn; El Halawani, Mohamed E

2013-09-01

The pathway for light transmission regulating the reproductive neuroendocrine system in temperate zone birds remains elusive. Based on the evidence provided from our studies with female turkeys, it is suggested that the circadian clock regulating reproductive seasonality is located in putatively photosensitive dopamine-melatonin (DA-MEL) neurons residing in the premammillary nucleus (PMM) of the caudal hypothalamus. Melanopsin is expressed by these neurons; a known photopigment which mediates light information pertaining to the entrainment of the clock. Exposure to a gonad stimulatory photoperiod enhances the activity of the DAergic system within DA-MEL neurons. DAergic activity encoding the light information is transmitted to the pars tuberalis, where thyroid-stimulating hormone, beta (TSHβ) cells reside, and induces the release of TSH. TSH stimulates tanycytes lining the base of the third ventricle and activates type 2 deiodinase in the ependymal which enhances triiodothyronine (T3) synthesis. T3 facilitates the release of gonadotropin-releasing hormone-I which stimulates luteinizing hormone/follicle stimulating hormone release and gonad recrudescence. These data taken together with the findings that clock genes are rhythmically expressed in the PMM where DA-MEL neurons are localized imply that endogenous oscillators containing photoreceptors within DA-MEL neurons are important in regulating the DA and MEL rhythms that drive the circadian cycle controlling seasonal reproduction. Published by Elsevier Inc.

Bidirectional synaptic plasticity in the cerebellum-like mammalian dorsal cochlear nucleus

NASA Astrophysics Data System (ADS)

Fujino, Kiyohiro; Oertel, Donata

2003-01-01

The dorsal cochlear nucleus integrates acoustic with multimodal sensory inputs from widespread areas of the brain. Multimodal inputs are brought to spiny dendrites of fusiform and cartwheel cells in the molecular layer by parallel fibers through synapses that are subject to long-term potentiation and long-term depression. Acoustic cues are brought to smooth dendrites of fusiform cells in the deep layer by auditory nerve fibers through synapses that do not show plasticity. Plasticity requires Ca2+-induced Ca2+ release; its sensitivity to antagonists of N-methyl-D-aspartate and metabotropic glutamate receptors differs in fusiform and cartwheel cells.

Observation of direct hadronic pairs in nucleus-nucleus collisions in JACEE emulsion chambers

NASA Technical Reports Server (NTRS)

Burnett, T. H.; Dake, S.; Fuki, M.; Gregory, J. C.; Hayashi, T.; Hayashi, T.; Holynski, R.; Iwai, J.; Jones, W. V.; Jurak, A.

1985-01-01

In a number of high energy ( or = 1 TeV/amu) nucleus-nucleus collisions observed in Japanese-American Cooperative Emulsion Experiment (JACEE) emulsion chambers, nonrandom spatial association of produced charged particles, mostly hadronic pairs, are observed. Similar narrow pairs are observed in about 100 events at much low energy (20 to 60 GeV/amu). Analysis shows that 30 to 50% of Pair abundances are understood by the Hambury-Brown-Twiss effect, and the remainder seems to require other explanations.

Satellite control system nucleus for the Brazilian complete space mission

NASA Astrophysics Data System (ADS)

Yamaguti, Wilson; Decarvalhovieira, Anastacio Emanuel; Deoliveira, Julia Leocadia; Cardoso, Paulo Eduardo; Dacosta, Petronio Osorio

1990-10-01

The nucleus of the satellite control system for the Brazilian data collecting and remote sensing satellites is described. The system is based on Digital Equipment Computers and the VAX/VMS operating system. The nucleus provides the access control, the system configuration, the event management, history files management, time synchronization, wall display control, and X25 data communication network access facilities. The architecture of the nucleus and its main implementation aspects are described. The implementation experience acquired is considered.

Toward centrality determination at NICA/MPD

NASA Astrophysics Data System (ADS)

Galoyan, A. S.; Uzhinsky, V. V.

2017-03-01

Geometrical properties of nucleus-nucleus interactions at various centralities are calculated for the NICA energy range. A modified version of the Glauber Monte Carlo simulation code has been used for the calculations. It is shown that the geometrical properties of nucleus-nucleus interactions at the energies 5 - 10 GeV (NICA/MPD) and at energy 200 GeV (RHIC) are quite close to each other. A possible determination of centrality at NICA/MPD experiment using calculations of various Monte Carlo event generators are considered.

Characterizing the interior of 67P in the vicinity of Abydos

NASA Astrophysics Data System (ADS)

Ciarletti, V.; Lasue, J.; Lemonnier, F.; Herique, A.; Kofman, W. W.; Guiffaut, C.; Levasseur-Regourd, A. C.; Plettemeier, D.

2016-12-01

Since the arrival of Rosetta at comet 67P, numerous pictures have been delivered by the cameras onboard both the main spacecraft and the Philae lander. They revealed, at the nucleus' surface and inside the walls of the deep pits, few-meters scale repeating structures, thus providing hints about the internal structure of the nucleus, and suggesting that primordial 'cometesimals' may be objects around 3m in size. The CONSERT (Comet Nucleus Sounding Experiment by Radiowave Transmission) experiment is a radar that has been designed to specifically sound the interior of the nucleus and to provide information on the nucleus internal structure. The work presented here is based on the CONSERT data collected during the First Science Sequence (FSS) and marginally during Philae's Separation Descent and Landing (SDL) for comparison. During FFS, the smaller lobe of the nucleus in the vicinity of Abydos has been actually sounded by CONSERT's electromagnetic waves at 90 MHz with a spatial resolution around 10 m. The propagation delays measured during FSS are consistent with a very low bulk permittivity value for the investigated cometary material, which confirms the high porosity of the nucleus. The sharp shape of the received pulses indicates that the electromagnetic waves suffered weak scattering when propagating through the nucleus. This suggests that the sounded part nucleus is thus fairly homogeneous on a spatial scale of tens of meters. We will present further results on the variation of the CONSERT's pulse shape transmitted through the small lobe of the nucleus. For a more accurate analysis and interpretation of the data, we split the FSS data into two distinct sets corresponding to soundings performed West and East of Philae in order to investigate potential differences. Tentative interpretation in terms of nucleus internal structure based on propagation simulations performed in non-homogeneous nucleus numerical models will be presented.

Comparison of speech perception performance between Sprint/Esprit 3G and Freedom processors in children implanted with nucleus cochlear implants.

PubMed

Santarelli, Rosamaria; Magnavita, Vincenzo; De Filippi, Roberta; Ventura, Laura; Genovese, Elisabetta; Arslan, Edoardo

2009-04-01

To compare speech perception performance in children fitted with previous generation Nucleus sound processor, Sprint or Esprit 3G, and the Freedom, the most recently released system from the Cochlear Corporation that features a larger input dynamic range. Prospective intrasubject comparative study. University Medical Center. Seventeen prelingually deafened children who had received the Nucleus 24 cochlear implant and used the Sprint or Esprit 3G sound processor. Cochlear implantation with Cochlear device. Speech perception was evaluated at baseline (Sprint, n = 11; Esprit 3G, n = 6) and after 1 month's experience with the Freedom sound processor. Identification and recognition of disyllabic words and identification of vowels were performed via recorded voice in quiet (70 dB [A]), in the presence of background noise at various levels of signal-to-noise ratio (+10, +5, 0, -5) and at a soft presentation level (60 dB [A]). Consonant identification and recognition of disyllabic words, trisyllabic words, and sentences were evaluated in live voice. Frequency discrimination was measured in a subset of subjects (n = 5) by using an adaptive, 3-interval, 3-alternative, forced-choice procedure. Identification of disyllabic words administered at a soft presentation level showed a significant increase when switching to the Freedom compared with the previously worn processor in children using the Sprint or Esprit 3G. Identification and recognition of disyllabic words in the presence of background noise as well as consonant identification and sentence recognition increased significantly for the Freedom compared with the previously worn device only in children fitted with the Sprint. Frequency discrimination was significantly better when switching to the Freedom compared with the previously worn processor. Serial comparisons revealed that that speech perception performance evaluated in children aged 5 to 15 years was superior with the Freedom than previous generations of Nucleus sound processors. These differences are deemed to ensue from an increased input dynamic range, a feature that offers potentially enhanced phonemic discrimination.

Purinergic A2b Receptor Activation by Extracellular Cues Affects Positioning of the Centrosome and Nucleus and Causes Reduced Cell Migration.

PubMed

Ou, Young; Chan, Gordon; Zuo, Jeremy; Rattner, Jerome B; van der Hoorn, Frans A

2016-07-15

The tight, relative positioning of the nucleus and centrosome in mammalian cells is important for the regulation of cell migration. Under pathophysiological conditions, the purinergic A2b receptor can regulate cell motility, but the underlying mechanism remains unknown. Expression of A2b, normally low, is increased in tissues experiencing adverse physiological conditions, including hypoxia and inflammation. ATP is released from such cells. We investigated whether extracellular cues can regulate centrosome-nucleus positioning and cell migration. We discovered that hypoxia as well as extracellular ATP cause a reversible increase in the distance between the centrosome and nucleus and reduced cell motility. We uncovered the underlying pathway: both treatments act through the A2b receptor and specifically activate the Epac1/RapGef3 pathway. We show that cells lacking A2b do not respond in this manner to hypoxia or ATP but transfection of A2b restores this response, that Epac1 is critically involved, and that Rap1B is important for the relative positioning of the centrosome and nucleus. Our results represent, to our knowledge, the first report demonstrating that pathophysiological conditions can impact the distance between the centrosome and nucleus. Furthermore, we identify the A2b receptor as a central player in this process. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Purinergic A2b Receptor Activation by Extracellular Cues Affects Positioning of the Centrosome and Nucleus and Causes Reduced Cell Migration*

PubMed Central

Ou, Young; Chan, Gordon; Zuo, Jeremy; Rattner, Jerome B.; van der Hoorn, Frans A.

2016-01-01

The tight, relative positioning of the nucleus and centrosome in mammalian cells is important for the regulation of cell migration. Under pathophysiological conditions, the purinergic A2b receptor can regulate cell motility, but the underlying mechanism remains unknown. Expression of A2b, normally low, is increased in tissues experiencing adverse physiological conditions, including hypoxia and inflammation. ATP is released from such cells. We investigated whether extracellular cues can regulate centrosome-nucleus positioning and cell migration. We discovered that hypoxia as well as extracellular ATP cause a reversible increase in the distance between the centrosome and nucleus and reduced cell motility. We uncovered the underlying pathway: both treatments act through the A2b receptor and specifically activate the Epac1/RapGef3 pathway. We show that cells lacking A2b do not respond in this manner to hypoxia or ATP but transfection of A2b restores this response, that Epac1 is critically involved, and that Rap1B is important for the relative positioning of the centrosome and nucleus. Our results represent, to our knowledge, the first report demonstrating that pathophysiological conditions can impact the distance between the centrosome and nucleus. Furthermore, we identify the A2b receptor as a central player in this process. PMID:27226580

Differential response of TRHergic neurons of the hypothalamic paraventricular nucleus (PVN) in female animals submitted to food-restriction or dehydration-induced anorexia and cold exposure.

PubMed

Jaimes-Hoy, Lorraine; Joseph-Bravo, Patricia; de Gortari, Patricia

2008-02-01

TRH neurons of the hypothalamic paraventricular nucleus (PVN), regulate pituitary-thyroid axis (HPT). Fasting activates expression of orexigenic peptides from the arcuate nucleus, increases corticosterone while reduces leptin, and pro-TRH mRNA levels despite low serum thyroid hormone concentration (tertiary hypothyroidism). TRH synthesis is positively regulated by anorexigenic peptides whose expression is reduced in fasting. The model of dehydration-induced anorexia (DIA) leads to decreased voluntary food intake but peptide expression in the arcuate is similar to forced-food restriction (FFR), where animals remain hungered. We compared the response of HPT axis of female Wistar rats submitted to DIA (2.5% saline solution, food ad libitum, 7 days) with FFR (provided with the amount of food ingested by DIA) and naïve (N) group fed ad libitum, as well as their response to acute cold exposure. Pro-TRH and pro-CRH mRNA levels in the PVN were measured by RT-PCR, TRH content, serum concentration of TSH and thyroid hormones by radioimmunoassay. DIA rats reduced 80% their food consumption compared to N, decreased PVN pro-CRH expression, serum estradiol and leptin levels, increased corticosterone similar to FFR. HPT axis of DIA animals failed to adapt: FFR presented tertiary hypothyroidism and DIA, primary. Response to cold stimulation leading to increased pro-TRH mRNA levels and TRH release was preserved under reduced energy availability in FFR rats but not in DIA, although the dynamics of hormonal release differed: TSH release augmented only in naïve; thyroxine in all but highest in DIA, and triiodothyronine in FFR and DIA suggesting a differential regulation of deiodinases.

Neuromedin B and gastrin releasing peptide excite arcuate nucleus neuropeptide Y neurons in a novel transgenic mouse expressing strong renilla GFP in NPY neurons

PubMed Central

van den Pol, Anthony N.; Yao, Yang; Fu, Li-Ying; Foo, Kylie; Huang, Hao; Coppari, Roberto; Lowell, Brad; Broberger, Christian

2009-01-01

Neuropeptide Y (NPY) is one of the most widespread neuropeptides in the brain. Transgenic mice were generated that expressed bright renilla GFP in most or all of the known NPY cells in the brain, which otherwise were not identifiable. GFP expression in NPY cells was confirmed with immunocytochemistry and single cell RT-PCR. NPY neurons in the hypothalamic arcuate nucleus play an important role in energy homeostasis and endocrine control. Whole cell patch clamp recording was used to study identified arcuate NPY cells. Primary agents that regulate energy balance include melanocortin receptor agonists, AgRP, and cannabinoids; none of these substances substantially influenced electrical properties of NPY neurons. In striking contrast, neuropeptides of the bombesin family, including gastrin releasing peptide and neuromedin B which are found in axons in the arcuate nucleus and may also be released from the gut to signal the brain, showed strong direct excitatory actions at nanomolar levels on the NPY neurons, stronger than the actions of ghrelin and hypocretin/orexin. Bombesin-related peptides reduced input resistance and depolarized the membrane potential. The depolarization was attenuated by several factors: substitution of choline for sodium, extracellular Ni2+, inclusion of BAPTA in the pipette, KB-R7943 and SKF96365. Reduced extracellular calcium enhanced the current, which reversed around − 20 mV. Together, these data suggest two mechanisms, activation of non-selective cation channels and the sodium/calcium exchanger. Since both NPY and POMC neurons, which we also studied, are similarly directly excited by bombesin-like peptides, the peptides may function to initiate broad activation, rather than the cell-type selective activation or inhibition reported for many other compounds that modulate energy homeostasis. PMID:19357287

On the evolution and activity of cometary nuclei.

PubMed

Prialnik, D; Bar-Nun, A

1987-02-15

The thermal evolution of a spherical cometary nucleus (initial radius of 2.5 km), composed initially of very cold amorphous ice and moving in comet Halley's orbit, is simulated numerically for 280 revolutions. It is found that the phase transition from amorphous to crystalline ice constitutes a major internal heat source. The transition does not occur continuously, but in five distinct rounds, during the following revolutions: 1, 7, 40-41, 110-112, and 248-252. Due to the (slow) heating of the amorphous ice between crystallization rounds, the phase transition front advances into the nucleus to progressively greater depths: 36 m on the first round, and then 91 m, 193 m, 381 m, and 605 m respectively. Each round of crystallization starts when when the boundary between amorphous and crystalline ice is brought to approximately 15 m below the surface, as the nucleus radius decreases due to sublimation. At the time of crystallization, the temperature of the transformed ice rises to 180 K. According to experimental studies of gas-laden amorphous ice, a large fraction of the gas trapped in the ice at low temperatures is released. Whereas some of the released gas may find its way out through cracks in the crystalline ice layer, the rest is expected to accumulate in gas pockets that may eventually explode, forming "volcanic calderas." The gas-laden amorphous ice thus exposed may be a major source of gas and dust jets into the coma, such as those observed on comet Halley by the Giotto spacecraft. The activity of new comets and, possibly, cometary outbursts and splits may also be explained in terms of explosive gas release following the transition from amorphous to crystalline ice.

Chronic lithium treatment rectifies maladaptive dopamine release in the nucleus accumbens.

PubMed

Can, Adem; Frost, Douglas O; Cachope, Roger; Cheer, Joseph F; Gould, Todd D

2016-11-01

Chronic lithium treatment effectively reduces behavioral phenotypes of mania in humans and rodents. The mechanisms by which lithium exerts these actions are poorly understood. Pre-clinical and clinical evidence have implicated increased mesolimbic dopamine (DA) neurotransmission with mania. We used fast-scan cyclic voltammetry to characterize changes in extracellular DA concentrations in the nucleus accumbens (NAc) core evoked by 20 and 60 Hz electrical stimulation of the ventral tegmental area (VTA) in C57BL6/J mice treated either acutely or chronically with lithium. The effects of chronic lithium treatment on the availability of DA for release were assessed by depleting readily releasable DA using short inter-train intervals, or administering d-amphetamine acutely to mobilize readily releasable DA. Chronic, but not acute, lithium treatment decreased the amplitude of DA responses in the NAc following 60 Hz pulse train stimulation. Neither lithium treatment altered the kinetics of DA release or reuptake. Chronic treatment did not impact the progressive reduction in the amplitude of DA responses when, using 20 or 60 Hz pulse trains, the VTA was stimulated every 6 s to deplete DA. Specifically, the amplitude of DA responses to 60 Hz pulse trains was initially reduced compared to control mice, but by the fifth pulse train, there was no longer a treatment effect. However, chronic lithium treatment attenuated d-amphetamine-induced increases in DA responses to 20 Hz pulse trains stimulation. Our data suggest that long-term administration of lithium may ameliorate mania phenotypes by normalizing the readily releasable DA pool in VTA axon terminals in the NAc. Read the Editorial Highlight for this article on Page 520. © 2016 International Society for Neurochemistry.

pH-responsive charge-reversal polymer-functionalized boron nitride nanospheres for intracellular doxorubicin delivery

PubMed Central

Feng, Shini; Zhi, Chunyi; Gao, Xiao-Dong

2018-01-01

Background Anticancer drug-delivery systems (DDSs) capable of responding to the physiological stimuli and efficiently releasing drugs inside tumor cells are highly desirable for effective cancer therapy. Herein, pH-responsive, charge-reversal poly(allylamine hydrochlorid)−citraconic anhydride (PAH-cit) functionalized boron nitride nanospheres (BNNS) were fabricated and used as a carrier for the delivery and controlled release of doxorubicin (DOX) into cancer cells. Methods BNNS was synthesized through a chemical vapor deposition method and then functionalized with synthesized charge-reversal PAH-cit polymer. DOX@PAH-cit–BNNS complexes were prepared via step-by-step electrostatic interactions and were fully characterized. The cellular uptake of DOX@PAH-cit–BNNS complexes and DOX release inside cancer cells were visualized by confocal laser scanning microscopy. The in vitro anticancer activity of DOX@ PAH-cit–BNNS was examined using CCK-8 and live/dead viability/cytotoxicity assay. Results The PAH-cit–BNNS complexes were nontoxic to normal and cancer cells up to a concentration of 100 µg/mL. DOX was loaded on PAH-cit–BNNS complexes with high efficiency. In a neutral environment, the DOX@PAH-cit–BNNS was stable, whereas the loaded DOX was effectively released from these complexes at low pH condition due to amide hydrolysis of PAH-cit. Enhanced cellular uptake of DOX@PAH-cit–BNNS complexes and DOX release in the nucleus of cancer cells were revealed by confocal microscopy. Additionally, the effective delivery and release of DOX into the nucleus of cancer cells led to high therapeutic efficiency. Conclusion Our findings indicated that the newly developed PAH-cit–BNNS complexes are promising as an efficient pH-responsive DDS for cancer therapy. PMID:29440891

Adolescent binge-like alcohol alters sensitivity to acute alcohol effects on dopamine release in the nucleus accumbens of adult rats

PubMed Central

Shnitko, Tatiana A.; Spear, Linda P.; Robinson, Donita L.

2015-01-01

Rationale Early onset of alcohol drinking has been associated with alcohol abuse in adulthood. The neurobiology of this phenomenon is unclear, but mesolimbic dopamine pathways, which are dynamic during adolescence, may play a role. Objectives We investigated the impact of adolescent binge-like alcohol on phasic dopaminergic neurotransmission during adulthood. Methods Rats received intermittent intragastric ethanol, water or nothing during adolescence. In adulthood, electrically-evoked dopamine release and subsequent uptake were measured in the nucleus accumbens core at baseline and after acute challenge of ethanol or saline. Results Adolescent ethanol exposure did not alter basal measures of evoked dopamine release or uptake. Ethanol challenge dose-dependently decreased the amplitude of evoked dopamine release in rats by 30–50% in control groups, as previously reported, but did not alter evoked release in ethanol-exposed animals. To address the mechanism by which ethanol altered dopamine signaling, the evoked signals were modeled to estimate dopamine efflux per impulse and the velocity of the dopamine transporter. Dopamine uptake was slower in all exposure groups after ethanol challenge compared to saline, while dopamine efflux per pulse of electrical stimulation was reduced by ethanol only in ethanol-naive rats. Conclusions The results demonstrate that exposure to binge levels of ethanol during adolescence blunts the effect of ethanol challenge to reduce the amplitude of phasic dopamine release in adulthood. Large dopamine transients may result in more extracellular dopamine after alcohol challenge in adolescent-exposed rats, and may be one mechanism by which alcohol is more reinforcing in people who initiated drinking at an early age. PMID:26487039

Interplay between presynaptic and postsynaptic activities is required for dendritic plasticity and synaptogenesis in the supraoptic nucleus.

PubMed

Chevaleyre, Vivien; Moos, Francoise C; Desarménien, Michel G

2002-01-01

Developing oxytocin and vasopressin (OT/AVP) supraoptic nucleus (SON) neurons positively autocontrol their electrical activity via dendritic release of their respective peptide. The effects of this autocontrol are maximum during the second postnatal week (PW2), when the dendritic arbor transiently increases and glutamatergic postsynaptic potentials appear. Here, we studied the role and interaction of dendritic OT/AVP release and glutamate release in dendritic plasticity and synaptogenesis in SON. In vivo treatment with the peptides antagonists or with an NMDA antagonist suppressed the transient increase in dendritic arbor of SON neurons at the beginning of PW2. Incubation of acute slices with these compounds decreased the dendritic arbor on a short time scale (3-8 hr) in slices of postnatal day 7 (P7) to P9 rats. Conversely, application of OT/AVP or NMDA increased dendritic branches in slices of P3-P6 rats. Their effects were inhibited by blockade of electrical activity, voltage-gated Ca2+ channels, or intracellular Ca2+ mobilization. They were also interdependent because both OT/AVP and NMDA (but not AMPA) receptor activation were required for increasing the dendritic arbor. Part of this interdependence probably results from a retrograde action of the peptides facilitating glutamate release. Finally, blocking OT/AVP receptors by in vivo treatment with the peptides antagonists during development decreased spontaneous glutamatergic synaptic activity recorded in young adults. These results show that an interplay between postsynaptic dendritic peptide release and presynaptic glutamate release is involved in the transient increase in dendritic arbor of SON neurons and indicate that OT/AVP are required for normal synaptogenesis of glutamatergic inputs in SON.

Nicotine-induced Conditional Place Preference is Affected by Head Injury: Correlation with Dopamine Release in the Nucleus Accumbens Shell.

PubMed

Yuan-Hao, Chen; Kuo, Tung-Tai; Huang, Eagle Yi-Kung; Hoffer, Barry J; Kao, Jen-Hsin; Chou, Yu-Ching; Chiang, Yung-Hsiao; Miller, Jonathan

2018-06-14

Traumatic brain injury (TBI) is known to impact dopamine-mediated reward pathways, but the underlying mechanisms have not been fully established. Nicotine-induced conditional place preference (CPP) was used to study rats exposed to a 6-psi fluid percussion injury (FPI) with and without prior exposure to nicotine. Preference was quantified as a score defined as (C1-C2) / (C1+C2), where C1 is time in the nicotine-paired compartment and C2 is time in the saline-paired compartment. Subsequent fast-scan cyclic voltammetry (FSCV) was used to analyze the impact of nicotine infusion on dopamine release in the shell portion of the nucleus accumbens (NAc). To further determine the influence of brain injury on nicotine withdrawal, nicotine infusion was administered to the rats after FPI. The effects of FPI on CPP after prior exposure to nicotine and abstinence or withdrawal from nicotine were also assessed. After TBI, dopamine release was reduced in the NAc shell, and nicotine-induced CPP preference was significantly impaired. Preference scores of control, sham-injured, and FPI groups were 0.1627 ± 0.04204, 0.1515 ± 0.03806, and -0.001300 ± 0.04286, respectively. Nicotine-induced CPP was also seen in animals after nicotine pre-treatment, with a CPP score of 0.07805 ± 0.02838. Nicotine pre-exposure substantially increased tonic dopamine release in sham-injured animals, but it did not change phasic release; nicotine exposure after FPI enhanced phasic release, though not to the same levels seen in sham-injured rats. Conditioned preference was related not only to phasic dopamine release (r= 0.8110) but also to the difference between tonic and phasic dopamine levels (r= 0.9521). TBI suppresses dopamine release from the shell portion of the NAc, which in turn significantly alters reward-seeking behavior. These results have important implications for tobacco and drug use after TBI.

A Simple Method for Nucleon-Nucleon Cross Sections in a Nucleus

NASA Technical Reports Server (NTRS)

Tripathi, R. K.; Cucinotta, Francis A.; Wilson, John W.

1999-01-01

A simple reliable formalism is presented for obtaining nucleon-nucleon cross sections within a nucleus in nuclear collisions for a given projectile and target nucleus combination at a given energy for use in transport, Monte Carlo, and other calculations. The method relies on extraction of these values from experiments and has been tested and found to give excellent results.

Long term potentiation depends on release of D-serine from astrocytes

PubMed Central

Henneberger, Christian; Papouin, Thomas; Oliet, Stéphane H. R.; Rusakov, Dmitri A.

2009-01-01

Long-term potentiation (LTP) of synaptic transmission provides an experimental model for studying mechanisms of memory1. The classical form of LTP relies on N-methyl-D-aspartate receptors (NMDARs), and it has emerged that astroglia can regulate their activation through Ca2+-dependent release of the NMDAR co-agonist D-serine2-4. Release of D-serine from glia enables LTP in cultures5 and explains a correlation between glial coverage of synapses and LTP in the supraoptic nucleus4. However, Ca2+ elevations in astroglia can also release other signalling molecules, most prominently glutamate6-8, Adenosine-5′-triphosphate9, and Tumor-Necrosis-Factor-α10,11 whereas neurons themselves can synthesise and supply D-serine12,13. Furthermore, loading an astrocyte with exogenous Ca2+ buffers does not suppress LTP in hippocampal area CA114-16, and the physiological relevance of experiments in cultures or strong exogenous stimuli applied to astrocytes has been questioned17,18. The involvement of glia in LTP induction thus remains controversial. Here we show that clamping internal Ca2+ in individual CA1 astrocytes blocks LTP induction at nearby excitatory synapses by reducing the occupancy of the NMDAR co-agonist sites. This LTP blockade can be reversed by exogenous D-serine or glycine whereas depletion of D-serine or disruption of exocytosis in an individual astrocyte blocks local LTP. We thus demonstrate that Ca2+-dependent release of D-serine from an astrocyte controls NMDAR-dependent plasticity in many thousands of excitatory synapses occurring nearby. PMID:20075918

Concomitant Release of Ventral Tegmental Acetylcholine and Accumbal Dopamine by Ghrelin in Rats

PubMed Central

Jerlhag, Elisabet; Janson, Anna Carin; Waters, Susanna; Engel, Jörgen A.

2012-01-01

Ghrelin, an orexigenic peptide, regulates energy balance specifically via hypothalamic circuits. Growing evidence suggest that ghrelin increases the incentive value of motivated behaviours via activation of the cholinergic-dopaminergic reward link. It encompasses the cholinergic afferent projection from the laterodorsal tegmental area (LDTg) to the dopaminergic cells of the ventral tegmental area (VTA) and the mesolimbic dopamine system projecting from the VTA to nucleus accumbens (N.Acc.). Ghrelin receptors (GHS-R1A) are expressed in these reward nodes and ghrelin administration into the LDTg increases accumbal dopamine, an effect involving nicotinic acetylcholine receptors in the VTA. The present series of experiments were undertaken directly to test this hypothesis. Here we show that ghrelin, administered peripherally or locally into the LDTg concomitantly increases ventral tegmental acetylcholine as well as accumbal dopamine release. A GHS-R1A antagonist blocks this synchronous neurotransmitter release induced by peripheral ghrelin. In addition, local perfusion of the unselective nicotinic antagonist mecamylamine into the VTA blocks the ability of ghrelin (administered into the LDTg) to increase N.Acc.-dopamine, but not VTA-acetylcholine. Collectively our data indicate that ghrelin activates the LDTg causing a release of acetylcholine in the VTA, which in turn activates local nicotinic acetylcholine receptors causing a release of accumbal dopamine. Given that a dysfunction in the cholinergic-dopaminergic reward system is involved in addictive behaviours, including compulsive overeating and alcohol use disorder, and that hyperghrelinemia is associated with such addictive behaviours, ghrelin-responsive circuits may serve as a novel pharmacological target for treatment of alcohol use disorder as well as binge eating. PMID:23166710

Electron Scattering Measurements applied to Neutrino Interactions on Nuclei

NASA Astrophysics Data System (ADS)

Christy, M. Eric

2013-04-01

The extraction of neutrino mass differences and flavor mixing parameters from oscillation experiments requires models of neutrino-nucleus scattering as input. With the reduction of other systematics, the uncertainties stemming from such models are expected to be one of the larger contributions to the systematic uncertainties for next generation oscillation experiments. The neutrino energy range sensitive to oscillations in long baseline experiments is typically the few GeV range, where the interactions with the nucleus and the subsequent production and propagation of hadrons within the nucleus is in the regime studied by nuclear physics experiments at facilities such as Jefferson Lab. While processes such as resonance production have been well studied in electron scattering, there is currently precious little corresponding data from neutrino scattering. Results from electron scattering experiments, therefore, have an important role to play in both building and constraining models for neutrino scattering. On the other hand, the study of nucleon structure via weak probes is very complementary to the program at Jefferson Lab utilizing electromagnetic probes. Neutrino scattering experiments such at MINERvA are expected to provide new experimental information on axial elastic and resonance transition form factors and on medium modifications via the axial coupling. This talk will focus on the application of electron scattering measurements to neutrino interactions on nuclei, but will also touch on where neutrino scattering measurements can add to our understanding of the nucleus.

Action potential-independent and pharmacologically unique vesicular serotonin release from dendrites

PubMed Central

Colgan, Lesley A.; Cavolo, Samantha L.; Commons, Kathryn G.; Levitan, Edwin S.

2012-01-01

Serotonin released within the dorsal raphe nucleus (DR) induces feedback inhibition of serotonin neuron activity and consequently regulates mood-controlling serotonin release throughout the forebrain. Serotonin packaged in vesicles is released in response to action potentials by the serotonin neuron soma and terminals, but the potential for release by dendrites is unknown. Here three-photon (3P) microscopy imaging of endogenous serotonin in living rat brain slice, immunofluorescence and immuno-gold electron microscopy detection of VMAT2 (vesicular monoamine transporter 2) establish the presence of vesicular serotonin within DR dendrites. Furthermore, activation of glutamate receptors is shown to induce vesicular serotonin release from dendrites. However, unlike release from the soma and terminals, dendritic serotonin release is independent of action potentials, relies on L-type Ca2+ channels, is induced preferentially by NMDA, and displays distinct sensitivity to the selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine. The unique control of dendritic serotonin release has important implications for DR physiology and the antidepressant action of SSRIs, dihydropyridines and NMDA receptor antagonists. PMID:23136413

Immunohistochemical localization of luteinizing hormone-releasing hormone (LHRH) in the hypothalamus of adult female hamsters treated neonatally with monosodium glutamate or hypertonic saline.

PubMed

Lamperti, A A; Pickard, G E

1984-05-01

The immunohistochemical localization of luteinizing hormone-releasing hormone (LHRH) was studied in paraffin and vibratome-sectioned tissue from adult female hamsters that were treated neonatally with monosodium glutamate (MSG) or hypertonic saline. There appeared to be a reduction in LHRH-positive fibers in the median eminence of animals with an MSG-induced lesion of the arcuate nucleus in paraffin-embedded tissue. However, when unembedded tissue was cut on a vibratome, the distribution of LHRH-positive fibers and perikarya was similar in both groups of animals. Fibers were seen coursing through the periventricular area and lateral hypothalamus to the median eminence. In addition, LHRH-positive fibers were seen in the organum vasculosum of the lamina terminalis, subfornical organ, septal and preoptic areas, fasciculus retroflexus, habenular complex, and several regions in the basal forebrain. Animals that were pretreated with colchicine had LHRH-positive perikarya in the medial habenular nucleus, diagonal band of Broca, and the medial olfactory tract.

Infection and Proliferation of Giant Viruses in Amoeba Cells.

PubMed

Takemura, Masaharu

2016-01-01

Acanthamoeba polyphaga mimivirus, the first discovered giant virus with genome size and particle size much larger than previously discovered viruses, possesses several genes for translation and CRISPER Cas system-like defense mechanism against virophages, which co-infect amoeba cells with the giant virus and which inhibit giant virus proliferation. Mimiviruses infect amoeba cells by phagocytosis and release their DNA into amoeba cytoplasm through their stargate structure. After infection, giant virion factories (VFs) form in amoeba cytoplasm, followed by DNA replication and particle formation at peripheral regions of VF. Marseilleviruses, the smallest giant viruses, infect amoeba cells by phagocytosis or endocytosis, form larger VF than Mimivirus's VF in amoeba cytoplasm, and replicate their particles. Pandoraviruses found in 2013 have the largest genome size and particle size among all viruses ever found. Pandoraviruses infect amoeba cells by phagocytosis and release their DNA into amoeba cytoplasm through their mouth-like apical pores. The proliferation of Pandoraviruses occurs along with nucleus disruption. New virions form at the periphery of the region formerly occupied by the amoeba cell nucleus.

Dynamics of rapid dopamine release in the nucleus accumbens during goal-directed behaviors for cocaine versus natural rewards

PubMed Central

Cameron, Courtney M.; Wightman, R. Mark; Carelli, Regina M.

2014-01-01

Electrophysiological studies show that distinct subsets of nucleus accumbens (NAc) neurons differentially encode information about goal-directed behaviors for intravenous cocaine versus natural (food/water) rewards. Further, NAc rapid dopamine signaling occurs on a timescale similar to phasic cell firing during cocaine and natural reward-seeking behaviors. However, it is not known whether dopamine signaling is reinforcer specific (i.e., is released during responding for only one type of reinforcer) within discrete NAc locations, similar to neural firing dynamics. Here, fast-scan cyclic voltammetry (FSCV) was used to measure rapid dopamine release during multiple schedules involving sucrose reward and cocaine self-administration (n=8 rats) and, in a separate group of rats (n = 6), during a sucrose/food multiple schedule. During the sucrose/cocaine multiple schedule, dopamine increased within seconds of operant responding for both reinforcers. Although dopamine release was not reinforcer specific, more subtle differences were observed in peak dopamine concentration [DA] across reinforcer conditions. Specifically, peak [DA] was higher during the first phase of the multiple schedule, regardless of reinforcer type. Further, the time to reach peak [DA] was delayed during cocaine-responding compared to sucrose. During the sucrose/food multiple schedule, increases in dopamine release were also observed relative to operant responding for both natural rewards. However, peak [DA] was higher relative to responding for sucrose than food, regardless of reinforcer order. Overall, the results reveal the dynamics of rapid dopamine signaling in discrete locations in the NAc across reward conditions, and provide novel insight into the functional role of this system in reward-seeking behaviors. PMID:25174553

Placebo and nocebo effects are defined by opposite opioid and dopaminergic responses.

PubMed

Scott, David J; Stohler, Christian S; Egnatuk, Christine M; Wang, Heng; Koeppe, Robert A; Zubieta, Jon-Kar

2008-02-01

Placebo and nocebo effects, the therapeutic and adverse effects, respectively, of inert substances or sham procedures, represent serious confounds in the evaluation of therapeutic interventions. They are also an example of cognitive processes, particularly expectations, capable of influencing physiology. To examine the contribution of 2 different neurotransmitters, the endogenous opioid and the dopaminergic (DA) systems, to the development of placebo and nocebo effects. Using a within-subject design, subjects twice underwent a 20-minute standardized pain challenge, in the absence and presence of a placebo with expected analgesic properties. Studies were conducted in a university hospital setting. Twenty healthy men and women aged 20 to 30 years recruited by advertisement. Activation of DA and opioid neurotransmission by a pain stressor with and without placebo (changes in the binding potential of carbon 11 [11C]-labeled raclopride and [11C] carfentanil with positron emission tomography) and ratings of pain, affective state, and anticipation and perception of analgesia. Placebo-induced activation of opioid neurotransmission was detected in the anterior cingulate, orbitofrontal and insular cortices, nucleus accumbens, amygdala, and periaqueductal gray matter. Dopaminergic activation was observed in the ventral basal ganglia, including the nucleus accumbens. Regional DA and opioid activity were associated with the anticipated and subjectively perceived effectiveness of the placebo and reductions in continuous pain ratings. High placebo responses were associated with greater DA and opioid activity in the nucleus accumbens. Nocebo responses were associated with a deactivation of DA and opioid release. Nucleus accumbens DA release accounted for 25% of the variance in placebo analgesic effects. Placebo and nocebo effects are associated with opposite responses of DA and endogenous opioid neurotransmission in a distributed network of regions. The brain areas involved in these phenomena form part of the circuit typically implicated in reward responses and motivated behavior.

The big CGRP flood - sources, sinks and signalling sites in the trigeminovascular system.

PubMed

Messlinger, Karl

2018-03-12

Calcitonin gene-related peptide (CGRP) has long been a focus of migraine research, since it turned out that inhibition of CGRP or CGRP receptors by antagonists or monoclonal IgG antibodies was therapeutic in frequent and chronic migraine. This contribution deals with the questions, from which sites CGRP is released, where it is drained and where it acts to cause its headache proliferating effects in the trigeminovascular system. The available literature suggests that the bulk of CGRP is released from trigeminal afferents both in meningeal tissues and at the first synapse in the spinal trigeminal nucleus. CGRP may be drained off into three different compartments, the venous blood plasma, the cerebrospinal fluid and possibly the glymphatic system. CGRP receptors in peripheral tissues are located on arterial vessel walls, mononuclear immune cells and possibly Schwann cells; within the trigeminal ganglion they are located on neurons and glial cells; in the spinal trigeminal nucleus they can be found on central terminals of trigeminal afferents. All these structures are potential signalling sites for CGRP, where CGRP mediates arterial vasodilatation but not direct activation of trigeminal afferents. In the spinal trigeminal nucleus a facilitating effect on synaptic transmission seems likely. In the trigeminal ganglion CGRP is thought to initiate long-term changes including cross-signalling between neurons and glial cells based on gene expression. In this way, CGRP may upregulate the production of receptor proteins and pro-nociceptive molecules. CGRP and other big molecules cannot easily pass the blood-brain barrier. These molecules may act in the trigeminal ganglion to influence the production of pronociceptive substances and receptors, which are transported along the central terminals into the spinal trigeminal nucleus. In this way peripherally acting therapeutics can have a central antinociceptive effect.

Stress and opioids: role of opioids in modulating stress-related behavior and effect of stress on morphine conditioned place preference.

PubMed

Bali, Anjana; Randhawa, Puneet Kaur; Jaggi, Amteshwar Singh

2015-04-01

Research studies have defined the important role of endogenous opioids in modulating stress-associated behavior. The release of β-endorphins in the amygdala in response to stress helps to cope with a stressor by inhibiting the over-activation of HPA axis. Administration of mu opioid agonists reduces the risk of developing post-traumatic stress disorder (PTSD) following a traumatic event by inhibiting fear-related memory consolidation. Similarly, the release of endogenous enkephalin and nociceptin in the basolateral amygdala and the nucleus accumbens tends to produce the anti-stress effects. An increase in dynorphin levels during prolonged exposure to stress may produce learned helplessness, dysphoria and depression. Stress also influences morphine-induced conditioned place preference (CPP) depending upon the intensity and duration of the stressor. Acute stress inhibits morphine CPP, while chronic stress potentiates CPP. The development of dysphoria due to increased dynorphin levels may contribute to chronic stress-induced potentiation of morphine CPP. The activation of ERK/cyclic AMP responsive element-binding (CREB) signaling in the mesocorticolimbic area, glucocorticoid receptors in the basolateral amygdala, and norepinephrine and galanin system in the nucleus accumbens may decrease the acute stress-induced inhibition of morphine CPP. The increase in dopamine levels in the nucleus accumbens and augmentation of GABAergic transmission in the median prefrontal cortex may contribute in potentiating morphine CPP. Stress exposure reinstates the extinct morphine CPP by activating the orexin receptors in the nucleus accumbens, decreasing the oxytocin levels in the lateral septum and amygdala, and altering the GABAergic transmission (activation of GABAA and inactivation of GABAB receptors). The present review describes these varied interactions between opioids and stress along with the possible mechanism. Copyright © 2015 Elsevier Ltd. All rights reserved.

Inhibition of monocarboxylate transporter 2 in the retrotrapezoid nucleus in rats – a test of the astrocyte-neuron lactate-shuttle hypothesis

PubMed Central

Erlichman, J.S.; Hewitt, Amy; Damon, Tracey L.; Hart, Michael; Kurascz, Jennifer; Li, A.; Leiter, J.C.

2009-01-01

The astrocyte-neuronal lactate shuttle hypothesis (ANLSH) posits that lactate released from astrocytes into the extracellular space is metabolized by neurons. The lactate released should alter extracellular pH (pHe), and changes in pH in central chemosensory regions of the brainstem stimulate ventilation. Therefore, we assessed the impact of disrupting the lactate shuttle by administering 100 microM α-cyano-4-hydroxy-cinnamate (4-CIN), a dose that blocks the neuronal monocarboxylate transporter (MCT2), but not the astrocytic MCTs (MCT1 and MCT4). Administration of 4-CIN focally in the retrotrapezoid nucleus (RTN), a medullary central chemosensory nucleus, increased ventilation and decreased pHe in intact animals. In medullary brain slices, 4-CIN reduced astrocytic intracellular pH (pHi) slightly, but alkalinized neuronal pHi. Nonetheless, pHi fell significantly in both cell types when they were treated with exogenous lactate, although 100 microM 4-CIN significantly reduced the magnitude of the acidosis in neurons, but not astrocytes. Finally, 4-CIN treatment increased the uptake of a fluorescent 2-deoxy-d-glucose analogue in neurons, but did not alter the uptake rate of this 2-deoxy-d-glucose analogue in astrocytes. These data confirm the existence of an astrocyte to neuron lactate shuttle in intact animals in the RTN, and lactate derived from astrocytes forms part of the central chemosensory stimulus for ventilation in this nucleus. When the lactate shuttle was disrupted by treatment with 4-CIN, neurons increased the uptake of glucose. Thus, neurons seem to metabolize a combination of glucose and lactate (and other substances such as pyruvate) depending, in part, on the availability of each of these particular substrates. PMID:18463242

Measurement of Charged Current Coherent Pion Production by Neutrinos on Carbon at MINER$$\

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mislivec, Aaron Robert

Neutrino-nucleus coherent pion production is a rare neutrino scattering process where the squared four-momentum transferred to the nucleus is small, a lepton and pion are produced in the forward direction, and the nucleus remains in its initial state. This process is an important background in neutrino oscillation experiments. Measurements of coherent pion production are needed to constrain models which are used to predict coherent pion production in oscillation experiments. This thesis reports measurements of νµ and νµ charged current coherent pion production on carbon for neutrino energies in the range 2 < Eν < 20 GeV. The measurements were mademore » using data from MINERνA, which is a dedicated neutrino-nucleus scattering experiment that uses a fi scintillator tracking detector in the high-intensity NuMI neutrino beam at Fermilab. Coherent interactions were isolated from the data using only model-independent signatures of the reaction, which are a forward muon and pion, no evidence of nuclear breakup, and small four-momentum transfer to the nucleus. The measurements were compared to the coherent pion production model used by oscillation experiments. The data and model agree in the total interaction rate and are similar in the dependence of the interaction rate on the squared four- momentum transferred from the neutrino. The data and model disagree significantly in the pion kinematics. The measured νµ and νµ interaction rates are consistent, which supports model predictions that the neutrino and antineutrino interaction rates are equal.« less

Acute and repeated ECS treatment increases CRF, POMC and PENK gene expression in selected regions of the rat hypothalamus.

PubMed

Garcia-Garcia, L; Llewellyn-Jones, V; Fernandez Fernandez, I; Fuentes, J A; Manzanares, J

1998-01-05

The purpose of this study was to investigate the effects of acute and repeated electroconvulsive shock (ECS) on corticotropin releasing factor (CRF), proopiomelanocortin (POMC) and proenkephalin (PENK) gene expression in selected regions of the brain and pituitary of the rat. Acute ECS increased CRF gene expression in the paraventricular nucleus (PVN) by 20%, an effect that was further enhanced to 38% when rats received repeated ECS treatment. Acute and repeated ECS increased POMC gene expression in the arcuate nucleus (ARC) by 49-59% but failed to alter these mRNA levels in the anterior lobe (AL) of the pituitary gland. PENK gene expression was increased by 35% in the nucleus accumbens (NA) and by 180% the ventromedial nucleus (VMN) after acute or repeated ECS treatment but no significant changes were found in the PVN or striatum (ST). Taken together, these results indicate a differential CRF and opioid gene expression regulation after acute or repeated ECS treatment that may be relevant to their therapeutic or side effects in depression.

Adolescent activity-based anorexia increases anxiety-like behavior in adulthood.

PubMed

Kinzig, Kimberly P; Hargrave, Sara L

2010-09-01

Activity-based anorexia is a paradigm that induces increased physical activity, reduced food intake, and heightened activity of the hypothalamic-pituitary-adrenal axis in adult rats. To investigate whether experience with activity-based anorexia produced enduring effects on brain and behavior, female adolescent rats experienced activity-based anorexia during adolescence and were tested in adulthood for anxiety-like behavior on an elevated plus maze and in an open field. Analysis of elevated plus maze and open field behavior in adulthood revealed that rats that experienced activity-based anorexia during adolescence, but not rats that were simply food restricted, displayed increased anxiety-like behavior in adulthood. Plasma corticosterone and expression levels of corticotropin-releasing hormone mRNA in the hypothalamic paraventricular nucleus and in the central nucleus of the amygdala were significantly elevated in adult rats that had undergone activity-based anorexia in adolescence in response to the open field exposure, as compared to control rats. These data demonstrate enduring effects of adolescent activity-based anorexia on anxiety-like behavior and neuroendocrine factors critical in stress responsivity in adulthood. Furthermore, we demonstrate that activity-based anorexia during adolescence serves as a model whereby prolonged anxiety is induced, allowing for evaluation of the behavioral and neural correlates of mediating anxiety-like behaviors in adulthood. Copyright 2010 Elsevier Inc. All rights reserved.

Adolescent Activity-Based Anorexia Increases Anxiety-Like Behavior in Adulthood

PubMed Central

Kinzig, Kimberly P.; Hargrave, Sara L.

2010-01-01

Activity-based anorexia is a paradigm that induces increased physical activity, reduced food intake, and heightened activity of the hypothalamic-pituitary-adrenal axis in adult rats. To investigate whether experience with activity-based anorexia produced enduring effects on brain and behavior, female adolescent rats experienced activity-based anorexia during adolescence and were tested in adulthood for anxiety-like behavior on an elevated plus maze and in an open field. Analysis of elevated plus maze and open field behavior in adulthood revealed that rats that experienced activity-based anorexia during adolescence, but not rats that were simply food restricted, displayed increased anxiety-like behavior in adulthood. Plasma corticosterone and expression levels of corticotropin- releasing hormone mRNA in the hypothalamic paraventricular nucleus and in the central nucleus of the amygdala were significantly elevated in adult rats that had undergone activity-based anorexia in adolescence in response to the open field exposure, as compared to control rats. These data demonstrate enduring effects of adolescent activity-based anorexia on anxiety-like behavior and neuroendocrine factors critical in stress responsivity in adulthood. Furthermore, we demonstrate that activity-based anorexia during adolescence serves as a model whereby prolonged anxiety is induced, allowing for evaluation of the behavioral and neural correlates of mediating anxiety-like behaviors in adulthood. PMID:20566408

Characterization of substance P release from the intermediate area of rat thoracic spinal cord.

PubMed

Yang, L; Thomas, N D; Helke, C J

1996-08-01

Substance P (SP) nerve terminals innervate the intermediolateral cell column (IML) of the thoracic spinal cord, where SP coexists with serotonin (5-HT), neurokinin A (NKA) and thyrotropin-releasing hormone (TRH). Neither the depolarization-induced release of SP nor the presence of other neurochemicals in the regulation of SP release has been directly studied in this system. In the present study, basal and K(+)-stimulated release of SP from the microdissected intermediate area (including the IML, intercalated nucleus and central autonomic nucleus) of the rat thoracic spinal cord, and the regulation of SP release by presynaptic autoreceptors and by coexisting neurochemicals (5-HT, NKA and TRH) were studied using an in vitro superfusion system. Potassium evoked a concentration- and extracellular Ca(2+)-dependent release of SP. In rats pretreated with the serotoninergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), both SP content and the absolute amount of SP released were decreased. However, the fraction of the remaining tissue content of SP released by K+ depolarization was not changed subsequent to 5,7-DHT treatment. Moreover, 5-HT, 5-HT1B agonists (CGS-12066B and RU 24969) and a 5-HT3 agonist (2-methyl-5-HT) did not alter the K(+)-evoked release of SP. These data demonstrate that SP is released from the intermediate area of the rat thoracic spinal cord and some of the SP released comes from serotoninergic nerve terminals. Although 5-HT coexists with SP in the IML, neither endogenous 5-HT nor 5-HT receptor ligands appear to regulate the release of SP. Other colocalized neuropeptides (NKA and TRH) are not involved in the regulation of SP release because neither NKA, a NK2 agonist (GR 64349) nor a TRH analog (MK-771) changed the K(+)-evoked release of SP. A neurokinin-1 (NK1) antagonist (GR 82334) dose-dependently (10(-9)-10(-7) M) increased the K(+)-stimulated release of SP. These data suggest the presence of presynaptic inhibitory NK1 autoreceptors. Whereas, NK1 agonists, [GR 73632 (10(-9)-10(-6) M) and [Sar9, Met (O2)11]SP (10(-8)-10(-6) M)], increased the basal and K(+)-stimulated release of SP, the excitatory effects of GR 73632 were not blocked by the NK1 antagonist. Moreover, GR 73632 increased the efflus of SP to a greater extent in the absence of peptidase inhibitors. Thus, the effect of NK1 agonists on the release of SP may be related to an inhibition of peptide degradation rather than activation of NK1 autoreceptors.

A search for the production of direct leptons in nucleon-nucleus and nucleus-nucleus collisions. [Intermediate Energy Nuclear Physics Group, Dept. of Physics and Astronomy, Louisiana State Univ. , Baton Rouge

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kirk, P.N.

1992-12-15

Activities included contributions to the AMY Collaboration, the transverse energy detector, the Di-Lepton Spectrometer, with emphasis on the single-lepton experiment. Elastic and inelastic scattering differential cross sections and total cross sections are shown for [pi][sup +] and [pi][sup [minus

Feeding-associated alterations in striatal neurotransmitter release

NASA Technical Reports Server (NTRS)

Acworth, I. N.; Ressler, K.; Wurtman, R. J.

1989-01-01

Published evidence suggests a role for dopaminergic (DA) brain pathways in feeding-associated behaviors. Using the novel technique of brain microdialysis of striatal extracellular fluid (ECF) as an index of DA release, Church et al. described increases in levels of DA when animals had limited access to pellets, but not with free access. Dopamine release from the nucleus accumbens did increase with free access to pellets post starvation or after food reward. We used permanently implanted microdialysis probes to measure ECF levels of DA, DOPAC, HVA, and large neutral amino acids (LNAA) for up to 72 hours after implantation among rats experiencing different dietary regimens.

The nonchromatin substructures of the nucleus: the ribonucleoprotein (RNP)-containing and RNP-depleted matrices analyzed by sequential fractionation and resinless section electron microscopy

PubMed Central

1986-01-01

The nonchromatin structure or matrix of the nucleus has been studied using an improved fractionation in concert with resinless section electron microscopy. The resinless sections show the nucleus of the intact cell to be filled with a dense network or lattice composed of soluble proteins and chromatin in addition to the structural nuclear constituents. In the first fractionation step, soluble proteins are removed by extraction with Triton X-100, and the dense nuclear lattice largely disappears. Chromatin and nonchromatin nuclear fibers are now sharply imaged. Nuclear constituents are further separated into three well-defined, distinct protein fractions. Chromatin proteins are those that require intact DNA for their association with the nucleus and are released by 0.25 M ammonium sulfate after internucleosomal DNA is cut with DNAase I. The resulting structure retains most heterogeneous nuclear ribonucleoprotein (hnRNP) and is designated the RNP-containing nuclear matrix. The proteins of hnRNP are those associated with the nucleus only if RNA is intact. These are released when nuclear RNA is briefly digested with RNAase A. Ribonuclease digestion releases 97% of the hnRNA and its associated proteins. These proteins correspond to the hnRNP described by Pederson (Pederson, T., 1974, J. Mol. Biol., 83:163- 184) and are distinct from the proteins that remain in the ribonucleoprotein (RNP)-depleted nuclear matrix. The RNP-depleted nuclear matrix is a core structure that retains lamins A and C, the intermediate filaments, and a unique set of nuclear matrix proteins (Fey, E. G., K. M. Wan, and S. Penman, 1984, J. Cell Biol. 98:1973- 1984). This core had been previously designated the nuclear matrix- intermediate filament scaffold and its proteins are a third, distinct, and nonoverlapping subset of the nuclear nonhistone proteins. Visualizing the nuclear matrix using resinless sections shows that nuclear RNA plays an important role in matrix organization. Conventional Epon-embedded electron microscopy sections show comparatively little of the RNP-containing and RNP-depleted nuclear matrix structure. In contrast, resinless sections show matrix interior to be a three-dimensional network of thick filaments bounded by the nuclear lamina. The filaments are covered with 20-30-nm electron dense particles which may contain the hnRNA. The large electron dense bodies, enmeshed in the interior matrix fibers, have the characteristic morphology of nucleoli. Treatment of the nuclear matrix with RNAase results in the aggregation of the interior fibers and the extensive loss of the 20-30-nm particles.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:3700470

Nutritional Programming of Accelerated Puberty in Heifers: Involvement of Pro-Opiomelanocortin Neurones in the Arcuate Nucleus.

PubMed

Cardoso, R C; Alves, B R C; Sharpton, S M; Williams, G L; Amstalden, M

2015-08-01

The timing of puberty and subsequent fertility in female mammals are dependent on the integration of metabolic signals by the hypothalamus. Pro-opiomelanocortin (POMC) neurones in the arcuate nucleus (ARC) comprise a critical metabolic-sensing pathway controlling the reproductive neuroendocrine axis. α-Melanocyte-stimulating hormone (αMSH), a product of the POMC gene, has excitatory effects on gonadotrophin-releasing hormone (GnRH) neurones and fibres containing αMSH project to GnRH and kisspeptin neurones. Because kisspeptin is a potent stimulator of GnRH release, αMSH may also stimulate GnRH secretion indirectly via kisspeptin neurones. In the present work, we report studies conducted in young female cattle (heifers) aiming to determine whether increased nutrient intake during the juvenile period (4-8 months of age), a strategy previously shown to advance puberty, alters POMC and KISS1 mRNA expression, as well as αMSH close contacts on GnRH and kisspeptin neurones. In Experiment 1, POMC mRNA expression, detected by in situ hybridisation, was greater (P < 0.05) in the ARC in heifers that gained 1 kg/day of body weight (high-gain, HG; n = 6) compared to heifers that gained 0.5 kg/day (low-gain, LG; n = 5). The number of KISS1-expressing cells in the middle ARC was reduced (P < 0.05) in HG compared to LG heifers. In Experiment 2, double-immunofluorescence showed limited αMSH-positive close contacts on GnRH neurones, and the magnitude of these inputs was not influenced by nutritional status. Conversely, a large number of kisspeptin-immunoreactive cells in the ARC were observed in close proximity to αMSH-containing varicosities. Furthermore, HG heifers (n = 5) exhibited a greater (P < 0.05) percentage of kisspeptin neurones in direct apposition to αMSH fibres and an increased (P < 0.05) number of αMSH close contacts per kisspeptin cell compared to LG heifers (n = 6). These results indicate that the POMC-kisspeptin pathway may be important in mediating the nutritional acceleration of puberty in heifers. © 2015 British Society for Neuroendocrinology.

Disintegration phenomena in Comet West

NASA Technical Reports Server (NTRS)

Sekanina, Z.

1976-01-01

Two peculiarities of Comet West, the multiple splitting of the nucleus as seen in telescope observations and the complex structure of the dust tail, are discussed. A method of analysis based on the premise that the observed rate of separation of a fragment from the principal nucleus is determined by the difference in effective solar attraction acting on the bodies is applied to investigate the motion of the four fragments that separated from the nucleus of Comet West. The predicted motion of the fragments is in good agreement with available observations. It is suggested that the 'synchronic' bands of the dust tail consist of tiny fragments from relatively large particles that burst after release from the comet. The unusual orientation of these bands and their high surface brightness relative to the diffuse tail are explained by a sudden increase in the particle acceleration and in the total scattering surface as the result of the disintegration of the larger particles.

Intracellular sphingosine releases calcium from lysosomes.

PubMed

Höglinger, Doris; Haberkant, Per; Aguilera-Romero, Auxiliadora; Riezman, Howard; Porter, Forbes D; Platt, Frances M; Galione, Antony; Schultz, Carsten

2015-11-27

To elucidate new functions of sphingosine (Sph), we demonstrate that the spontaneous elevation of intracellular Sph levels via caged Sph leads to a significant and transient calcium release from acidic stores that is independent of sphingosine 1-phosphate, extracellular and ER calcium levels. This photo-induced Sph-driven calcium release requires the two-pore channel 1 (TPC1) residing on endosomes and lysosomes. Further, uncaging of Sph leads to the translocation of the autophagy-relevant transcription factor EB (TFEB) to the nucleus specifically after lysosomal calcium release. We confirm that Sph accumulates in late endosomes and lysosomes of cells derived from Niemann-Pick disease type C (NPC) patients and demonstrate a greatly reduced calcium release upon Sph uncaging. We conclude that sphingosine is a positive regulator of calcium release from acidic stores and that understanding the interplay between Sph homeostasis, calcium signaling and autophagy will be crucial in developing new therapies for lipid storage disorders such as NPC.

Fusion cross sections for reactions involving medium and heavy nucleus-nucleus systems

NASA Astrophysics Data System (ADS)

Atta, Debasis; Basu, D. N.

2014-12-01

Existing data on near-barrier fusion excitation functions of medium and heavy nucleus-nucleus systems have been analyzed by using a simple diffused-barrier formula derived assuming the Gaussian shape of the barrier-height distributions. The fusion cross section is obtained by folding the Gaussian barrier distribution with the classical expression for the fusion cross section for a fixed barrier. The energy dependence of the fusion cross section, thus obtained, provides good description to the existing data on near-barrier fusion and capture excitation functions for medium and heavy nucleus-nucleus systems. The theoretical values for the parameters of the barrier distribution are estimated which can be used for fusion or capture cross-section predictions that are especially important for planning experiments for synthesizing new superheavy elements.

Electrospun scaffold containing TGF-β1 promotes human mesenchymal stem cell differentiation towards a nucleus pulposus-like phenotype under hypoxia.

PubMed

Cui, Xiang; Liu, Minghan; Wang, Jiaxu; Zhou, Yue; Xiang, Qiang

2015-04-01

The study was aimed at evaluating the effect of electrospun scaffold containing TGF-β1 on promoting human mesenchymal stem cells (MSCs) differentiation towards a nucleus pulposus-like phenotype under hypoxia. Two kinds of nanofibrous scaffolds containing TGF-β1 were fabricated using uniaxial electrospinning (Group I) and coaxial electrospinning (Group II). Human MSCs were seeded on both kinds of scaffolds and cultured in a hypoxia chamber (2% O2), and then the scaffolds were characterised. Cell proliferation and differentiation were also evaluated after 3 weeks of cell culture. Results showed that both kinds of scaffolds shared similar diameter distributions and protein release. However, Group I scaffolds were more hydrophilic than that of Group II. Both kinds of scaffolds induced the MSCs to differentiate towards the nucleus pulposus-type phenotype in vitro. In addition, the expression of nucleus pulposus-associated genes (aggrecan, type II collagen, HIF-1α and Sox-9) in Group I increased more than that of Group II. These results indicate that electrospinning nanofibrous scaffolds containing TGF-β1 supports the differentiation of MSCs towards the pulposus-like phenotype in a hypoxia chamber, which would be a more appropriate choice for nucleus pulposus regeneration.

Cellular Interactions in the Suprachiasmatic Nucleus.

DTIC Science & Technology

2000-07-10

role in determining the phase of the circadian cycle. We examined neuromodulation of GABA and glutamate actions in cells of the SCN. Neuromodulation is...based on the concept that neuromodulators can alter the release or response of SCN cells to the fast-acting neurotransmitters GABA and glutamate that

Role of GABAA receptors in dorsal raphe nucleus in stress-induced reinstatement of morphine-conditioned place preference in rats.

PubMed

Li, Chen; Staub, Daniel R; Kirby, Lynn G

2013-12-01

The serotonin (5-hydroxytryptamine, 5-HT) system plays an important role in stress-related psychiatric disorders and substance abuse. Our data indicate that stress inhibits the dorsal raphe nucleus (DRN)-5-HT system via stimulation of GABA synaptic activity by the stress neurohormone corticotropin-releasing factor and, more recently, that morphine history sensitizes DRN-5-HT neurons to GABAergic inhibitory effects of stress. We tested the hypothesis that DRN GABAA receptors contribute to stress-induced reinstatement of morphine-conditioned place preference (CPP). First, we tested if activation of GABAA receptors in the DRN would reinstate morphine CPP. Second, we tested if blockade of GABAA receptors in the DRN would attenuate swim stress-induced reinstatement of morphine CPP. CPP was induced by morphine (5 mg/kg) in a 4-day conditioning phase followed by a conditioning test. Upon acquiring conditioning criteria, subjects underwent 4 days of extinction training followed by an extinction test. Upon acquiring extinction criteria, animals underwent a reinstatement test. For the first experiment, the GABAA receptor agonist muscimol (50 ng) or vehicle was injected into the DRN prior to the reinstatement test. For the second experiment, the GABAA receptor antagonist bicuculline (75 ng) or vehicle was injected into the DRN prior to a forced swim stress, and then, animals were tested for reinstatement of CPP. Intraraphe injection of muscimol reinstated morphine CPP, while intraraphe injection of bicuculline attenuated swim stress-induced reinstatement. These data provide evidence that GABAA receptor-mediated inhibition of the serotonergic DRN contributes to stress-induced reinstatement of morphine CPP.

Breaking bonds in male prairie vole: Long-term effects on emotional and social behavior, physiology, and neurochemistry

PubMed Central

Sun, P; Smith, AS; Lei, K; Liu, Y; Wang, Z

2014-01-01

Social relationships are essential for many fundamental aspects of life while bond disruption can be detrimental to mental and physical health. Male prairie voles form enduring social bonds with their female partners, allowing the evaluation of partner loss on behavior, physiology, and neurochemistry. Males were evaluated for partner preference formation induced by 24 h of mating, and half were separated from their partner for 4 wk. In Experiment 1, partner loss significantly increased anxiety-like behaviors in the elevated plus maze and light-dark box tests and marginally increased depressive-like behaviors in the forced swim test. In addition, while intruder-directed aggression is common in pair bonded prairie voles, separated males were affiliative and lacked aggression toward an unfamiliar female and an intruding male conspecific. Partner loss increased the density of oxytocin-immunoreactivity (-ir), vasopressin-ir, and corticotrophin-releasing hormone-ir cells in the paraventricular nucleus of the hypothalamus and oxytocin-ir cells in the supraoptic nucleus. Tyrosine hydroxylase-ir was not affected. In Experiment 2, partner preference was observed after 2 wk of partner loss but eliminated after 4 wk partner loss. Body weight gain and plasma corticosterone concentrations were elevated throughout the 4 wk. No effects were observed for plasma oxytocin or vasopressin. Together, partner loss elicits anxiety-like and depression-like behaviors, disrupts bond-related behaviors, and alters neuropeptide systems that regulate such behaviors. Thus, partner loss in male prairie voles may provide a model to better understand the behavior, pathology, and neurobiology underlying partner loss and grief. PMID:24561258

Attributed relational graphs for cell nucleus segmentation in fluorescence microscopy images.

PubMed

Arslan, Salim; Ersahin, Tulin; Cetin-Atalay, Rengul; Gunduz-Demir, Cigdem

2013-06-01

More rapid and accurate high-throughput screening in molecular cellular biology research has become possible with the development of automated microscopy imaging, for which cell nucleus segmentation commonly constitutes the core step. Although several promising methods exist for segmenting the nuclei of monolayer isolated and less-confluent cells, it still remains an open problem to segment the nuclei of more-confluent cells, which tend to grow in overlayers. To address this problem, we propose a new model-based nucleus segmentation algorithm. This algorithm models how a human locates a nucleus by identifying the nucleus boundaries and piecing them together. In this algorithm, we define four types of primitives to represent nucleus boundaries at different orientations and construct an attributed relational graph on the primitives to represent their spatial relations. Then, we reduce the nucleus identification problem to finding predefined structural patterns in the constructed graph and also use the primitives in region growing to delineate the nucleus borders. Working with fluorescence microscopy images, our experiments demonstrate that the proposed algorithm identifies nuclei better than previous nucleus segmentation algorithms.

Meson-nucleus potentials and the search for meson-nucleus bound states

NASA Astrophysics Data System (ADS)

Metag, V.; Nanova, M.; Paryev, E. Ya.

2017-11-01

Recent experiments studying the meson-nucleus interaction to extract meson-nucleus potentials are reviewed. The real part of the potentials quantifies whether the interaction is attractive or repulsive while the imaginary part describes the meson absorption in nuclei. The review is focused on mesons which are sufficiently long-lived to potentially form meson-nucleus quasi-bound states. The presentation is confined to meson production off nuclei in photon-, pion-, proton-, and light-ion induced reactions and heavy-ion collisions at energies near the production threshold. Tools to extract the potential parameters are presented. In most cases, the real part of the potential is determined by comparing measured meson momentum distributions or excitation functions with collision model or transport model calculations. The imaginary part is extracted from transparency ratio measurements. Results on K+ ,K0 ,K- , η ,η‧ , ω, and ϕ mesons are presented and compared with theoretical predictions. The interaction of K+ and K0 mesons with nuclei is found to be weakly repulsive, while the K- , η ,η‧ , ω and ϕ meson-nucleus potentials are attractive, however, with widely different strengths. Because of meson absorption in the nuclear medium the imaginary parts of the meson-nucleus potentials are all negative, again with a large spread. An outlook on planned experiments in the charm sector is given. In view of the determined potential parameters, the criteria and chances for experimentally observing meson-nucleus quasi-bound states are discussed. The most promising candidates appear to be the η and η‧ mesons.

Vasopressin synthesis by the magnocellular neurons is different in the supraoptic nucleus and in the paraventricular nucleus in human and experimental septic shock.

PubMed

Sonneville, Romain; Guidoux, Céline; Barrett, Lucinda; Viltart, Odile; Mattot, Virginie; Polito, Andrea; Siami, Shidasp; de la Grandmaison, Geoffroy Lorin; Blanchard, Anne; Singer, Mervyn; Annane, Djillali; Gray, Françoise; Brouland, Jean-Philippe; Sharshar, Tarek

2010-05-01

Impaired arginine vasopressin (AVP) synthesis and release by the neurohypophyseal system, which includes the neurohypophysis and magnocellular neurons of the paraventricular and supraoptic nuclei, have been postulated in septic shock, but changes in this system have never been assessed in human septic shock, and only partially experimentally. We investigated AVP synthesis and release by the neurohypophyseal system in 9 patients who died from septic shock and 10 controls, and in 20 rats with fecal peritonitis-induced sepsis and 8 sham-operation controls. Ten rats died spontaneously from septic shock, and the others were sacrificed. In patients with septic shock, as in rats that died spontaneously following sepsis induction, AVP immunohistochemical expression was decreased in the neurohypophysis and supraoptic magnocellular neurons, whereas it was increased in the paraventricular magnocellular neurons. No significant change was observed in AVP messenger RiboNucleic Acid (mRNA) expression assessed by in situ hybridization in either paraventricular or supraoptic magnocellular cells. This study shows that both in human and experimental septic shock, AVP posttranscriptional synthesis and transport are differently modified in the magnocellular neurons of the supraoptic and paraventricular nuclei. This may account for the inappropriate AVP release in septic shock and suggests that distinct pathogenic mechanisms operate in these nuclei.

Effect of acute administration of hypericum perforatum-CO2 extract on dopamine and serotonin release in the rat central nervous system.

PubMed

Di Matteo, V; Di Giovanni, G; Di Mascio, M; Esposito, E

2000-01-01

The hydromethanolic extract of Hypericum perforatum has been shown to be an effective antidepressant, although its mechanism of action is still unclear. In this study, in vivo microdialysis was used to investigate the effects of Hypericum perforatum-CO2 extract on dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) release in various areas of brain. Administration of Hypericum perforatum extract (1 mg/kg, p.o.) caused a slight, but significant increase of DA outflow both in the nucleus accumbens and the striatum. The maximal increase of DA efflux (+19.22+/-1.93%, relative to the control group) in the nucleus accumbens occurred 100 min after administration of Hypericum perforatum. In the striatum, the extract maximally enhanced DA outflow (+24.83+/-7.49 %, relative to the control group) 80 min after administration. Extraneuronal DOPAC levels were not significantly affected by Hypericum perforatum treatment. Moreover, Hypericum perforatum (1 mg/kg, p.o.) did not produce any significant effect on either 5-HT or 5-HIAA efflux in the ventral hippocampus. This study shows for the first time that Hypericum perforatum extract is capable of increasing in vivo DA release.

Gamma-vinyl GABA increases nonvesicular release of GABA and glutamate in the nucleus accumbens in rats via action on anion channels and GABA transporters

PubMed Central

Peng, Xiao-Qing; Gardner, Eliot L.

2013-01-01

Rationale γ-Amino butyric acid (GABA) is a well-characterized inhibitory neurotransmitter in the central nervous system, which may also stimulate nonvesicular release of other neurotransmitters under certain conditions. We have recently reported that γ-vinyl GABA (GVG), an irreversible GABA transaminase inhibitor, elevates extracellular GABA but fails to alter dopamine release in the nucleus accumbens (NAc). Objectives Here, we investigated the mechanism(s) by which GVG elevates extracellular GABA levels and whether GVG also alters glutamate release in the NAc. Materials and methods In vivo microdialysis was used to simultaneously measure extracellular NAc GABA and glutamate before and after GVG administration in freely moving rats. Results Systemic administration of GVG or intra-NAc local perfusion of GVG significantly increased extracellular NAc GABA and glutamate. GVG-enhanced GABA was completely blocked by intra-NAc local perfusion of 5-nitro-2, 3-(phenylpropylamino)-benzoic acid (NPPB), a selective anion channel blocker and partially blocked by SKF89976A, a type 1 GABA transporter inhibitor. GVG-enhanced glutamate was completely blocked by NPPB or SKF89976A. Tetrodotoxin, a voltage-dependent Na+-channel blocker, failed to alter GVG-enhanced GABA and glutamate. Conclusions These data suggest that GVG-enhanced extracellular GABA and glutamate are mediated predominantly by the opening of anion channels and partially by the reversal of GABA transporters. Enhanced extracellular glutamate may functionally attenuate the pharmacological action of GABA and prevent enhanced GABA-induced excess inhibition. PMID:20033132

Molecular Mechanisms for Synaptic Modification in the Visual Cortex: Interaction between Theory and Experiment

DTIC Science & Technology

1989-02-03

known that the large majority of neurons in layers Ill, IV and VI receive direct monosynaptic input from the lateral geniculate nucleus (Toyama et al...1974; Ferster and Lindstrom, 1983; Martin, 1987). The receptive fields of lateral geniculate nucleus (LGN) neurons resemble those of retinal ganglion...the lateral geniculate nucleus only. The second stage of the theoretical analysis requires that relevant intracortical connections be incorporated

Morphine-induced changes in acetylcholine release in the interpeduncular nucleus and relationship to changes in motor behavior in rats

PubMed Central

Taraschenko, Olga D.; Rubbinaccio, Heather Y.; Shulan, Joseph M.; Glick, Stanley D.; Maisonneuve, Isabelle M.

2007-01-01

Owing to multiple anatomical connections and functional interactions between the habenulo-interpeduncular and the mesolimbic pathways, it has been proposed that these systems could together mediate the reinforcing properties of addictive drugs. 18-Methoxycoronaridine, an agent that reduces morphine self-administration and attenuates dopamine sensitization in the nucleus accumbens in response to repeated morphine, has been shown to produce these effects by acting in the medial habenula and interpeduncular nucleus. Acetylcholine, one of the predominant neurotransmitters in the interpeduncular nucleus, may be a major determinant of these interactions. To determine if and how morphine acts in the interpeduncular nucleus, the effects of acute and repeated administration of morphine on extracellular acetylcholine levels in this brain area were assessed. In addition, the motor behavior of rats receiving repeated morphine administration was monitored during microdialysis sessions. Acutely, morphine produced a biphasic effect on extracellular acetylcholine levels in the interpeduncular nucleus such that low and high doses of morphine (i.e., 5 and 20 mg/kg i.p.) significantly increased and decreased acetylcholine levels, respectively. Repeated administration of the same doses of morphine resulted in tolerance to the inhibitory but not to the stimulatory effects; tolerance was accompanied by sensitization to morphine-induced changes in locomotor activity and stereotypic behavior. The latter results suggest that tolerance to morphine's effect on the cholinergic habenulo-interpeduncular pathway is related to its sensitizing effects on the mesostriatal dopaminergic pathways. PMID:17544456

Extraction of In-Medium Nucleon-Nucleon Amplitude From Experiment

NASA Technical Reports Server (NTRS)

Tripathi, R. K.; Cucinotta, Francis A.; Wilson, John W.

1998-01-01

The in-medium nucleon-nucleon amplitudes are extracted from the available proton-nucleus total reaction cross sections data. The retrieval of the information from the experiment makes the estimate of reaction cross sections very reliable. Simple expressions are given for the in-medium nucleon-nucleon amplitudes for any system of colliding nuclei as a function of energy. Excellent agreement with experimental observations is demonstrated in the ion-nucleus interactions.

Ethanol Exposure History and Alcoholic Reward Differentially Alter Dopamine Release in the Nucleus Accumbens to a Reward-Predictive Cue.

PubMed

Fiorenza, Amanda M; Shnitko, Tatiana A; Sullivan, Kaitlin M; Vemuru, Sudheer R; Gomez-A, Alexander; Esaki, Julie Y; Boettiger, Charlotte A; Da Cunha, Claudio; Robinson, Donita L

2018-06-01

Conditioned stimuli (CS) that predict reward delivery acquire the ability to induce phasic dopamine release in the nucleus accumbens (NAc). This dopamine release may facilitate conditioned approach behavior, which often manifests as approach to the site of reward delivery (called "goal-tracking") or to the CS itself (called "sign-tracking"). Previous research has linked sign-tracking in particular to impulsivity and drug self-administration, and addictive drugs may promote the expression of sign-tracking. Ethanol (EtOH) acutely promotes phasic release of dopamine in the accumbens, but it is unknown whether an alcoholic reward alters dopamine release to a CS. We hypothesized that Pavlovian conditioning with an alcoholic reward would increase dopamine release triggered by the CS and subsequent sign-tracking behavior. Moreover, we predicted that chronic intermittent EtOH (CIE) exposure would promote sign-tracking while acute administration of naltrexone (NTX) would reduce it. Rats received 14 doses of EtOH (3 to 5 g/kg, intragastric) or water followed by 6 days of Pavlovian conditioning training. Rewards were a chocolate solution with or without 10% (w/v) alcohol. We used fast-scan cyclic voltammetry to measure phasic dopamine release in the NAc core in response to the CS and the rewards. We also determined the effect of NTX (1 mg/kg, subcutaneous) on conditioned approach. Both CIE and alcoholic reward, individually but not together, associated with greater dopamine to the CS than control conditions. However, this increase in dopamine release was not linked to greater sign-tracking, as both CIE and alcoholic reward shifted conditioned approach from sign-tracking behavior to goal-tracking behavior. However, they both also increased sensitivity to NTX, which reduced goal-tracking behavior. While a history of EtOH exposure or alcoholic reward enhanced dopamine release to a CS, they did not promote sign-tracking under the current conditions. These findings are consistent with the interpretation that EtOH can stimulate conditioned approach, but indicate that the conditioned response may manifest as goal-tracking. Copyright © 2018 by the Research Society on Alcoholism.

GABAergic projections from lateral hypothalamus to paraventricular hypothalamic nucleus promote feeding

USDA-ARS?s Scientific Manuscript database

Lesions of the lateral hypothalamus (LH) cause hypophagia. However, activation of glutamatergic neurons in LH inhibits feeding. These results suggest a potential importance for other LH neurons in stimulating feeding. Our current study in mice showed that disruption of GABA release from adult LH GAB...

Recent Results and the Future of the NA61/SHINE Strong Interactions Program

NASA Astrophysics Data System (ADS)

Łysakowski, B.

NA61/SHINE is a fixed target experiment at the CERN Super-Proton- Synchrotron. The main goals of the experiment are to discover the critical point of strongly interacting matter and study the properties of the onset of deconfnement. In order to reach these goals the collaboration studies hadron production properties in nucleus-nucleus, proton-proton and proton-nucleus interactions. In this talk, recent results on particle production in p+p interactions, as well as Be+Be and Ar+Sc collisions in the SPS energy range are reviewed. The results are compared with available world data. The future of the NA61/SHINE scientifc program is also presented.

Kinesin-8 Motors Improve Nuclear Centering by Promoting Microtubule Catastrophe

NASA Astrophysics Data System (ADS)

Glunčić, Matko; Maghelli, Nicola; Krull, Alexander; Krstić, Vladimir; Ramunno-Johnson, Damien; Pavin, Nenad; Tolić, Iva M.

2015-02-01

In fission yeast, microtubules push against the cell edge, thereby positioning the nucleus in the cell center. Kinesin-8 motors regulate microtubule catastrophe; however, their role in nuclear positioning is not known. Here we develop a physical model that describes how kinesin-8 motors affect nuclear centering by promoting a microtubule catastrophe. Our model predicts the improved centering of the nucleus in the presence of motors, which we confirmed experimentally in living cells. The model also predicts a characteristic time for the recentering of a displaced nucleus, which is supported by our experiments where we displaced the nucleus using optical tweezers.

Late Maturation Steps Preceding Selective Nuclear Export and Egress of Progeny Parvovirus

PubMed Central

Wolfisberg, Raphael; Kempf, Christoph

2016-01-01

ABSTRACT Although the mechanism is not well understood, growing evidence indicates that the nonenveloped parvovirus minute virus of mice (MVM) may actively egress before passive release through cell lysis. We have dissected the late maturation steps of the intranuclear progeny with the aims of confirming the existence of active prelytic egress and identifying critical capsid rearrangements required to initiate the process. By performing anion-exchange chromatography (AEX), we separated intranuclear progeny particles by their net surface charges. Apart from empty capsids (EC), two distinct populations of full capsids (FC) arose in the nuclei of infected cells. The earliest population of FC to appear was infectious but, like EC, could not be actively exported from the nucleus. Further maturation of this early population, involving the phosphorylation of surface residues, gave rise to a second, late population with nuclear export potential. While capsid surface phosphorylation was strictly associated with nuclear export capacity, mutational analysis revealed that the phosphoserine-rich N terminus of VP2 (N-VP2) was dispensable, although it contributed to passive release. The reverse situation was observed for the incoming particles, which were dephosphorylated in the endosomes. Our results confirm the existence of active prelytic egress and reveal a late phosphorylation event occurring in the nucleus as a selective factor for initiating the process. IMPORTANCE In general, the process of egress of enveloped viruses is active and involves host cell membranes. However, the release of nonenveloped viruses seems to rely more on cell lysis. At least for some nonenveloped viruses, an active process before passive release by cell lysis has been reported, although the underlying mechanism remains poorly understood. By using the nonenveloped model parvovirus minute virus of mice, we could confirm the existence of an active process of nuclear export and further characterize the associated capsid maturation steps. Following DNA packaging in the nucleus, capsids required further modifications, involving the phosphorylation of surface residues, to acquire nuclear export potential. Inversely, those surface residues were dephosphorylated on entering capsids. These spatially controlled phosphorylation-dephosphorylation events concurred with the nuclear export-import potential required to complete the infectious cycle. PMID:27009963

Late Maturation Steps Preceding Selective Nuclear Export and Egress of Progeny Parvovirus.

PubMed

Wolfisberg, Raphael; Kempf, Christoph; Ros, Carlos

2016-06-01

Although the mechanism is not well understood, growing evidence indicates that the nonenveloped parvovirus minute virus of mice (MVM) may actively egress before passive release through cell lysis. We have dissected the late maturation steps of the intranuclear progeny with the aims of confirming the existence of active prelytic egress and identifying critical capsid rearrangements required to initiate the process. By performing anion-exchange chromatography (AEX), we separated intranuclear progeny particles by their net surface charges. Apart from empty capsids (EC), two distinct populations of full capsids (FC) arose in the nuclei of infected cells. The earliest population of FC to appear was infectious but, like EC, could not be actively exported from the nucleus. Further maturation of this early population, involving the phosphorylation of surface residues, gave rise to a second, late population with nuclear export potential. While capsid surface phosphorylation was strictly associated with nuclear export capacity, mutational analysis revealed that the phosphoserine-rich N terminus of VP2 (N-VP2) was dispensable, although it contributed to passive release. The reverse situation was observed for the incoming particles, which were dephosphorylated in the endosomes. Our results confirm the existence of active prelytic egress and reveal a late phosphorylation event occurring in the nucleus as a selective factor for initiating the process. In general, the process of egress of enveloped viruses is active and involves host cell membranes. However, the release of nonenveloped viruses seems to rely more on cell lysis. At least for some nonenveloped viruses, an active process before passive release by cell lysis has been reported, although the underlying mechanism remains poorly understood. By using the nonenveloped model parvovirus minute virus of mice, we could confirm the existence of an active process of nuclear export and further characterize the associated capsid maturation steps. Following DNA packaging in the nucleus, capsids required further modifications, involving the phosphorylation of surface residues, to acquire nuclear export potential. Inversely, those surface residues were dephosphorylated on entering capsids. These spatially controlled phosphorylation-dephosphorylation events concurred with the nuclear export-import potential required to complete the infectious cycle. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Involvement of anteroventral periventricular metastin/kisspeptin neurons in estrogen positive feedback action on luteinizing hormone release in female rats.

PubMed

Adachi, Sachika; Yamada, Shunji; Takatsu, Yoshihiro; Matsui, Hisanori; Kinoshita, Mika; Takase, Kenji; Sugiura, Hitomi; Ohtaki, Tetsuya; Matsumoto, Hirokazu; Uenoyama, Yoshihisa; Tsukamura, Hiroko; Inoue, Kinji; Maeda, Kei-Ichiro

2007-04-01

Metastin/kisspeptin, the KiSS-1 gene product, has been identified as an endogenous ligand of GPR54 that reportedly regulates GnRH/LH surges and estrous cyclicity in female rats. The aim of the present study was to determine if metastin/kisspeptin neurons are a target of estrogen positive feedback to induce GnRH/LH surges. We demonstrated that preoptic area (POA) infusion of the anti-rat metastin/kisspeptin monoclonal antibody blocked the estrogen-induced LH surge, indicating that endogenous metastin/kisspeptin released around the POA mediates the estrogen positive feedback effect on GnRH/LH release. Metastin/kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) may be responsible for mediating the feedback effect because the percentage of c-Fos-expressing KiSS-1 mRNA-positive cells to total KiSS-1 mRNA-positive cells was significantly higher in the afternoon than in the morning in the anteroventral periventricular nucleus (AVPV) of high estradiol (E(2))-treated females. The percentage of c-Fos-expressing metastin/kisspeptin neurons was not different between the afternoon and morning in the arcuate nucleus (ARC). Most of the KiSS-1 mRNA expressing cells contain ERalpha immunoreactivity in the AVPV and ARC. In addition, AVPV KiSS-1 mRNA expressions were highest in the proestrous afternoon and lowest in the diestrus 1 in females and were increased by estrogen treatment in ovariectomized animals. On the other hand, the ARC KiSS-1 mRNA expressions were highest at diestrus 2 and lowest at proestrous afternoon and were increased by ovariectomy and decreased by high estrogen treatment. Males lacking the surge mode of GnRH/LH release showed no obvious cluster of metastin/kisspeptin-immunoreactive neurons in the AVPV when compared with high E(2)-treated females, which showed a much greater density of these neurons. Taken together, the present study demonstrates that the AVPV metastin/kisspeptin neurons are a target of estrogen positive feedback to induce GnRH/LH surges in female rats.

Possibility of measuring Adler angles in charged current single pion neutrino-nucleus interactions

NASA Astrophysics Data System (ADS)

Sánchez, F.

2016-05-01

Uncertainties in modeling neutrino-nucleus interactions are a major contribution to systematic errors in long-baseline neutrino oscillation experiments. Accurate modeling of neutrino interactions requires additional experimental observables such as the Adler angles which carry information about the polarization of the Δ resonance and the interference with nonresonant single pion production. The Adler angles were measured with limited statistics in bubble chamber neutrino experiments as well as in electron-proton scattering experiments. We discuss the viability of measuring these angles in neutrino interactions with nuclei.

Design of an expert system for the development and formulation of push-pull osmotic pump tablets containing poorly water-soluble drugs.

PubMed

Zhang, Zhi-hong; Dong, Hong-ye; Peng, Bo; Liu, Hong-fei; Li, Chun-lei; Liang, Min; Pan, Wei-san

2011-05-30

The purpose of this article was to build an expert system for the development and formulation of push-pull osmotic pump tablets (PPOP). Hundreds of PPOP formulations were studied according to different poorly water-soluble drugs and pharmaceutical acceptable excipients. The knowledge base including database and rule base was built based on the reported results of hundreds of PPOP formulations containing different poorly water-soluble drugs and pharmaceutical excipients and the experiences available from other researchers. The prediction model of release behavior was built using back propagation (BP) neural network, which is good at nonlinear mapping and learning function. Formulation design model was established based on the prediction model of release behavior, which was the nucleus of the inference engine. Finally, the expert system program was constructed by VB.NET associating with SQL Server. Expert system is one of the most popular aspects in artificial intelligence. To date there is no expert system available for the formulation of controlled release dosage forms yet. Moreover, osmotic pump technology (OPT) is gradually getting consummate all over the world. It is meaningful to apply expert system on OPT. Famotidine, a water insoluble drug was chosen as the model drug to validate the applicability of the developed expert system. Copyright © 2011 Elsevier B.V. All rights reserved.

In situ monitoring of intracellular controlled drug release from mesoporous silica nanoparticles coated with pH-responsive charge-reversal polymer.

PubMed

Zhang, Peng; Wu, Tong; Kong, Ji-Lie

2014-10-22

Therapeutic platforms such as chemotherapy that respond to physical and biological stimuli are highly desirable for effective cancer therapy. In this study, pH-responsive charge-reversal, polymer-coated mesoporous silica nanoparticles [PAH-cit/APTES-MSNs; PAH-cit refers to poly(allylamine)-citraconic anhydride; APTES refers to (3-aminopropyl)triethoxysilane] were synthesized for application as drug-delivery systems for the treatment of malignant cells. Confocal laser scanning microscopy (CLSM) revealed that the PAH-cit/APTES-MSNs nanocomposite effectively delivered and released doxorubicin hydrochloride to the nucleus of HeLa (human cervical carcinoma) cells. Additionally, the real-time dynamic drug-release process was monitored by CLSM. The current pH-controlled-smart-release platform holds promise in drug-delivery and cancer therapy-related applications.

Insights into the Structural Dynamics of Nucleocytoplasmic Transport of tRNA by Exportin-t

PubMed Central

Gupta, Asmita; Kailasam, Senthilkumar; Bansal, Manju

2016-01-01

Exportin-t (Xpot) transports mature 5′- and 3′-end processed tRNA from the nucleus to the cytoplasm by associating with a small G-protein Ran (RAs-related nuclear protein), in the nucleus. The release of tRNA in cytoplasm involves RanGTP hydrolysis. Despite the availability of crystal structures of nuclear and cytosolic forms of Xpot, the molecular details regarding the sequential events leading to tRNA release and subsequent conformational changes occurring in Xpot remain unknown. We have performed a combination of classical all-atom and accelerated molecular dynamics simulations on a set of complexes involving Xpot to study a range of features including conformational flexibility of free and cargo-bound Xpot and functionally critical contacts between Xpot and its cargo. The systems investigated include free Xpot and its different complexes, bound either to Ran (GTP/GDP) or tRNA or both. This approach provided a statistically reliable estimate of structural dynamics of Xpot after cargo release. The mechanistic basis for Xpot opening after cargo release has been explained in terms of dynamic structural hinges, about which neighboring region could be displaced to facilitate the nuclear to cytosolic state transition. Post-RanGTP hydrolysis, a cascade of events including local conformational change in RanGTP and loss of critical contacts at Xpot/tRNA interface suggest factors responsible for eventual release of tRNA. The level of flexibility in different Xpot complexes varied depending on the arrangement of individual HEAT repeats. Current study provides one of the most comprehensive and robust analysis carried out on this protein using molecular dynamics schemes. PMID:27028637

Central GLP-1 receptor activation modulates cocaine-evoked phasic dopamine signaling in the nucleus accumbens core.

PubMed

Fortin, Samantha M; Roitman, Mitchell F

2017-07-01

Drugs of abuse increase the frequency and magnitude of brief (1-3s), high concentration (phasic) dopamine release events in terminal regions. These are thought to be a critical part of drug reinforcement and ultimately the development of addiction. Recently, metabolic regulatory peptides, including the satiety signal glucagon-like peptide-1 (GLP-1), have been shown to modulate cocaine reward-driven behavior and sustained dopamine levels after cocaine administration. Here, we use fast-scan cyclic voltammetry (FSCV) to explore GLP-1 receptor (GLP-1R) modulation of dynamic dopamine release in the nucleus accumbens (NAc) during cocaine administration. We analyzed dopamine release events in both the NAc shell and core, as these two subregions are differentially affected by cocaine and uniquely contribute to motivated behavior. We found that central delivery of the GLP-1R agonist Exendin-4 suppressed the induction of phasic dopamine release events by intravenous cocaine. This effect was selective for dopamine signaling in the NAc core. Suppression of phasic signaling in the core by Exendin-4 could not be attributed to interference with cocaine binding to one of its major substrates, the dopamine transporter, as cocaine-induced increases in reuptake were unaffected. The results suggest that GLP-1R activation, instead, exerts its suppressive effects by altering dopamine release - possibly by suppressing the excitability of dopamine neurons. Given the role of NAc core dopamine in the generation of conditioned responses based on associative learning, suppression of cocaine-induced dopamine signaling in this subregion by GLP-1R agonism may decrease the reinforcing properties of cocaine. Thus, GLP-1Rs remain viable targets for the treatment and prevention of cocaine seeking, taking and relapse. Copyright © 2017 Elsevier Inc. All rights reserved.

Glutamatergic transmission in the central nucleus of the amygdala is selectively altered in Marchigian Sardinian alcohol-preferring rats: alcohol and CRF effects

PubMed Central

Herman, Melissa A.; Varodayan, Florence P.; Oleata, Christopher S.; Luu, George; Kirson, Dean; Heilig, Markus; Ciccocioppo, Roberto; Roberto, Marisa

2015-01-01

The CRF system of the central nucleus of the amygdala (CeA) is important for the processing of anxiety, stress, and effects of acute and chronic ethanol. We previously reported that ethanol decreases evoked glutamate transmission in the CeA of Sprague Dawley rats and that ethanol dependence alters glutamate release in the CeA. Here, we examined the effects of ethanol, CRF and a CRF1 receptor antagonist on spontaneous and evoked glutamatergic transmission in CeA neurons from Wistar and Marchigian Sardinian Preferring (msP) rats, a rodent line genetically selected for excessive alcohol drinking and characterized by heightened activity of the CRF1 system. Basal spontaneous and evoked glutamate transmission in CeA neurons from msP rats was increased compared to Wistar rats. Ethanol had divergent effects, either increasing or decreasing spontaneous glutamate release in the CeA of Wistar rats. This bidirectional effect was retained in msP rats, but the magnitude of the ethanol-induced increase in glutamate release was significantly smaller. The inhibitory effect of ethanol on evoked glutamatergic transmission was similar in both strains. CRF also either increased or decreased spontaneous glutamate release in CeA neurons of Wistar rats, however, in msP rats CRF only increased glutamate release. The inhibitory effect of CRF on evoked glutamatergic transmission was also lost in neurons from msP rats. A CRF1 antagonist produced only minor effects on spontaneous glutamate transmission, which were consistent across strains, and no effects on evoked glutamate transmission. These results demonstrate that the genetically altered CRF system of msP rats results in alterations in spontaneous and stimulated glutamate signaling in the CeA that may contribute to both the anxiety and drinking behavioral phenotypes. PMID:26519902

Dynamics of rapid dopamine release in the nucleus accumbens during goal-directed behaviors for cocaine versus natural rewards.

PubMed

Cameron, Courtney M; Wightman, R Mark; Carelli, Regina M

2014-11-01

Electrophysiological studies show that distinct subsets of nucleus accumbens (NAc) neurons differentially encode information about goal-directed behaviors for intravenous cocaine versus natural (food/water) rewards. Further, NAc rapid dopamine signaling occurs on a timescale similar to phasic cell firing during cocaine and natural reward-seeking behaviors. However, it is not known whether dopamine signaling is reinforcer specific (i.e., is released during responding for only one type of reinforcer) within discrete NAc locations, similar to neural firing dynamics. Here, fast-scan cyclic voltammetry (FSCV) was used to measure rapid dopamine release during multiple schedules involving sucrose reward and cocaine self-administration (n = 8 rats) and, in a separate group of rats (n = 6), during a sucrose/food multiple schedule. During the sucrose/cocaine multiple schedule, dopamine increased within seconds of operant responding for both reinforcers. Although dopamine release was not reinforcer specific, more subtle differences were observed in peak dopamine concentration [DA] across reinforcer conditions. Specifically, peak [DA] was higher during the first phase of the multiple schedule, regardless of reinforcer type. Further, the time to reach peak [DA] was delayed during cocaine-responding compared to sucrose. During the sucrose/food multiple schedule, increases in dopamine release were also observed relative to operant responding for both natural rewards. However, peak [DA] was higher relative to responding for sucrose than food, regardless of reinforcer order. Overall, the results reveal the dynamics of rapid dopamine signaling in discrete locations in the NAc across reward conditions, and provide novel insight into the functional role of this system in reward-seeking behaviors. Copyright © 2014 Elsevier Ltd. All rights reserved.

In Vivo Comparison of Norepinephrine and Dopamine Release in Rat Brain by Simultaneous Measurements with Fast-Scan Cyclic Voltammetry

PubMed Central

Park, Jinwoo; Takmakov, Pavel; Wightman, R. Mark

2011-01-01

Brain norepinephrine and dopamine regulate a variety of critical behaviors such as stress, learning, memory, and drug addiction. Here, we demonstrate differences in the regulation of in vivo neurotransmission for dopamine in the anterior nucleus accumbens (NAc) and norepinephrine in the ventral bed nucleus of the stria terminalis (vBNST) of the anesthetized rat. Release of the two catecholamines was measured simultaneously using fast-scan cyclic voltammetry (FSCV) at two different carbon-fiber microelectrodes, each implanted in the brain region of interest. Simultaneous dopamine and norepinephrine release was evoked by electrical stimulation of a region where the ventral noradrenergic bundle (VNB), the pathway of noradrenergic neurons, courses through the ventral tegmental area/substantia nigra (VTA/SN), the origin of dopaminergic cell bodies. The release and uptake of norepinephrine in the vBNST were both significantly slower than for dopamine in the NAc. Pharmacological manipulations in the same animal demonstrated that the two catecholamines are differently regulated. The combination of a dopamine autoreceptor antagonist and amphetamine significantly increased basal extracellular dopamine whereas a norepinephrine autoreceptor antagonist and amphetamine did not change basal norepinephrine concentration. α-Methyl-p-tyrosine, a tyrosine hydroxylase inhibitor, decreased electrically evoked dopamine release faster than norepinephrine. The dual-microelectrode FSCV technique along with anatomical and pharmacological evidence confirms that dopamine in the NAc and norepinephrine in the vBNST can be monitored selectively and simultaneously in the same animal. The high temporal and spatial resolution of the technique enabled us to examine differences in the dynamics of extracellular norepinephrine and dopamine concurrently in two different limbic structures. PMID:21933188

Toward construction of the unified lepton-nucleus interaction model from a few hundred MeV to GeV region

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nakamura, S. X.; Hayato, Y.; Hirai, M.

2015-05-15

Next generation neutrino oscillation experiments will need a quantitative understanding of neutrino-nucleus interaction far better than ever. Kinematics covered by the relevant neutrino-nucleus interaction spans wide region, from the quasi-elastic, through the resonance region, to the deeply inelastic scattering region. The neutrino-nucleus interaction in each region has quite different characteristics. Obviously, it is essential to combine different expertise to construct a unified model that covers all the kinematical region of the neutrino-nucleus interaction. Recently, several experimentalists and theorists got together to form a collaboration to tackle this problem. In this contribution, we report the collaboration’s recent activity and a goalmore » in near future.« less

Forced swimming-induced oxytocin release into blood and brain: Effects of adrenalectomy and corticosterone treatment.

PubMed

Torner, Luz; Plotsky, Paul M; Neumann, Inga D; de Jong, Trynke R

2017-03-01

The oxytocin (OXT) system is functionally linked to the HPA axis in a reciprocal and complex manner. Certain stressors are known to cause the simultaneous release of OXT and adrenocorticotrophic hormone (ACTH) followed by corticosterone (CORT). Furthermore, brain OXT attenuates ACTH and CORT responses. Although there are some indications of CORT influencing OXT neurotransmission, specific effects of CORT on neurohypophyseal or intra-hypothalamic release of OXT have not been studied in detail. In the present set of experiments, adult male rats were adrenalectomized (ADX) or sham-operated and fitted with a jugular vein catheter and/or microdialysis probe targeting the hypothalamic paraventricular nucleus (PVN). Blood samples and dialysates were collected before and after forced swimming (FS) and analyzed for CORT, ACTH and AVP concentrations (in plasma) and OXT concentrations (in plasma and dialysates). Experimental treatments included acute infusion of CORT (70 or 175μg/kg i.v.) 5min prior to FS, or subcutaneous placement of 40% CORT pellets resulting in stable CORT levels in the normal basal range. Although ADX did not alter basal OXT concentrations either in plasma or in microdialysates from the PVN, it did cause an exaggerated peripheral secretion of OXT and a blunted intra-PVN release of OXT in response to FS. CORT pellets did not influence either of these ADX-induced effects, while acute infusion of 175μg/kg CORT rescued the stress-induced rise in OXT release within the PVN and modestly increased peripheral OXT secretion. In conclusion, these results indicate that CORT regulates both peripheral and intracerebral OXT release, but in an independent manner. Whereas the peripheral secretion of OXT occurs simultaneously to HPA axis activation in response to FS and is modestly influenced by CORT, HPA axis activation and circulating CORT strongly contribute to the stress-induced stimulation of OXT release within the PVN. Copyright © 2016 Elsevier Ltd. All rights reserved.

In Vivo Dentate Nucleus Gamma-aminobutyric Acid Concentration in Essential Tremor vs. Controls.

PubMed

Louis, Elan D; Hernandez, Nora; Dyke, Jonathan P; Ma, Ruoyun E; Dydak, Ulrike

2018-04-01

Despite its high prevalence, essential tremor (ET) is among the most poorly understood neurological diseases. The presence and extent of Purkinje cell (PC) loss in ET is the subject of controversy. PCs are a major storehouse of central nervous system gamma-aminobutyric acid (GABA), releasing GABA at the level of the dentate nucleus. It is therefore conceivable that cerebellar dentate nucleus GABA concentration could be an in vivo marker of PC number. We used in vivo 1 H magnetic resonance spectroscopy (MRS) to quantify GABA concentrations in two cerebellar volumes of interest, left and right, which included the dentate nucleus, comparing 45 ET cases to 35 age-matched controls. 1 H MRS was performed using a 3.0-T Siemens Tim Trio scanner. The MEGA-PRESS J-editing sequence was used for GABA detection in two cerebellar volumes of interest (left and right) that included the dentate nucleus. The two groups did not differ with respect to our primary outcome of GABA concentration (given in institutional units). For the right dentate nucleus, [GABA] in ET cases = 2.01 ± 0.45 and [GABA] in controls = 1.86 ± 0.53, p = 0.17. For the left dentate nucleus, [GABA] in ET cases = 1.68 ± 0.49 and [GABA] controls = 1.80 ± 0.53, p = 0.33. The controls had similar dentate nucleus [GABA] in the right vs. left dentate nucleus (p = 0.52); however, in ET cases, the value on the right was considerably higher than that on the left (p = 0.001). We did not detect a reduction in dentate nucleus GABA concentration in ET cases vs. One interpretation of the finding is that it does not support the existence of PC loss in ET; however, an alternative interpretation is the observed pattern could be due to the effects of terminal sprouting in ET (i.e., collateral sprouting from surviving PCs making up for the loss of GABA-ergic terminals from PC degeneration). Further research is needed.

[Vesicular and nonvesicular glutamate release in the nucleus accumbens during a forced switch in behavioral strategy].

PubMed

Saul'skaia, N B; Mikhaĭlova, M O

2004-01-01

By means of in vivo microdialysis combined with HPLC analysis, we have shown that glutamate extracellular level in the rat n. accumbens increases during a forced switch in behavioral strategy. When infused in the n. accumbens, a Na+ channel blocker tetrodotoxin (TTX, 1 microM) completely prevents this increase whereas a potent cystine/glutamate exchanger blocker (S)-4-carboxyphenylglycine ((S)-4-CPG, 5 microM) has no effect. In contrast, TT (1 microM), infused in the n. accumbens, fails to significantly alter basal level of extracellular glutamate in this region whereas (S)-4-CPG (5 microM) produced a significant decrease. Our data suggest that basal and factional glutamate releases in the n. accumbens are differently regulated. The source of basal glutamate release is a non-vesicular release via cystine/glutamate exchanger. Functional glutamate release observed during a forced switch in behavioral strategy derives from vesicular synaptic pool.

Integrating Neural Circuits Controlling Female Sexual Behavior.

PubMed

Micevych, Paul E; Meisel, Robert L

2017-01-01

The hypothalamus is most often associated with innate behaviors such as is hunger, thirst and sex. While the expression of these behaviors important for survival of the individual or the species is nested within the hypothalamus, the desire (i.e., motivation) for them is centered within the mesolimbic reward circuitry. In this review, we will use female sexual behavior as a model to examine the interaction of these circuits. We will examine the evidence for a hypothalamic circuit that regulates consummatory aspects of reproductive behavior, i.e., lordosis behavior, a measure of sexual receptivity that involves estradiol membrane-initiated signaling in the arcuate nucleus (ARH), activating β-endorphin projections to the medial preoptic nucleus (MPN), which in turn modulate ventromedial hypothalamic nucleus (VMH) activity-the common output from the hypothalamus. Estradiol modulates not only a series of neuropeptides, transmitters and receptors but induces dendritic spines that are for estrogenic induction of lordosis behavior. Simultaneously, in the nucleus accumbens of the mesolimbic system, the mating experience produces long term changes in dopamine signaling and structure. Sexual experience sensitizes the response of nucleus accumbens neurons to dopamine signaling through the induction of a long lasting early immediate gene. While estrogen alone increases spines in the ARH, sexual experience increases dendritic spine density in the nucleus accumbens. These two circuits appear to converge onto the medial preoptic area where there is a reciprocal influence of motivational circuits on consummatory behavior and vice versa . While it has not been formally demonstrated in the human, such circuitry is generally highly conserved and thus, understanding the anatomy, neurochemistry and physiology can provide useful insight into the motivation for sexual behavior and other innate behaviors in humans.

Integrating Neural Circuits Controlling Female Sexual Behavior

PubMed Central

Micevych, Paul E.; Meisel, Robert L.

2017-01-01

The hypothalamus is most often associated with innate behaviors such as is hunger, thirst and sex. While the expression of these behaviors important for survival of the individual or the species is nested within the hypothalamus, the desire (i.e., motivation) for them is centered within the mesolimbic reward circuitry. In this review, we will use female sexual behavior as a model to examine the interaction of these circuits. We will examine the evidence for a hypothalamic circuit that regulates consummatory aspects of reproductive behavior, i.e., lordosis behavior, a measure of sexual receptivity that involves estradiol membrane-initiated signaling in the arcuate nucleus (ARH), activating β-endorphin projections to the medial preoptic nucleus (MPN), which in turn modulate ventromedial hypothalamic nucleus (VMH) activity—the common output from the hypothalamus. Estradiol modulates not only a series of neuropeptides, transmitters and receptors but induces dendritic spines that are for estrogenic induction of lordosis behavior. Simultaneously, in the nucleus accumbens of the mesolimbic system, the mating experience produces long term changes in dopamine signaling and structure. Sexual experience sensitizes the response of nucleus accumbens neurons to dopamine signaling through the induction of a long lasting early immediate gene. While estrogen alone increases spines in the ARH, sexual experience increases dendritic spine density in the nucleus accumbens. These two circuits appear to converge onto the medial preoptic area where there is a reciprocal influence of motivational circuits on consummatory behavior and vice versa. While it has not been formally demonstrated in the human, such circuitry is generally highly conserved and thus, understanding the anatomy, neurochemistry and physiology can provide useful insight into the motivation for sexual behavior and other innate behaviors in humans. PMID:28642689

Experimental results on the ω- and η'-nucleus potential - on the way to mesic states

NASA Astrophysics Data System (ADS)

Nanova, Mariana

2015-06-01

Different experimental approaches to determine the meson-nucleus optical potential are discussed. The experiments have been performed with the Crystal Barrel/TAPS detector system at the ELSA accelerator in Bonn and the Crystal Ball/TAPS at the MAMI accelerator in Mainz. Experimental results about the real and imaginary part of the η'- and ω-nucleus optical potential are presented. The imaginary part of the meson-nucleus optical potential is determined from the in-medium width of the meson by the measurement of the transparency ratio. Information on the real part of the optical potential is deduced from measurements of the excitation function and momentum distribution which are sensitive to the sign and depth of the potential. The results are discussed and compared to theoretical predictions. The data for both mesons are consistent with a weakly attractive potential. The formation and population of ω-nucleus and η'-nucleus bound states is additionally discussed.

Characterization of beta-phenylethylamine-induced monoamine release in rat nucleus accumbens: a microdialysis study.

PubMed

Nakamura, M; Ishii, A; Nakahara, D

1998-05-22

In vivo microdialysis was used to investigate the effect of beta-phenylethylamine on extracellular levels of monoamines and their metabolites in the nucleus accumbens of conscious rats. At all doses tested (1, 10 and 100 microM), infusion of beta-phenylethylamine through the microdialysis probe significantly increased extracellular levels of dopamine in the nucleus accumbens. These increases were dose-related. The increase in dopamine levels induced by 100 microM beta-phenylethylamine was not affected by co-perfusion of 4 microM tetrodotoxin. The ability of 100 microM beta-phenylethylamine to increase the extracellular level of dopamine was comparable to that of the same dose of methamphetamine. On the other hand, beta-phenylethylamine had a much less potent enhancing effect on 5-hydroxytryptamine (5-HT) than dopamine levels. Only the highest dose (100 microM) caused a statistically significant effect on 5-HT levels. Over the dose range tested (1, 10 and 100 microM), beta-phenylethylamine had no effect on extracellular metabolite levels of dopamine and 5-HT. The results suggest that beta-phenylethylamine increases the efflux of monoamines, preferentially dopamine, without affecting monoamine metabolism, in the nucleus accumbens.

Brief Social Isolation in the Adolescent Wistar-Kyoto Rat Model of Endogenous Depression Alters Corticosterone and Regional Monoamine Concentrations.

PubMed

Shetty, Reshma A; Sadananda, Monika

2017-05-01

The Wistar-Kyoto rat (WKY) model has been suggested as a model of adult and adolescent depression though face, predictive and construct validities of the model to depression remain equivocal. The suitability of the WKY as a diathesis model that tests the double-hit hypothesis, particularly during critical periods of brain and behavioural development remains to be established. Here, effects of post-weaning social isolation were assessed during early adolescence (~30pnd) on behavioural despair and learned helplessness in the forced swim test (FST), plasma corticosterone levels and tissue monoamine concentrations in brain areas critically involved in depression, such as prefrontal cortex, nucleus accumbens, striatum and hippocampus. Significantly increased immobility in the FST was observed in socially-isolated, adolescent WKY with a concomitant increase in corticosterone levels over and above the FST-induced stress. WKY also demonstrated a significantly increased release and utilization of dopamine, as manifested by levels of metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid in nucleus accumbens, indicating that the large dopamine storage pool evident during adolescence induces greater dopamine release when stimulated. The serotonin metabolite 5-hydroxy-indoleacetic acid was also significantly increased in nucleus accumbens, indicating increased utilization of serotonin, along with norepinephrine levels which were also signficantly elevated in socially-isolated adolescent WKY. Differences in neurochemistry suggest that social or environmental stimuli during critical periods of brain and behavioural development can determine the developmental trajectories of implicated pathways.

Nicotine modulates multiple regions in the limbic stress network regulating activation of hypophysiotrophic neurons in hypothalamic paraventricular nucleus.

PubMed

Yu, Guoliang; Sharp, Burt M

2012-08-01

Nicotine intake affects CNS responses to stressors. We reported that nicotine self-administration (SA) augmented the hypothalamo-pituitary-adrenal (HPA) stress response, in part because of the altered neurotransmission and neuropeptide expression within hypothalamic paraventricular nucleus (PVN). Limbic-PVN interactions involving medial prefrontal cortex, amygdala, and bed nucleus of the stria terminalis (BST) greatly impact the HPA stress response. Therefore, we investigated the effects of nicotine SA on stress-induced neuronal activation in limbic-PVN network, using c-Fos protein immunohistochemistry and retrograde tracing. Nicotine decreased stress-induced c-Fos in prelimbic cortex (PrL), anteroventral BST (avBST), and peri-PVN, but increased c-Fos induction in medial amygdala (MeA), locus coeruleus, and PVN. Fluoro-gold (FG) was injected into avBST or PVN, as GABAergic neurons in avBST projecting to PVN corticotrophin-releasing factor neurons relay information from both PrL glutamatergic and MeA GABAergic neurons. The stress-induced c-Fos expression in retrograde-labeled FG+ neurons was decreased in PrL by nicotine, but increased in MeA, and also reduced in avBST. Therefore, within limbic-PVN network, nicotine SA exerts selective regional effects on neuronal activation by stress. These findings expand the mechanistic framework by demonstrating altered limbic-BST-PVN interactions underlying the disinhibition of PVN corticotrophin-releasing factor neurons, an essential component of the amplified HPA response to stress by nicotine. © 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.

PROTEINS IN NUCLEOCYTOPLASMIC INTERACTIONS

PubMed Central

Prescott, David; Goldstein, Lester

1968-01-01

The behavior of nuclear proteins in Amoeba proteus was studied by tritiated amino acid labeling, nuclear transplantation, and cytoplasmic amputation. During prophase at least 77% (but probably over 95%) of the nuclear proteins is released to the cytoplasm. These same proteins return to the nucleus within the first 3 hr of interphase. When cytoplasm is amputated from an ameba in mitosis (shen the nuclear proteins are in the cytoplasm), the resultant daughter nuclei are depleted in the labeled nuclear proteins. The degree of depletion is less than proportional to the amount of cytoplasm removed because a portion of rapidly migrating protein (a nuclear protein that is normally shuttling between nucleus and cytoplasm and is thus also present in the cytoplasm) which would normally remain in the cytoplasm is taken up by the reconstituting daughter nuclei. Cytoplasmic fragments cut from mitotic cells are enriched in both major classes of nuclear proteins, i.e. rapidly migrating protein and slow turn-over protein. An interphase nucleus implanted into such an enucleated cell acquires from the cytoplasm essentially all of the excess nuclear proteins of both classes. The data indicate that there is a lack of binding sites in the cytoplasm for the rapidly migrating nuclear protein. The quantitative aspects of the distribution of rapidly migrating protein between the nucleus and the cytoplasm indicate that the distribution is governed primarily by factors within the nucleus. PMID:5677972

Lack of Intrinsic GABAergic Connections in the Thalamic Reticular Nucleus of the Mouse.

PubMed

Hou, Guoqiang; Smith, Alison G; Zhang, Zhong-Wei

2016-07-06

It is generally thought that neurons in the thalamic reticular nucleus (TRN) form GABAergic synapses with other TRN neurons and that these interconnections are important for the function of the TRN. However, the existence of such intrinsic connections is controversial. We combine two complementary approaches to examine intrinsic GABAergic connections in the TRN of the mouse. We find that optogenetic stimulation of TRN neurons and their axons evokes GABAergic IPSCs in TRN neurons in mice younger than 2 weeks of age but fails to do so after that age. Blocking synaptic release from TRN neurons through conditional deletion of vesicular GABA transporter has no effect on spontaneous IPSCs recorded in TRN neurons aged 2 weeks or older while dramatically reducing GABAergic transmission in thalamic relay neurons. These results demonstrate that except for a short period after birth, the TRN of the mouse lacks intrinsic GABAergic connections. The thalamic reticular nucleus has a critical role in modulating information transfer from the thalamus to the cortex. It has been proposed that neurons in the thalamic reticular nucleus are interconnected through GABAergic synapses and that these connections serve important functions. Our results show that except for the first 2 weeks after birth, the thalamic reticular nucleus of the mouse lacks intrinsic GABAergic connections. Copyright © 2016 the authors 0270-6474/16/367246-07$15.00/0.

INHIBITION OF VASOPRESSIN RELEASE IN THE RAT SUPRAOPTIC NUCLEUS BY EXPOSRUE TO THE PBDE MIXTURE (DE-71) IN VITRO.

EPA Science Inventory

Introduction

Persistent organic pollutants (POPs) are long-lived toxic organic compounds and are of major concern for human

and ecosystem health1,2 . Polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) are

examples of such chemicals...

GABA and NMDA receptors in CRF neurons have opposing effects in fear acquisition and anxiety in central amygdala vs. bed nucleus of the stria terminalis

PubMed Central

Gafford, Georgette M.; Ressler, Kerry J.

2016-01-01

Beginning with Vale and Colleagues in 1981, corticotropin releasing factor (CRF) also called corticotropin releasing hormone (CRH) has repeatedly been identified as an important contributor to fear and anxiety behavior. These findings have proven useful to further our understanding of disorders that have significant fear-dysregulation, such as post-traumatic stress, as well as other stress- and anxiety-related disorders. Unfortunately, the data are not all in agreement. In particular the role of CRF in fear learning is controversial, with studies pointing to contradictory effects from CRF manipulation even within the same brain structure. Further, very few studies address the potentially promising role of CRF manipulation in fear extinction behavior. Here, we briefly review the role of CRF in anxiety, fear learning and extinction, focusing on recent cell-type and neurotransmitter-specific studies in the amygdala and bed nucleus of the stria terminalis (BNST) that may help to synthesize the available data on the role of CRF in fear and anxiety-related behaviors. PMID:25888455

High energy interactions of cosmic ray particles

NASA Technical Reports Server (NTRS)

Jones, L. W.

1986-01-01

The highlights of seven sessions of the Conference dealing with high energy interactions of cosmic rays are discussed. High energy cross section measurements; particle production-models of experiments; nuclei and nuclear matter; nucleus-nucleus collision; searches for magnetic monopoles; and studies of nucleon decay are covered.

Excitatory innervation of caudal hypoglossal nucleus from nucleus reticularis gigantocellularis in the rat.

PubMed

Yang, C C; Chan, J Y; Chan, S H

1995-03-01

We examined the possible innervation of the caudal hypoglossal nucleus by the nucleus reticularis gigantocellularis of the medulla oblongata, based on single-neuron recording and retrograde tracing experiments in Sprague-Dawley rats. Under pentobarbital sodium (50 mg/kg, i.p.) anesthesia, electrical stimulation of the caudal portion of the nucleus reticularis gigantocellularis with repetitive 0.5-ms rectangular pulses increased (46 of 51 neurons) the basal discharge frequency of spontaneously active cells, or evoked spike activity in silent, hypoglossal neurons located at the level of the obex. This excitatory effect was related to the intensity (25-100 microA) and/or frequency (0.5-20 Hz) of the stimulating pulses to the nucleus reticularis gigantocellularis. Perikaryal activation of neurons by microinjection of L-glutamate (0.5 nmol, 25 nl) into the caudal portion of the nucleus reticularis gigantocellularis similarly produced an excitatory action on eight of 14 hypoglossal neurons. Retrogradely labeled neurons were found bilaterally within the confines of the nucleus reticularis gigantocellularis following unilateral microinjection of wheatgerm agglutinin-conjugated horseradish peroxidase or Fast Blue into the corresponding hypoglossal recording sites. Furthermore, the distribution of labeled neurons in the nucleus reticularis gigantocellularis substantially overlapped with the loci of electrical or chemical stimulation. These complementary electrophysiological and neuroanatomical results support the conclusion that an excitatory link exists between the nucleus reticularis gigantocellularis and at least the caudal portion of the hypoglossal nucleus in the rat.

New high resolution measurements of open and hidden charm production in proton-nucleus collisions at √{ s} = 110GeV with LHCb

NASA Astrophysics Data System (ADS)

Maurice, Émilie; LHCb Collaboration

2017-11-01

Open and hidden charm production in nucleus-nucleus collisions is considered as a key probe of Quark Gluon Plasma (QGP) formation. In the search of specific QGP effects, proton-nucleus collisions are used as the reference as they account for the corresponding Cold Nuclear Matter (CNM) effects. The LHCb experiment, thanks to its System for Measuring Overlap with Gas (SMOG) can be operated in a fixed target mode with the LHC beams, at an intermediate center-of-mass energy between nominal SPS and RHIC energies. In 2015, for the first time, reactions of incident LHC proton beams on noble gas targets have been recorded by the LHCb experiment at a center-of-mass energy of 110 GeV and within the center-of-mass rapidity range - 2.77

Different Classes of Glutamate Receptors Mediate Distinct Behaviors in a Single Brainstem Nucleus

NASA Astrophysics Data System (ADS)

Dye, John; Heiligenberg, Walter; Keller, Clifford H.; Kawasaki, Masashi

1989-11-01

We have taken advantage of the increasing understanding of glutamate neuropharmacology to probe mechanisms of well-defined vertebrate behaviors. Here we report a set of experiments that suggests distinct roles for two major classes of glutamate receptors in a discrete premotor nucleus of the brainstem. The medullary pacemaker nucleus of weakly electric fish is an endogenous oscillator that controls the electric organ discharge (EOD). Its regular frequency of firing is modulated during several distinct behaviors. The pacemaker nucleus continues firing regularly when isolated in vitro, and modulatory behaviors can be reproduced by stimulating the descending input pathway. Glutamate agonists applied to the pacemaker in vitro produced increases in frequency, while glutamate antagonists selectively blocked stimulus-induced modulations. Experiments with glutamate antagonists in the intact animal resulted in specific effects on two well-characterized behaviors. Our data indicate that these behaviors are separately mediated in the pacemaker by receptors displaying characteristics of the kainate/quisqualate and N-methyl-D-aspartate subtypes of glutamate receptor, respectively.

Pharmacological examination of trifluoromethyl ring-substituted methcathinone analogs.

PubMed

Cozzi, Nicholas V; Brandt, Simon D; Daley, Paul F; Partilla, John S; Rothman, Richard B; Tulzer, Andreas; Sitte, Harald H; Baumann, Michael H

2013-01-15

Cathinones are a class of drugs used to treat various medical conditions including depression, obesity, substance abuse, and muscle spasms. Some "designer" cathinones, such as methcathinone, mephedrone, and methylone, are used nonclinically for their stimulant or entactogenic properties. Given the recent rise in nonmedical use of designer cathinones, we aimed to improve understanding of cathinone pharmacology by investigating analogs of methcathinone with a CF(3) substituent at the 2-, 3-, or 4-position of the phenyl ring (TFMAPs). We compared the TFMAPs with methcathinone for effects on monoamine uptake transporter function in vitro and in vivo, and for effects on locomotor activity in rats. At the serotonin transporter (SERT), 3-TFMAP and 4-TFMAP were 10-fold more potent than methcathinone as uptake inhibitors and as releasing agents, but 2-TFMAP was both a weak uptake inhibitor and releaser. At the norepinephrine and dopamine transporters (NET and DAT), all TFMAP isomers were less potent than methcathinone as uptake inhibitors and releasers. In vivo, 4-TFMAP released 5-HT, but not dopamine, in rat nucleus accumbens and did not affect locomotor activity, whereas methcathinone increased both 5-HT and dopamine and produced locomotor stimulation. These experiments reveal that TFMAPs are substrates for the monoamine transporters and that phenyl ring substitution at the 3- or 4-position increases potency at SERT but decreases potency at NET and DAT, resulting in selectivity for SERT. The TFMAPs might have a therapeutic value for a variety of medical and psychiatric conditions and may have lower abuse liability compared to methcathinone due to their decreased DAT activity. Copyright © 2012 Elsevier B.V. All rights reserved.

Subthalamic nucleus deep brain stimulation for Parkinson's disease: evidence for effectiveness and limitations from 12 years' experience.

PubMed

Chan, Anne Y Y; Yeung, Jonas H M; Mok, Vincent C T; Ip, Vincent H L; Wong, Adrian; Kuo, S H; Chan, Danny T M; Zhu, X L; Wong, Edith; Lau, Claire K Y; Wong, Rosanna K M; Tang, Venus; Lau, Christine; Poon, W S

2014-12-01

To present the result and experience of subthalamic nucleus deep brain stimulation for Parkinson's disease. Case series. Prince of Wales Hospital, Hong Kong. A cohort of patients with Parkinson's disease received subthalamic nucleus deep brain stimulation from September 1998 to January 2010. Patient assessment data before and after the operation were collected prospectively. Forty-one patients (21 male and 20 female) with Parkinson's disease underwent bilateral subthalamic nucleus deep brain stimulation and were followed up for a median interval of 12 months. For the whole group, the mean improvements of Unified Parkinson's Disease Rating Scale (UPDRS) parts II and III were 32.5% and 31.5%, respectively (P<0.001). Throughout the years, a multidisciplinary team was gradually built. The deep brain stimulation protocol evolved and was substantiated by updated patient selection criteria and outcome assessment, integrated imaging and neurophysiological targeting, refinement of surgical technique as well as the accumulation of experience in deep brain stimulation programming. Most of the structural improvement occurred before mid-2005. Patients receiving the operation before June 2005 (19 cases) and after (22 cases) were compared; the improvements in UPDRS part III were 13.2% and 55.2%, respectively (P<0.001). There were three operative complications (one lead migration, one cerebral haematoma, and one infection) in the group operated on before 2005. There was no operative mortality. The functional state of Parkinson's disease patients with motor disabilities refractory to best medical treatment improved significantly after subthalamic nucleus deep brain stimulation. A dedicated multidisciplinary team building, refined protocol for patient selection and assessment, improvement of targeting methods, meticulous surgical technique, and experience in programming are the key factors contributing to the improved outcome.

Determination of electron-nucleus collisions geometry with forward neutrons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zheng, L.; Aschenauer, E.; Lee, J. H.

2014-12-29

There are a large number of physics programs one can explore in electron-nucleus collisions at a future electron-ion collider. Collision geometry is very important in these studies, while the measurement for an event-by-event geometric control is rarely discussed in the prior deep-inelastic scattering experiments off a nucleus. This paper seeks to provide some detailed studies on the potential of tagging collision geometries through forward neutron multiplicity measurements with a zero degree calorimeter. As a result, this type of geometry handle, if achieved, can be extremely beneficial in constraining nuclear effects for the electron-nucleus program at an electron-ion collider.

Neutrino-induced reactions on nuclei

NASA Astrophysics Data System (ADS)

Gallmeister, K.; Mosel, U.; Weil, J.

2016-09-01

Background: Long-baseline experiments such as the planned deep underground neutrino experiment (DUNE) require theoretical descriptions of the complete event in a neutrino-nucleus reaction. Since nuclear targets are used this requires a good understanding of neutrino-nucleus interactions. Purpose: Develop a consistent theory and code framework for the description of lepton-nucleus interactions that can be used to describe not only inclusive cross sections, but also the complete final state of the reaction. Methods: The Giessen-Boltzmann-Uehling-Uhlenbeck (GiBUU) implementation of quantum-kinetic transport theory is used, with improvements in its treatment of the nuclear ground state and of 2p2h interactions. For the latter an empirical structure function from electron scattering data is used as a basis. Results: Results for electron-induced inclusive cross sections are given as a necessary check for the overall quality of this approach. The calculated neutrino-induced inclusive double-differential cross sections show good agreement data from neutrino and antineutrino reactions for different neutrino flavors at MiniBooNE and T2K. Inclusive double-differential cross sections for MicroBooNE, NOvA, MINERvA, and LBNF/DUNE are given. Conclusions: Based on the GiBUU model of lepton-nucleus interactions a good theoretical description of inclusive electron-, neutrino-, and antineutrino-nucleus data over a wide range of energies, different neutrino flavors, and different experiments is now possible. Since no tuning is involved this theory and code should be reliable also for new energy regimes and target masses.

Intracellular trafficking pathways for nuclear delivery of plasmid DNA complexed with highly efficient endosome escape polymers.

PubMed

Gillard, Marianne; Jia, Zhongfan; Hou, Jeff Jia Cheng; Song, Michael; Gray, Peter P; Munro, Trent P; Monteiro, Michael J

2014-10-13

Understanding the pathways for nuclear entry could see vast improvements in polymer design for the delivery of genetic materials to cells. Here, we use a novel diblock copolymer complexed with plasmid DNA (pDNA) to determine both its cellular entry and nuclear pathways. The diblock copolymer (A-C3) is specifically designed to bind and protect pDNA, release it at a specific time, but more importantly, rapidly escape the endosome. The copolymer was taken up by HEK293 cells preferentially via the clathrin-mediated endocytosis (CME) pathway, and the pDNA entered the nucleus to produce high gene expression levels in all cells after 48 h, a similar observation to the commercially available polymer transfection agent, PEI Max. This demonstrates that the polymers must first escape the endosome and then mediate transport of pDNA to the nucleus for occurrence of gene expression. The amount of pDNA within the nucleus was found to be higher for our A-C3 polymer than PEI Max, with our polymer delivering 7 times more pDNA than PEI Max after 24 h. We further found that entry into the nucleus was primarily through the small nuclear pores and did not occur during mitosis when the nuclear envelope becomes compromised. The observation that the polymers are also found in the nucleus supports the hypothesis that the large pDNA/polymer complex (size ~200 nm) must dissociate prior to nucleus entry and that cationic and hydrophobic monomer units on the polymer may facilitate active transport of the pDNA through the nuclear pore.

The Aftermath of the Largest Cometary Outburst in Recorded History - An In-Depth Study of Comet 17P/Holmes

NASA Astrophysics Data System (ADS)

Stevenson, Rachel Ann

On UT 2007 Oct. 23, Jupiter Family comet 17P/Holmes underwent the largest cometary outburst in recorded history when it brightened by a factor of nearly a million in less than 2 days. This unprecedented event prompted a four-month observing campaign to observe the aftermath of the outburst. The wide field imager, MegaCam mounted on the Canada-France-Hawaii telescope was used to obtain r' images of the nucleus and the rapidly expanding dust coma. These images are unequaled in their quality and scope, and form a unique dataset with which to study the outburst aftermath. This original work examines the morphology of the outburst, and constrains the characteristics of the ejected material. Spatial filtering of images obtained in 2007 Nov. revealed numerous fragments moving away from the nucleus. The fragments were too bright to have been inactive, monolithic blocks and must have been acting as mini-comets with their own sources of sublimating volatiles and dust comae. They represented a significant (~ 10%) of the total ejected mass. The fragments had unusually high velocities relative to the nucleus, suggesting that they were accelerated by high gas pressure inside the nucleus prior to ejection. This work presents the first detection of such large, rapidly moving cometary fragments. The scarcity of similar ejecta around other fragmenting comets may be due to observational biases, rather than being unique to 17P/Holmes. Aperture photometry was used to study the evolution of the inner coma, which faded rapidly in the weeks and months following the initial outburst. Despite the observed fading, the nucleus must have remained active, continuing to supply fresh material to the inner coma. A second, much smaller outburst was detected on UT 2007 Nov. 12, which released an estimated 106 kg of dust into the inner coma. The secondary outburst showed that the nucleus remained unstable for several weeks after the initial event. Surface brightness profiles of the inner coma were constructed for each night of observation. The slopes of the profiles between 10000 km and 25000 km are consistent with dust grains fragmenting near the nucleus. Such fragmenting may be caused by thermal stressing or sublimation of cohesive volatiles. As the comet moved away from the Sun, the profiles also showed a persistent bump, interpreted as a halo of freshly released ice grains. The expected sublimation rates of such grains were examined, and it is concluded that the ice grains must have been contaminated with albedo-lowering regolith that significantly shortened their life-times. The possible characteristics of these dirty ice grains are examined within the context of the observations. The mini-comet fragments, dirty ice grains, and continuing but declining activity together suggest that the outburst of 17P/Holmes excavated material from within the nucleus, and left exposed patches of sublimating volatiles on its surface. The long-term fate of 17P/Holmes is uncertain, but micro-outbursts are likely as the nucleus settles over coming apparitions.

Intracellular sphingosine releases calcium from lysosomes

PubMed Central

Höglinger, Doris; Haberkant, Per; Aguilera-Romero, Auxiliadora; Riezman, Howard; Porter, Forbes D; Platt, Frances M; Galione, Antony; Schultz, Carsten

2015-01-01

To elucidate new functions of sphingosine (Sph), we demonstrate that the spontaneous elevation of intracellular Sph levels via caged Sph leads to a significant and transient calcium release from acidic stores that is independent of sphingosine 1-phosphate, extracellular and ER calcium levels. This photo-induced Sph-driven calcium release requires the two-pore channel 1 (TPC1) residing on endosomes and lysosomes. Further, uncaging of Sph leads to the translocation of the autophagy-relevant transcription factor EB (TFEB) to the nucleus specifically after lysosomal calcium release. We confirm that Sph accumulates in late endosomes and lysosomes of cells derived from Niemann-Pick disease type C (NPC) patients and demonstrate a greatly reduced calcium release upon Sph uncaging. We conclude that sphingosine is a positive regulator of calcium release from acidic stores and that understanding the interplay between Sph homeostasis, calcium signaling and autophagy will be crucial in developing new therapies for lipid storage disorders such as NPC. DOI: http://dx.doi.org/10.7554/eLife.10616.001 PMID:26613410

Functional Peptidomics: Stimulus- and Time-of-Day-Specific Peptide Release in the Mammalian Circadian Clock.

PubMed

Atkins, Norman; Ren, Shifang; Hatcher, Nathan; Burgoon, Penny W; Mitchell, Jennifer W; Sweedler, Jonathan V; Gillette, Martha U

2018-06-20

Daily oscillations of brain and body states are under complex temporal modulation by environmental light and the hypothalamic suprachiasmatic nucleus (SCN), the master circadian clock. To better understand mediators of differential temporal modulation, we characterize neuropeptide releasate profiles by nonselective capture of secreted neuropeptides in an optic nerve horizontal SCN brain slice model. Releasates are collected following electrophysiological stimulation of the optic nerve/retinohypothalamic tract under conditions that alter the phase of the SCN activity state. Secreted neuropeptides are identified by intact mass via matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). We found time-of-day-specific suites of peptides released downstream of optic nerve stimulation. Peptide release was modified differentially with respect to time-of-day by stimulus parameters and by inhibitors of glutamatergic or PACAPergic neurotransmission. The results suggest that SCN physiology is modulated by differential peptide release of both known and unexpected peptides that communicate time-of-day-specific photic signals via previously unreported neuropeptide signatures.

A potent and selective calcitonin gene-related peptide (CGRP) receptor antagonist, MK-8825, inhibits responses to nociceptive trigeminal activation: Role of CGRP in orofacial pain.

PubMed

Romero-Reyes, Marcela; Pardi, Vanessa; Akerman, Simon

2015-09-01

Temporomandibular disorders (TMDs) are orofacial pains within the trigeminal distribution, which involve the masticatory musculature, the temporomandibular joint or both. Their pathophysiology remains unclear, as inflammatory mediators are thought to be involved, and clinically TMD presents pain and sometimes limitation of function, but often appears without gross indications of local inflammation, such as visible edema, redness and increase in temperature. Calcitonin gene-related peptide (CGRP) has been implicated in other pain disorders with trigeminal distribution, such as migraine, of which TMD shares a significant co-morbidity. CGRP causes activation and sensitization of trigeminal primary afferent neurons, independent of any inflammatory mechanisms, and thus may also be involved in TMD. Here we used a small molecule, selective CGRP receptor antagonist, MK-8825, to dissect the role of CGRP in inducing spontaneous nociceptive facial grooming behaviors, neuronal activation in the trigeminal nucleus, and systemic release of pro-inflammatory cytokines, in a mouse model of acute orofacial masseteric muscle pain that we have developed, as a surrogate of acute TMD. We show that CFA masseteric injection causes significant spontaneous orofacial pain behaviors, neuronal activation in the trigeminal nucleus, and release of interleukin-6 (IL-6). In mice pre-treated with MK-8825 there is a significant reduction in these spontaneous orofacial pain behaviors. Also, at 2 and 24h after CFA injection the level of Fos immunoreactivity in the trigeminal nucleus, used as a marker of neuronal activation, was much lower on both ipsilateral and contralateral sides after pre-treatment with MK-8825. There was no effect of MK-8825 on the release of IL-6. These data suggest that CGRP may be involved in TMD pathophysiology, but not via inflammatory mechanisms, at least in the acute stage. Furthermore, CGRP receptor antagonists may have therapeutic efficacy in the treatment of TMD, as they do with migraine. Copyright © 2015 Elsevier Inc. All rights reserved.

Recovery of stress-impaired social behavior by an antagonist of the CRF binding protein, CRF6-33, in the bed nucleus of the stria terminalis of male rats.

PubMed

Vasconcelos, Mailton; Stein, Dirson J; Albrechet-Souza, Lucas; Miczek, Klaus A; de Almeida, Rosa Maria M

2018-01-09

Social stress is recognized to promote the development of neuropsychiatric and mood disorders. Corticotropin releasing factor (CRF) is an important neuropeptide activated by social stress, and it contributes to neural and behavioral adaptations, as indicated by impaired social interactions and anhedonic effects. Few studies have focused on the role of the CRF binding protein (CRFBP), a component of the CRF system, and its activity in the bed nucleus of stria terminalis (BNST), a limbic structure connecting amygdala and hypothalamus. In this study, animals' preference for sweet solutions was examined as an index of stress-induced anhedonic responses in Wistar rats subjected to four brief intermittent episodes of social defeat. Next, social approach was assessed after local infusions of the CRFBP antagonist, CRF fragment 6-33 (CRF 6-33 ) into the BNST. The experience of brief episodes of social defeat impaired social approach behaviors in male rats. However, intra-BNST CRF 6-33 infusions restored social approach in stressed animals to the levels of non-stressed rats. CRF 6-33 acted selectively on social interaction and did not alter general exploration in nether stressed nor non-stressed rats. These findings suggest that BNST CRFBP is involved in the modulation of anxiety-like responses induced by social stress. Copyright © 2018 Elsevier B.V. All rights reserved.

Anxiety-like behavior in transgenic mice with brain expression of neuropeptide Y.

PubMed

Inui, A; Okita, M; Nakajima, M; Momose, K; Ueno, N; Teranishi, A; Miura, M; Hirosue, Y; Sano, K; Sato, M; Watanabe, M; Sakai, T; Watanabe, T; Ishida, K; Silver, J; Baba, S; Kasuga, M

1998-01-01

Neuropeptide Y (NPY), one of the most abundant peptide transmitters in the mammalian brain, is assumed to play an important role in behavior and its disorders. To understand the long-term modulation of neuronal functions by NPY, we raised transgenic mice created with a novel central nervous system (CNS) neuron-specific expression vector of human Thy- gene fragment linked to mouse NPY cDNA. In situ hybridization analysis demonstrated transgene-derived NPY expression in neurons (e.g., in the hippocampus, cerebral cortex, and the arcuate nucleus of the hypothalamus) in the transgenic mice. The modest increase of NPY protein in the brain was demonstrated by semiquantitative immunohistochemical analysis and by radioreceptor assay (115% in transgenic mice compared to control littermates). Double-staining experiments indicated colocalization of the transgene-derived NPY message and NPY protein in the same neurons, such as in the arcuate nucleus. The transgenic mice displayed behavioral signs of anxiety and hypertrophy of adrenal zona fasciculata cells, but no change in food intake was observed. The anxiety-like behavior of transgenic mice was reversed, at least in part, by administration of corticotropin-releasing factor (CRF) antagonists, alpha-helical CRF9-41, into the third cerebral ventricle. These results suggest that NPY has a role in anxiety and behavioral responses to stress partly via the CRF neuronal system. This genetic model may provide a unique opportunity to study human anxiety and emotional disorders.

Somatodendritic dopamine release: recent mechanistic insights

PubMed Central

Rice, Margaret E.; Patel, Jyoti C.

2015-01-01

Dopamine (DA) is a key transmitter in motor, reward and cogitative pathways, with DA dysfunction implicated in disorders including Parkinson's disease and addiction. Located in midbrain, DA neurons of the substantia nigra pars compacta project via the medial forebrain bundle to the dorsal striatum (caudate putamen), and DA neurons in the adjacent ventral tegmental area project to the ventral striatum (nucleus accumbens) and prefrontal cortex. In addition to classical vesicular release from axons, midbrain DA neurons exhibit DA release from their cell bodies and dendrites. Somatodendritic DA release leads to activation of D2 DA autoreceptors on DA neurons that inhibit their firing via G-protein-coupled inwardly rectifying K+ channels. This helps determine patterns of DA signalling at distant axonal release sites. Somatodendritically released DA also acts via volume transmission to extrasynaptic receptors that modulate local transmitter release and neuronal activity in the midbrain. Thus, somatodendritic release is a pivotal intrinsic feature of DA neurons that must be well defined in order to fully understand the physiology and pathophysiology of DA pathways. Here, we review recent mechanistic aspects of somatodendritic DA release, with particular emphasis on the Ca2+ dependence of release and the potential role of exocytotic proteins. PMID:26009764

Neuroanatomical pathways underlying the effects of hypothalamo-hypophysial-adrenal hormones on exploratory activity.

PubMed

Lalonde, Robert; Strazielle, Catherine

2017-07-26

When injected via the intracerebroventricular route, corticosterone-releasing hormone (CRH) reduced exploration in the elevated plus-maze, the center region of the open-field, and the large chamber in the defensive withdrawal test. The anxiogenic action of CRH in the elevated plus-maze also occurred when infused in the basolateral amygdala, ventral hippocampus, lateral septum, bed nucleus of the stria terminalis, nucleus accumbens, periaqueductal grey, and medial frontal cortex. The anxiogenic action of CRH in the defensive withdrawal test was reproduced when injected in the locus coeruleus, while the amygdala, hippocampus, lateral septum, nucleus accumbens, and lateral globus pallidus contribute to center zone exploration in the open-field. In addition to elevated plus-maze and open-field tests, the amygdala appears as a target region for CRH-mediated anxiety in the elevated T-maze. Thus, the amygdala is the principal brain region identified with these three tests, and further research must identify the neural circuits underlying this form of anxiety.

Yeast Ran-Binding Protein 1 (Yrb1) Shuttles between the Nucleus and Cytoplasm and Is Exported from the Nucleus via a CRM1 (XPO1)-Dependent Pathway

PubMed Central

Künzler, Markus; Gerstberger, Thomas; Stutz, Françoise; Bischoff, F. Ralf; Hurt, Ed

2000-01-01

The RanGTP-binding protein RanBP1, which is located in the cytoplasm, has been implicated in release of nuclear export complexes from the cytoplasmic side of the nuclear pore complex. Here we show that Yrb1 (the yeast homolog of RanBP1) shuttles between the nucleus and the cytoplasm. Nuclear import of Yrb1 is a facilitated process that requires a short basic sequence within the Ran-binding domain (RBD). By contrast, nuclear export of Yrb1 requires an intact RBD, which forms a ternary complex with the Xpo1 (Crm1) NES receptor in the presence of RanGTP. Nuclear export of Yrb1, however, is insensitive towards leptomycin B, suggesting a novel type of substrate recognition between Yrb1 and Xpo1. Taken together, these data suggest that ongoing nuclear import and export is an important feature of Yrb1 function in vivo. PMID:10825193

The 5-HT(1A) receptor agonist, 8-OH-DPAT, attenuates stress-induced anorexia in conjunction with the suppression of hypothalamic serotonin release in rats.

PubMed

Shimizu, N; Hori, T; Ogino, C; Kawanishi, T; Hayashi, Y

2000-12-22

The effect of the selective 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) on stress-induced anorexia and serotonin (5-HT) release in the rat hypothalamus was studied with brain microdialysis. Subcutaneous injection of 8-OH-DPAT (1 mg/kg) significantly attenuated the immobilization-induced anorexia for 3 h, but had no effect during the following 9 h. Injection of 8-OH-DPAT itself had no effect on basal release of 5-HT, while it significantly blocked the immobilization-induced 5-HT release in the lateral hypothalamus. The results suggest that 8-OH-DPAT attenuated the stress-induced anorexia through the activation of 5-HT(1A) autoreceptors in dorsal raphe nucleus.

A new look on brain mechanisms of acute illness anorexia.

PubMed

Asarian, Lori; Langhans, Wolfgang

2010-07-14

Bacterial lipopolysaccharide (LPS) and other microbial substances trigger the organism's acute phase response and cause acute illness anorexia. Pro-inflammatory cytokines are major endogenous mediators of acute illness anorexia, but how LPS or cytokines stimulate the brain to inhibit eating is not fully resolved. One emerging mechanism involves the activation of the enzyme cyclooxygenase-2 (COX-2) in blood-brain barrier endothelial cells and the subsequent release of prostaglandin E2 (PGE2). Serotonin neurons in the midbrain raphe are targets of PGE2, and serotonergic projections from the midbrain raphe to the hypothalamus appear to be crucial for LPS anorexia. That is, raphe projections activate (1) the corticotrophin-releasing hormone neurons in the paraventricular nucleus which then elicit the stress response and (2) the pro-opiomelanocortin neurons in the arcuate nucleus which then release alphaMSH and elicit anorexia. Here we review available data to support a role for this brain mechanism in acute illness anorexia by center staging PGE2 signaling pathways that converge on central neural circuits that control normal eating. In addition, we review interactions between gonadal hormones and immune function that lead to sex differences in acute illness anorexia. The paper represents an invited review by a symposium, award winner or keynote speaker at the Society for the Study of Ingestive Behavior [SSIB] Annual Meeting in Portland, July 2009. 2010 Elsevier Inc. All rights reserved.

Formation of ions and radicals from icy grains in comets

NASA Technical Reports Server (NTRS)

Jackson, William M.; Gerth, Christopher; Hendricks, Charles

1991-01-01

Ion and radical formation in comets are thought to occur primarily by photodissociation of gas phase molecules. Experimental evidence and theoretical calculations are presented that show that some of the radical and ions can come directly from ice grains. The experimental evidence suggest that if the frozen molecules on the surface of grains undergo direct dissociation then they may be able to release radicals directly in the gas phase. If the molecules undergo predissociation it is unlikely that they will release radicals in the gas phase since they should be quenched. Calculations of this direct photodissociation mechanism further indicate that even if the parent molecule undergoes direct dissociation, the yield will not be high enough to explain the rays structure in comets unless the radicals are stored in the grains and then released when the grain evaporates. Calculations were also performed to determine the maximum number of ions that can be stored in an icy grain's radius. This number is compared with the ratio of the ion to neutral molecular density. The comparison suggests that some of the ions observed near the nucleus of the comet could have originally been present in the cometary nucleus. It is also pointed out that the presence of these ions in icy grains could lead to radical formation via electron recombination. Finally, an avalanche process was evaluated as another means of producing ions in comets.

Vasopressin and sympathetic system mediate the cardiovascular effects of the angiotensin II in the bed nucleus of the stria terminalis in rat.

PubMed

Nasimi, Ali; Kafami, Marzieh

2016-07-01

The bed nucleus of the stria terminalis (BST) is involved in cardiovascular regulation. The angiotensin II (Ang II) receptor (AT1), and angiotensinogen were found in the BST. In our previous study we found that microinjection of Ang II into the BST produced a pressor response. This study was performed to find the mechanisms mediating this response in anesthetized rats. Ang II was microinjected into the BST and the cardiovascular responses were re-tested after systemic injection of a blocker of autonomic or vasopressin V1 receptor. The ganglionic nicotinic receptor blocker, hexamethonium dichloride, attenuated the pressor response to Ang II, indicating that the cardiovascular sympathetic system is involved in the pressor effect of Ang II. A selective vasopressin V1 receptor antagonist greatly attenuated the pressor effect of Ang II, indicating that the Ang II increases the arterial pressure via stimulation of vasopressin release as well. In conclusion, in the BST, Ang II as a neurotransmitter increases blood pressure by exciting cardiovascular sympathetic system and directly or indirectly causing vasopressin to release into bloodstream by VPN. This is an interesting new finding that not only circulating Ang II but also brain Ang II makes vasopressin release. Copyright © 2016 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

Early life experience alters behavior during social defeat: focus on serotonergic systems.

PubMed

Gardner, K L; Thrivikraman, K V; Lightman, S L; Plotsky, P M; Lowry, C A

2005-01-01

Early life experience can have prolonged effects on neuroendocrine, autonomic, and behavioral responses to stress. The objective of this study was to investigate the effects of early life experience on behavior during social defeat, as well as on associated functional cellular responses in serotonergic and non-serotonergic neurons within the dorsal raphe nucleus, a structure which plays an important role in modulation of stress-related physiology and behavior. Male Long Evans rat pups were exposed to either normal animal facility rearing or 15 min or 180 min of maternal separation from postnatal days 2-14. As adults, these rats were exposed to a social defeat protocol. Differences in behavior were seen among the early life treatment groups during social defeat; rats exposed to 180 min of maternal separation from postnatal days 2-14 displayed more passive-submissive behaviors and less proactive coping behaviors. Analysis of the distribution of tryptophan hydroxylase and c-Fos-like immunoreactivity in control rats exposed to a novel cage and rats exposed to social defeat revealed that, independent of the early life experience, rats exposed to social defeat showed an increase in the number of c-Fos-like immunoreactive nuclei in serotonergic neurons in the middle and caudal parts of the dorsal dorsal raphe nucleus and caudal part of the ventral dorsal raphe nucleus, regions known to contain serotonergic neurons projecting to central autonomic and emotional motor control systems. This is the first study to show that the dorsomedial part of the mid-rostrocaudal dorsal raphe nucleus is engaged by a naturalistic stressor and supports the hypothesis that early life experience alters behavioral coping strategies during social conflict; furthermore, this study is consistent with the hypothesis that topographically organized subpopulations of serotonergic neurons principally within the mid-rostrocaudal and caudal part of the dorsal dorsal raphe nucleus modulate stress-related physiological and behavioral responses.

Monosodium glutamate-induced arcuate nucleus damage affects both natural torpor and 2DG-induced torpor-like hypothermia in Siberian hamsters.

PubMed

Pelz, Kimberly M; Routman, David; Driscoll, Joseph R; Kriegsfeld, Lance J; Dark, John

2008-01-01

Siberian hamsters (Phodopus sungorus) have the ability to express daily torpor and decrease their body temperature to approximately 15 degrees C, providing a significant savings in energy expenditure. Daily torpor in hamsters is cued by winterlike photoperiods and occurs coincident with the annual nadirs in body fat reserves and chronic leptin concentrations. To better understand the neural mechanisms underlying torpor, Siberian hamster pups were postnatally treated with saline or MSG to ablate arcuate nucleus neurons that likely possess leptin receptors. Body temperature was studied telemetrically in cold-acclimated (10 degrees C) male and female hamsters moved to a winterlike photoperiod (10:14-h light-dark cycle) (experiments 1 and 2) or that remained in a summerlike photoperiod (14:10-h light-dark cycle) (experiment 3). In experiment 1, even though other photoperiodic responses persisted, MSG-induced arcuate nucleus ablations prevented the photoperiod-dependent torpor observed in saline-treated Siberian hamsters. MSG-treated hamsters tended to possess greater fat reserves. To determine whether reductions in body fat would increase frequency of photoperiod-induced torpor after MSG treatment, hamsters underwent 2 wk of food restriction (70% of ad libitum) in experiment 2. Although food restriction did increase the frequency of torpor in both MSG- and saline-treated hamsters, it failed to normalize the proportion of MSG-treated hamsters undergoing photoperiod-dependent torpor. In experiment 3, postnatal MSG treatments reduced the proportion of hamsters entering 2DG-induced torpor-like hypothermia by approximately 50% compared with saline-treated hamsters (38 vs. 72%). In those MSG-treated hamsters that did become hypothermic, their minimum temperature during hypothermia was significantly greater than comparable saline-treated hamsters. We conclude that 1) arcuate nucleus mechanisms mediate photoperiod-induced torpor, 2) food-restriction-induced torpor may also be reduced by MSG treatments, and 3) arcuate nucleus neurons make an important, albeit partial, contribution to 2DG-induced torpor-like hypothermia.

Kaon-nucleus scattering

NASA Technical Reports Server (NTRS)

Hong, Byungsik; Buck, Warren W.; Maung, Khin M.

1989-01-01

Two kinds of number density distributions of the nucleus, harmonic well and Woods-Saxon models, are used with the t-matrix that is taken from the scattering experiments to find a simple optical potential. The parameterized two body inputs, which are kaon-nucleon total cross sections, elastic slope parameters, and the ratio of the real to imaginary part of the forward elastic scattering amplitude, are shown. The eikonal approximation was chosen as the solution method to estimate the total and absorptive cross sections for the kaon-nucleus scattering.

Sex differences in activated CRF neurons within stress-related neurocircuitry and HPA axis hormones following restraint in rats

PubMed Central

Babb, Jessica A; Masini, Cher V; Day, Heidi E W; Campeau, Serge

2013-01-01

Women may be more vulnerable to certain stress-related psychiatric illnesses than men due to differences in hypothalamic-pituitary-adrenocortical (HPA) axis function. To investigate potential sex differences in forebrain regions associated with HPA axis activation in rats, these experiments utilized acute exposure to a psychological stressor. Male and female rats in various stages of the estrous cycle were exposed to 30 min of restraint, producing a robust HPA axis hormonal response in all animals, the magnitude of which was significantly higher in female rats. Although both male and female animals displayed equivalent c-fos expression in many brain regions known to be involved in the detection of threatening stimuli, three regions had significantly higher expression in females: the paraventricular nucleus of the hypothalamus (PVN), the anteroventral division of the bed nucleus of the stria terminalis (BSTav), and the medial preoptic area (MPOA). Dual fluorescence in-situ hybridization analysis of neurons containing c-fos and corticotropin-releasing factor (CRF) mRNA in these regions revealed significantly more c-fos and CRF single-labeled neurons, as well as significantly more double-labeled neurons in females. Surprisingly, there was no effect of the estrous cycle on any measure analyzed, and an additional experiment revealed no demonstrable effect of estradiol replacement following ovariectomy on HPA axis hormone induction following stress. Taken together, these data suggest sex differences in HPA axis activation in response to perceived threat may be influenced by specific populations of CRF neurons in key stress-related brain regions, the BSTav, MPOA, and PVN, which may be independent of circulating sex steroids. PMID:23305762

Serotonin2C receptors in the nucleus accumbens are involved in enhanced alcohol-drinking behavior

PubMed Central

Yoshimoto, Kanji; Watanabe, Yoshihisa; Tanaka, Masaki; Kimura, Minoru

2012-01-01

Dopamine and serotonin (5-HT) in the nucleus accumbens (ACC) and ventral tegmental area of the mesoaccumbens reward pathways have been implicated in the mechanisms underlying development of alcohol dependence. We used a C57BL/6J mouse model with increased voluntary alcohol-drinking behavior by exposing the mice to alcohol vapor for 20 consecutive days. In the alcohol-exposed mice, the expression of 5-HT2C receptor mRNA increased in the ACC, caudate nucleus and putamen, dorsal raphe nucleus (DRN), hippocampus and lateral hypothalamus, while the protein level of 5-HT2C receptor significantly increased in the ACC. The expression of 5-HT7 receptor mRNA increased in the ACC and DRN. Contents of 5-HT decreased in the ACC shell (ACCS) and DRN of the alcohol-exposed mice. The basal extracellular releases of dopamine (DA) and 5-HT in the ACCS increased more in the alcohol-exposed mice than in alcohol-naïve mice. The magnitude of the alcohol-induced ACCS DA and 5-HT release in the alcohol-exposed mice was increased compared with the control mice. Intraperitoneal (i.p.) administration or local injection into ACCS of the 5-HT2C receptor antagonist, SB-242084, suppressed voluntary alcohol-drinking behavior in the alcohol-exposed mice. But the i.p. administration of the 5-HT7 receptor antagonist, SB-258719, did not have significant effects on alcohol-drinking behavior in the alcohol-exposed mice. The effects of the 5-HT2C receptor antagonist were not observed in the air-exposed control mice. These results suggest that adaptations of the 5-HT system, especially the upregulation of 5-HT2C receptors in the ACCS, are involved in the development of enhanced voluntary alcohol-drinking behavior. PMID:22512261

Gamow–Teller resonances in the {sup 118}Sb compound nucleus: Puzzles of an experiment in Sarov

DOE Office of Scientific and Technical Information (OSTI.GOV)

Urin, M. H., E-mail: urin@theor.mephi.ru

2016-03-15

Contradictory data on the observation of Gamow–Teller resonances in the {sup 118}Sb compound nucleus are discussed along with the available interpretation of these data and planned experimental and theoretical investigations into Gamow–Teller resonances in a number of antimony isotopes.

LPLRFamide exerts short-term anorexigenic effects that coincide with magnocellular division of the hypothalamic paraventricular nucleus activation.

PubMed

Scheel, Amy; Deal, Nick; St John, Natalie; Wells, Amy; Caruso, Maggie; Gilbert, Elizabeth R; Cline, Mark

2017-05-15

LPLRFamide is a member of the RFamide peptide family that elicits an anorexigenic effect when centrally injected in chicks although the mechanism mediating this response is poorly understood. Therefore, the purpose of this experiment was to elucidate the hypothalamic mechanism of short-term anorexia after central administration of LPLRFamide in chicks. In Experiment 1 chicks centrally injected with LPLRFamide decreased food intake at 15min but not 30min following administration compared to vehicle-injected chicks. For Experiment 2, c-Fos immunoreactivity was quantified in several appetite-associated hypothalamic nuclei and in LPLRF-injected chicks, compared to vehicle-injected chicks, there was an increase in the number of reactive cells in the magnocellular division of the paraventricular nucleus. Lastly in Experiment 3, real time-PCR was performed and hypothalamic proopiomelanocortin (POMC) mRNA abundance was increased in LPRLFamide-injected chicks compared to vehicle-injected chicks. Thus, following central injection of LPLRFamide there is activation of the paraventricular nucleus of the hypothalamus and increased expression of hypothalamic POMC mRNA in chicks. Copyright © 2016 Elsevier Inc. All rights reserved.

Heavy nucleus collisions between 20 and 60 GeV/nucleon

NASA Technical Reports Server (NTRS)

Burnett, T. H.; Dake, S.; Fuki, M.; Gregory, J. C.; Hayashi, T.; Holynski, R.; Iwai, J.; Jones, W. V.; Jurak, A.; Lord, J. J.

1985-01-01

Interest in studying relativistic nucleus-nucleus interations arises from the fact that they offer an opportunity to probe nuclear matter at high density and temperature. It is expected that under such extreme conditions a transition from hadronic matter into quark-gluon plasma occurs and that in the interactions of highly relativistic nuclei such conditions are created. Cosmic rays remain a unique source of high energy heavy nuclei. The Japanese-American Cooperative Emulsion Experiment (JACEE-3) was designed to study the collisions of heavy cosmic ray nuclei with different nuclear targets at energies beyond 20 GeV/nucleon. JACEE-3 experiment was carried out using a combined electronic counters and an emulsion chamber detector, which was exposed to the cosmic rays on a balloon at an altitude of 5 g/sq cm.

The glycine reuptake inhibitor org 25935 interacts with basal and ethanol-induced dopamine release in rat nucleus accumbens.

PubMed

Lidö, Helga Höifödt; Stomberg, Rosita; Fagerberg, Anne; Ericson, Mia; Söderpalm, Bo

2009-07-01

The mesolimbic dopamine (DA) projection from the ventral tegmental area to nucleus accumbens (nAc), a central part of the reward system, is activated by ethanol (EtOH) and other drugs of abuse. We have previously demonstrated that the glycine receptor in the nAc and its amino acid agonists may be implicated in the DA activation and reinforcing properties of EtOH. We have also reported that the glycine transporter 1 inhibitor, Org 25935, produces a robust and dose-dependent decrease in EtOH consumption in Wistar rats. The present study explores the interaction between EtOH and Org 25935 with respect to DA levels in the rat nAc. The effects of Org 25935 (6 mg/kg, i.p.) and/or EtOH (2.5 g/kg, i.p.) on accumbal DA levels were examined by means of in vivo microdialysis (coupled to HPLC-ED) in freely moving male Wistar rats. The effect of Org 25935 on accumbal glycine output was also investigated. Systemic Org 25935 increased DA output in a subpopulation of rats (52% in Experiment 1 and 38% in Experiment 2). In Experiment 2, EtOH produced a significant increase in DA levels in vehicles (35%) and in Org 25935 nonresponders (19%), whereas EtOH did not further increase the DA level in rats responding to Org 25935 (2%). The same dose of Org 25935 increased glycine levels by 87% in nAc. This study demonstrates that Org 25935, probably via increased glycine levels, (i) counteracts EtOH-induced increases of accumbal DA levels and (ii) increases basal DA levels in a subpopulation of rats. The results are in line with previous findings and it is suggested that the effects observed involve interference with accumbal GlyRs and are related to the alcohol consumption modulating effect of Org 25935.

Chronic Anabolic Androgenic Steroid Exposure Alters Corticotropin Releasing Factor Expression and Anxiety-Like Behaviors in the Female Mouse

PubMed Central

Costine, Beth A; Oberlander, Joseph G; Davis, Matthew C; Penatti, Carlos A A; Porter, Donna M; Leaton, Robert N; Henderson, Leslie P

2010-01-01

Summary In the past several decades, the therapeutic use of anabolic androgenic steroids (AAS) has been overshadowed by illicit use of these drugs by elite athletes and a growing number of adolescents to enhance performance and body image. As with adults, AAS use by adolescents is associated with a range of behavioral effects, including increased anxiety and altered responses to stress. It has been suggested that adolescents, especially adolescent females, may be particularly susceptible to the effects of these steroids, but few experiments in animal models have been performed to test this assertion. Here we show that chronic exposure of adolescent female mice to a mixture of three commonly abused AAS (testosterone cypionate, nandrolone decanoate and methandrostenolone; 7.5 mg/kg/day for 5 days) significantly enhanced anxiety-like behavior as assessed by the acoustic startle response (ASR), but did not augment the fear-potentiated startle response (FPS) or alter sensorimotor gating as assessed by prepulse inhibition of the acoustic startle response (PPI). AAS treatment also significantly increased the levels of corticotropin releasing factor (CRF) mRNA and somal-associated CRF immunoreactivity in the central amygdala (CeA), as well as neuropil-associated immunoreactivity in the dorsal aspect of the anterolateral division of the bed nucleus of the stria terminalis (dBnST). AAS treatment did not alter CRF receptor 1 or 2 mRNA in either the CeA or the dBnST; CRF immunoreactivity in the ventral BNST, the paraventricular nucleus (PVN) or the median eminence (ME); or peripheral levels of corticosterone. These results suggest that chronic AAS treatment of adolescent female mice may enhance generalized anxiety, but not sensorimotor gating or learned fear, via a mechanism that involves increased CRF-mediated signaling from CeA neurons projecting to the dBnST. PMID:20537804

α-Conotoxin MII-Sensitive Nicotinic Acetylcholine Receptors in the Nucleus Accumbens Shell Regulate Progressive Ratio Responding Maintained by Nicotine

PubMed Central

Brunzell, Darlene H; Boschen, Karen E; Hendrick, Elizabeth S; Beardsley, Patrick M; McIntosh, J Michael

2010-01-01

β2 subunit containing nicotinic acetylcholine receptors (β2*nAChRs; asterisk (*) denotes assembly with other subunits) are critical for nicotine self-administration and nicotine-associated dopamine (DA) release that supports nicotine reinforcement. The α6 subunit assembles with β2 on DA neurons where α6β2*nAChRs regulate nicotine-stimulated DA release at neuron terminals. Using local infusion of α-conotoxin MII (α-CTX MII), an antagonist with selectivity for α6β2*nAChRs, the purpose of these experiments was to determine if α6β2*nAChRs in the nucleus accumbens (NAc) shell are required for motivation to self-administer nicotine. Long-Evans rats lever-pressed for 0.03 mg/kg, i.v., nicotine accompanied by light+tone cues (NIC) or for light+tone cues unaccompanied by nicotine (CUEonly). Following extensive training, animals were tested under a progressive ratio (PR) schedule that required an increasing number of lever presses for each nicotine infusion and/or cue delivery. Immediately before each PR session, rats received microinfusions of α-CTX MII (0, 1, 5, or 10 pmol per side) into the NAc shell or the overlying anterior cingulate cortex. α-CTX MII dose dependently decreased break points and number of infusions earned by NIC rats following infusion into the NAc shell but not the anterior cingulate cortex. Concentrations of α-CTX MII that were capable of attenuating nicotine self-administration did not disrupt locomotor activity. There was no effect of infusion on lever pressing in CUEonly animals and NAc infusion α-CTX MII did not affect locomotor activity in an open field. These data suggest that α6β2*nAChRs in the NAc shell regulate motivational aspects of nicotine reinforcement but not nicotine-associated locomotor activation. PMID:19890263

M1 distributions for 163Dy and 157Gd in the SUBFsdg(3) and SUBFsd(3) × 1g limits of pn-sdgIBFM

NASA Astrophysics Data System (ADS)

Devi, Y. D.; Kota, V. K. B.

1996-02-01

The SU sdgBF(3) limit of pn-sdgIBFM, which was developed earlier, is applied with success in analyzing the recently observed M1 data in the 163Dy nucleus. As new experiments are being planned for 157Gd nucleus and that 156Gd is known to be a good SU sd(3)×1g nucleus, in the second part of the paper a formalism for M1 distributions in the SU sdBF(3)×1g limit is developed. In both these analytically solvable limiting situations, predictions are made for M1 distributions in the 157Gd nucleus.

Membrane-bound transcription factors: regulated release by RIP or RUP.

PubMed

Hoppe, T; Rape, M; Jentsch, S

2001-06-01

Regulated nuclear transport of transcription factors from cytoplasmic pools is a major route by which eukaryotes control gene expression. Exquisite examples are transcription factors that are kept in a dormant state in the cytosol by membrane anchors; such proteins are released from membranes by proteolytic cleavage, which enables these transcription factors to enter the nucleus. Cleavage can be mediated either by regulated intramembrane proteolysis (RIP) catalysed by specific membrane-bound proteases or by regulated ubiquitin/proteasome-dependent processing (RUP). In both cases processing can be controlled by cues that originate at or in the vicinity of the membrane.

Reimplantation with a conventional length electrode following residual hearing loss in four hybrid implant recipients

PubMed Central

Carlson, Matthew L; Archibald, David J; Gifford, Rene H; Driscoll, Colin LW; Beatty, Charles W

2014-01-01

Hypothesis Revision surgery using a newer-generation conventional length cochlear implant electrode will provide improved speech perception in patients that initially underwent hybrid electrode implantation and experienced post-operative loss of residual hearing and performance deterioration. Clinical presentation We present four patients who experienced delayed post-operative hearing loss following implantation with the Nucleus Hybrid S8 device and underwent reimplantation with the Nucleus Freedom or Nucleus 5 device using the Contour Advance array. Pure-tone thresholds and speech perception data were retrospectively reviewed. Intervention Four subjects underwent reimplantation with the Nucleus Freedom or Nucleus 5 device after experiencing deteriorating performance related to delayed acoustic hearing loss. Comparison of pre-revision performance to the most recent post-revision performance demonstrated improved speech perception performance in all subjects following reimplantation. Conclusions A small percent of patients will experience a significant loss of residual low-frequency hearing following hybrid implantation thereby becoming completely reliant on a shorter electrode for electrical stimulation. In the current series, reimplantation with a conventional length electrode provided improved speech perception performance in such patients. Revision surgery with a conventional length electrode should be considered in ‘short electrode’ recipients who experience performance deterioration following loss of residual hearing. PMID:22333755

A search for ϕ meson nucleus bound state using antiproton annihilation on nucleus

NASA Astrophysics Data System (ADS)

Ohnishi, H.; Bühler, P.; Cargnelli, M.; Curceanu, C.; Guaraldo, C.; Hartmann, O.; Hicks, K.; Iwasaki, M.; Ishiwatari, T.; Kienle, P.; Marton, J.; Muto, R.; Naruki, M.; Niiyama, M.; Noumi, H.; Okada, S.; Vidal, A. Romero; Sakaguchi, A.; Sakuma, F.; Sawada, S.; Sirghi, D.; Sirghi, F.; Suzuki, K.; Tsukada, K.; Doce, O. Vazquez; Widmann, E.; Yokkaichi, S.; Zmeskal, J.

2012-12-01

The mass shift of the vector mesons in nuclei is known to be a powerful tool for investigating the mechanism of generating hadron mass from the QCD vacuum. The mechanism is known to be the spontaneous breaking of chiral symmetry. In 2007, KEK-PS E325 experiment reported about 3.4 % mass reduction of the ϕ meson in medium-heavy nuclei (Cu). This result is possibly one of the indications of the partial restoration of chiral symmetry in nuclei, however, unfortunately it is hard to make strong conclusions from the data. One of the ways to conclude the strength of the ϕ meson mass shift in nuclei will be by trying to produce only slowly moving ϕ mesons where the maximum nuclear matter effect can be probed. The observed mass reduction of the ϕ meson in the nucleus can be translated as the existence of an attractive force between ϕ meson and nucleus. Thus, one of the extreme conditions that can be achieved in the laboratory is indeed the formation of a ϕ-nucleus bound state, where the ϕ meson is "trapped" in the nucleus. The purpose of the experiment is to search for a ϕ-nucleus bound state and measure the binding energy of the system. We will demonstrate that a completely background-free missing-mass spectrum can be obtained efficiently by (bar{p}, φ) spectroscopy together with K + Λ tagging, using the primary reaction channel bar{p} p rightarrow φ φ. This paper gives an overview of the physics motivation and the detector concept, and explains the direction of the initial research and development effort.

A search for ϕ meson nucleus bound state using antiproton annihilation on nucleus

NASA Astrophysics Data System (ADS)

Ohnishi, H.; Bühler, P.; Cargnelli, M.; Curceanu, C.; Guaraldo, C.; Hartmann, O.; Hicks, K.; Iwasaki, M.; Ishiwatari, T.; Kienle, P.; Marton, J.; Muto, R.; Naruki, M.; Niiyama, M.; Noumi, H.; Okada, S.; Vidal, A. Romero; Sakaguchi, A.; Sakuma, F.; Sawada, S.; Sirghi, D.; Sirghi, F.; Suzuki, K.; Tsukada, K.; Doce, O. Vazquez; Widmann, E.; Yokkaichi, S.; Zmeskal, J.

The mass shift of the vector mesons in nuclei is known to be a powerful tool for investigating the mechanism of generating hadron mass from the QCD vacuum. The mechanism is known to be the spontaneous breaking of chiral symmetry. In 2007, KEK-PS E325 experiment reported about 3.4 % mass reduction of the ϕ meson in medium-heavy nuclei (Cu). This result is possibly one of the indications of the partial restoration of chiral symmetry in nuclei, however, unfortunately it is hard to make strong conclusions from the data. One of the ways to conclude the strength of the ϕ meson mass shift in nuclei will be by trying to produce only slowly moving ϕ mesons where the maximum nuclear matter effect can be probed. The observed mass reduction of the ϕ meson in the nucleus can be translated as the existence of an attractive force between ϕ meson and nucleus. Thus, one of the extreme conditions that can be achieved in the laboratory is indeed the formation of a ϕ-nucleus bound state, where the ϕ meson is "trapped" in the nucleus. The purpose of the experiment is to search for a ϕ-nucleus bound state and measure the binding energy of the system. We will demonstrate that a completely background-free missing-mass spectrum can be obtained efficiently by (bar{p}, φ) spectroscopy together with K + Λ tagging, using the primary reaction channel bar{p} p rightarrow φ φ. This paper gives an overview of the physics motivation and the detector concept, and explains the direction of the initial research and development effort.

Brain prolactin is involved in stress-induced REM sleep rebound.

PubMed

Machado, Ricardo Borges; Rocha, Murilo Ramos; Suchecki, Deborah

2017-03-01

REM sleep rebound is a common behavioural response to some stressors and represents an adaptive coping strategy. Animals submitted to multiple, intermittent, footshock stress (FS) sessions during 96h of REM sleep deprivation (REMSD) display increased REM sleep rebound (when compared to the only REMSD ones, without FS), which is correlated to high plasma prolactin levels. To investigate whether brain prolactin plays a role in stress-induced REM sleep rebound two experiments were carried out. In experiment 1, rats were either not sleep-deprived (NSD) or submitted to 96h of REMSD associated or not to FS and brains were evaluated for PRL immunoreactivity (PRL-ir) and determination of PRL concentrations in the lateral hypothalamus and dorsal raphe nucleus. In experiment 2, rats were implanted with cannulas in the dorsal raphe nucleus for prolactin infusion and were sleep-recorded. REMSD associated with FS increased PRL-ir and content in the lateral hypothalamus and all manipulations increased prolactin content in the dorsal raphe nucleus compared to the NSD group. Prolactin infusion in the dorsal raphe nucleus increased the time and length of REM sleep episodes 3h after the infusion until the end of the light phase of the day cycle. Based on these results we concluded that brain prolactin is a major mediator of stress-induced REMS. The effect of PRL infusion in the dorsal raphe nucleus is discussed in light of the existence of a bidirectional relationship between this hormone and serotonin as regulators of stress-induced REM sleep rebound. Copyright © 2016 Elsevier Inc. All rights reserved.

Pharmacological studies upon neurones of the lateral geniculate nucleus of the cat

PubMed Central

Curtis, D. R.; Davis, R.

1962-01-01

Indoles related to 5-hydroxytryptamine, lysergic acid derivatives, phenethylamine derivatives and some other compounds have been applied electrophoretically to the neurones of the lateral geniculate nucleus of the cat anaesthetized with pentobarbitone sodium. Many of these compounds, particularly 4-, 5- and 7-hydroxytryptamine and ergometrine, depress the orthodromic excitation of the neurones by volleys in optic nerve fibres, but do not affect antidromic excitation by volleys in the optic radiation or chemical excitation by L-glutamic acid. It is concluded that the active depressants either block the access of the excitatory transmitter to subsynaptic receptors or prevent the release of the transmitter from optic nerve terminals. The structure-activity relationships of the depressant substances are discussed. PMID:13882768

The effect of hyperdynamic fields on the oxidative metabolism of the paraventricular nucleus

NASA Technical Reports Server (NTRS)

Murakami, Dean M.; Fuller, Charles A.

1990-01-01

An important issue in space biology and medicine is understanding the effect of gravitational changes on the mechanisms that regulate fluid homeostasis. The results of this study show that, following 7-d exposure to a 2 G or 3 G hyperdynamic field, rats exhibited a linear increase in the cytochrome oxidase staining of neurons in the paraventricular nucleus (PVN). The elevated oxidative metabolism in the PVN suggests that there was an increase in the manufacturing and release of vasopressin into the plasma in response to a perceived hypovolemic condition caused by increased hydrostatic pressure and redistribution of fluid to the periphery. Since vasopressin also has widespread cardiovascular effects, it will be important to understand the relationship between vasopressin and altered gravitational fields.

VEGA - EN route to Venus and comet Halley

NASA Astrophysics Data System (ADS)

Gombosi, T. I.

1985-01-01

In December 1984, the Soviet Union launched the two spacecraft Vega 1 and Vega 2. After reaching Venus and releasing entry probes for a study of the planet, the two modified Venera-class, three-axis stabilized spacecraft will continue their voyage toward an encounter with the comet Halley. The two spacecraft carry an international scientific payload. The instruments will be used in a study of the comet. Scientific objectives are related to the determination of the physical characteristics and chemical structure of the nucleus, the identification of the parent molecules of the coma, the characteristics of the dust particles at different distances from the nucleus, and the interaction between the solar wind and the comet. The various instruments are discussed in some detail.

INTRINSIC NEURONAL PLASTICITY IN THE JUXTACAPSULAR NUCLEUS OF THE BED NUCLEI OF THE STRIA TERMINALIS (jcBNST)

PubMed Central

Francesconi, Walter; Berton, Fulvia; Koob, George F.; Sanna, Pietro Paolo

2010-01-01

The juxtacapsular nucleus of the anterior division of the BNST (jcBNST) receives robust glutamatergic projections from the basolateral nucleus of the amygdala (BLA), the postpiriform transition area, and the insular cortex as well as dopamine (DA) inputs from the midbrain. In turn the jcBNST sends GABAergic projections to the medial division of the central nucleus of the amygdala (CEAm) as well as other brain regions. We recently described a form of long-term potentiation of the intrinsic excitability (LTP-IE) of neurons of the juxtacapsular nucleus of BNST (jcBNST) in response to high-frequency stimulation (HFS) of the stria terminalis that was impaired during protracted withdrawal from alcohol, cocaine, and heroin and in rats chronically treated with corticotropin releasing factor (CRF) intracerebroventricularly. Here we show that DAergic neurotransmission is required for the induction of LTP-IE of jcBNTS neurons through dopamine (DA) D1 receptors. Thus, activation of the central CRF stress system and altered DAergic neurotransmission during protracted withdrawal from alcohol and drugs of abuse may contribute to the disruption of LTP-IE in the jcBNST. Impairment of this form of intrinsic neuronal plasticity in the jcBNST could result in inadequate neuronal integration and reduced inhibition of the CEA, contributing to the negative affective state that characterizes protracted abstinence in post-dependent individuals. These results provide a novel neurobiological target for vulnerability to alcohol and drug dependence. PMID:19683025

Effect of meter-scale heterogeneities inside 67P nucleus on CONSERT data

NASA Astrophysics Data System (ADS)

Ciarletti, Valérie; Lasue, Jérémie; Lemonnier, Florentin; Kofman, Wlodek; Levasseur-Regourd, Anny-Chantal; Herique, Alain; Guiffaut, Christophe

2016-10-01

Since their arrival at comet 67P in August 2014, a number of instruments onboard Rosetta's main spacecraft and Philae lander have been observing the surface of the nucleus and revealed details of amazing surficial structures (hundreds of meters deep pits and cliffs, surface roughness of the order of a couple of meters in size, non-continuous apparent layers on both lobes of the comet). After two years of observations, the activity of the comet has also been better constrained, while the origin of sporadic jet activities remains debated. This surficial information is complemented by relevant measurements assessing the nucleus internal structure that have been collected by the CONSERT (Comet Nucleus Sounding Experiment by Radiowave Transmission) experiment in order to constrain the nucleus formation and evolution.The CONSERT experiment is a bistatic radar with receivers and transmitters on-board both Rosetta's main spacecraft and the Philae lander. The instrument transmits electromagnetic waves at 90 MHz (10 MHz bandwidth) between Philae and Rosetta. The signal propagated through the small lobe of 67P over distances ranging from approximately 200 to 800 meters depending on the spacecraft location and probed a maximum depth of about one hundred meters in the vicinity of the final landing site Abydos. The CONSERT data have been used to obtain an estimate of the permittivity mean value. Thanks to the 10 MHz frequency bandwidth of the signal used by the instrument, a spatial resolution around 10m is obtained inside the sounded volume of the nucleus.In this work, we analyze the effect of internal heterogeneities of 67P on the CONSERT data by simulating the propagation of the signal through a fractal model of the comet interior. We considered for the simulations a range of realistic permittivity values and characteristic sizes of the material heterogeneities. The different parameters values used have an impact on the width of the signal propagating through the modeled nucleus. Comparison with the values measured by CONSERT will allow us to determine the possible permittivity variations and heterogeneities size compatible with 67P internal structure.

Changes of growth hormone-releasing hormone and somatostatin neurons in the rat hypothalamus induced by genistein: a stereological study.

PubMed

Trifunović, Svetlana; Manojlović-Stojanoski, Milica; Ristić, Nataša; Nestorović, Nataša; Medigović, Ivana; Živanović, Jasmina; Milošević, Verica

2016-12-01

Genistein is a plant-derived estrogenic isoflavone commonly found in dietary and therapeutic supplements, due to its potential health benefits. Growth hormone-releasing hormone (GHRH) and somatostatin (SS) are neurosecretory peptides synthesized in neurons of the hypothalamus and regulate the growth hormone secretion. Early reports indicate that estrogens have highly involved in the regulation of GHRH and SS secretions. Since little is known about the potential effects of genistein on GHRH and SS neurons, we exposed rats to genistein. Genistein were administered to adult rats in dose of 30 mg/kg, for 3 weeks. The estradiol-dipropionate treatment was used as the adequate controls to genistein. Using applied stereology on histological sections of hypothalamus, we obtained the quantitative information on arcuate (Arc) and periventricular (Pe) nucleus volume and volume density of GHRH neurons and SS neurons. Image analyses were used to obtain GHRH and SS contents in the median eminence (ME). Administration of estradiol-dipropionate caused the increase of Arc and Pe nucleus volume, SS neuron volume density, GHRH and SS staining intensity in the ME, when compared with control. Genistein treatment increased: Arc nucleus volume and the volume density of GHRH neurons (by 26%) and SS neurons (1.5 fold), accompanied by higher GHRH and SS staining intensity in the ME, when compared to the orhidectomized group. These results suggest that genistein has a significant effect on hypothalamic region, involved in the regulation of somatotropic system function, and could contribute to the understanding of genistein as substance that alter the hormonal balance.

Suppression of vasoactive intestinal polypeptide in the suprachiasmatic nucleus leads to aging-like alterations in cAMP rhythms and activation of gonadotropin-releasing hormone neurons.

PubMed

Gerhold, Lynnette M; Rosewell, Katherine L; Wise, Phyllis M

2005-01-05

Input from the suprachiasmatic nucleus (SCN) to gonadotropin-releasing hormone (GnRH) neurons is critical to the occurrence of regular cyclic GnRH secretion. It is thought that an essential neuropeptide in the SCN that communicates this cyclic information to GnRH neurons is vasoactive intestinal polypeptide (VIP) and that it may act through cAMP. We tested the hypothesis that (1) aging involves a blunting of cAMP diurnal rhythmicity in the SCN; (2) administration of antisense oligonucleotides (anti-oligos) against VIP, which produces an aging-like pattern in VIP, would lead to an aging-like suppression of cAMP; and (3) this in turn would lead to inhibition of the steroid-induced activation of GnRH neurons. We measured cAMP concentrations in the SCN and rostral preoptic nucleus throughout the day in young and middle-aged rats that were ovariectomized (OVX) or OVX and treated with estradiol. Our results show that cAMP concentrations exhibit a diurnal rhythm in young rats, and that this rhythm is totally abolished by the time rats are middle age. Administration of antisense oligonucleotides against VIP or random oligos suppresses VIP concentrations and abolishes the cAMP rhythm, leading to significantly reduced activation of GnRH neurons. Together, these findings strongly suggest that the SCN conveys diurnal information to GnRH neurons by driving VIP-dependent cAMP rhythms. In addition, aging involves deterioration in this VIP-driven rhythmicity, which impacts the ability of steroids to induce GnRH neuronal activation.

5-HT3A -driven green fluorescent protein delineates gustatory fibers innervating sour-responsive taste cells: A labeled line for sour taste?

PubMed

Stratford, J M; Larson, E D; Yang, R; Salcedo, E; Finger, T E

2017-07-01

Taste buds contain multiple cell types with each type expressing receptors and transduction components for a subset of taste qualities. The sour sensing cells, Type III cells, release serotonin (5-HT) in response to the presence of sour (acidic) tastants and this released 5-HT activates 5-HT 3 receptors on the gustatory nerves. We show here, using 5-HT 3A GFP mice, that 5-HT 3 -expressing nerve fibers preferentially contact and receive synaptic contact from Type III taste cells. Further, these 5-HT 3 -expressing nerve fibers terminate in a restricted central-lateral portion of the nucleus of the solitary tract (nTS)-the same area that shows increased c-Fos expression upon presentation of a sour tastant (30 mM citric acid). This acid stimulation also evokes c-Fos in the laterally adjacent mediodorsal spinal trigeminal nucleus (DMSp5), but this trigeminal activation is not associated with the presence of 5-HT 3 -expressing nerve fibers as it is in the nTS. Rather, the neuronal activation in the trigeminal complex likely is attributable to direct depolarization of acid-sensitive trigeminal nerve fibers, for example, polymodal nociceptors, rather than through taste buds. Taken together, these findings suggest that transmission of sour taste information involves communication between Type III taste cells and 5-HT 3 -expressing afferent nerve fibers that project to a restricted portion of the nTS consistent with a crude mapping of taste quality information in the primary gustatory nucleus. © 2017 Wiley Periodicals, Inc.

Prospects for detection of target-dependent annual modulation in direct dark matter searches

DOE PAGES

Nobile, Eugenio Del; Gelmini, Graciela B.; Witte, Samuel J.

2016-02-03

Earth's rotation about the Sun produces an annual modulation in the expected scattering rate at direct dark matter detection experiments. The annual modulation as a function of the recoil energy E R imparted by the dark matter particle to a target nucleus is expected to vary depending on the detector material. However, for most interactions a change of variables from E R to v min, the minimum speed a dark matter particle must have to impart a fixed E R to a target nucleus, produces an annual modulation independent of the target element. We recently showed that if the darkmore » matter-nucleus cross section contains a non-factorizable target and dark matter velocity dependence, the annual modulation as a function of v min can be target dependent. Here we examine more extensively the necessary conditions for target-dependent modulation, its observability in present-day experiments, and the extent to which putative signals could identify a dark matter-nucleus differential cross section with a non-factorizable dependence on the dark matter velocity.« less

Preabsorptive insulin release and hypoglycemia in rats.

PubMed

Louis-Sylvestre, J

1976-01-01

Peripheral blood glucose and immunologically reactive insulin levels were determined in freely moving normal rats which were submitted either to a free oral glucose load or to a gastric administration of the glucose load. Identical determinations were performed in ventromedial hypothalamic nucleus-(VMH) lesioned and vagotomized rats after the same oral intake. It was demonstrated that: 1) a free oral glucose intake was immediately followed by two peaks of insulun release and a resultant decrease in blood glucose; 2) a gastric glucose load resulted in a single peak of insulin release and the concomitant decline in blood glucose; 3) the recorded blood glucose level was the resultant of the insulin-induced hypoglycemia and the postabsorptive hyperglycemia; and 4) the responses were largely exaggerated in VMH-lesioned rats and abolished by vagotomy. It is concluded that the early prandial insulin release reflexly induced by food-related stimuli temporarily enhances the metabolic conditions which provoke feeding.

Sexual Experience Modulates Neuronal Activity in Male Japanese Quail

PubMed Central

Can, Adem; Domjan, Michael; Delville, Yvon

2008-01-01

After an initial increase, repeated exposure to a particular stimulus or familiarity with an event results in lower immediate early gene expression levels in relevant brain structures. We predicted that similar effects would occur in Japanese quail after repeated sexual experience within brain areas involved in sexual behavior, namely, the medial preoptic nucleus (POM), the bed nucleus of stria terminalis (BST), and the nucleus taeniae of the amygdala (TnA), an avian homolog of medial amygdala. High experience subjects copulated with a female once on each of 16 consecutive days, whereas low experience subjects were allowed to copulate either once or twice. Control subjects were never exposed to a female. High experience subjects were faster to initiate sexual interaction, performed more cloacal contacts, and completed each cloacal contact faster than low experience subjects. Low experience subjects showed an increase in egr-1 (ZENK) expression, an immediate early gene product used as marker of neural activation in birds, in the areas of interest. In contrast, in high experience animals, egr-1 expression in the POM, BST and the periaqueductal gray (PAG) was not different than the level of expression in unmated controls. These results show that experience modulates the level of immediate early gene expression in the case of sexual behavior. Our results also indicate that immediate early gene expression in specific brain areas is not necessarily related to behavioral output, but depends on the behavioral history of the subjects. PMID:17826778

Burst discharges in neurons of the thalamic reticular nucleus are shaped by calcium-induced calcium release.

PubMed

Coulon, Philippe; Herr, David; Kanyshkova, Tatyana; Meuth, Patrick; Budde, Thomas; Pape, Hans-Christian

2009-01-01

The nucleus reticularis thalami (NRT) is a layer of inhibitory neurons that surrounds the dorsal thalamus. It appears to be the 'pacemaker' of certain forms of slow oscillations in the thalamus and was proposed to be a key determinant of the internal attentional searchlight as well as the origin of hypersynchronous activity during absence seizures. Neurons of the NRT exhibit a transient depolarization termed low threshold spike (LTS) following sustained hyperpolarization. This is caused by the activation of low-voltage-activated Ca2+ channels (LVACC). Although the role of these channels in thalamocortical oscillations was studied in great detail, little is known about the downstream intracellular Ca2+ signalling pathways and their feedback onto the oscillations. A signalling triad consisting of the sarco(endo)plasmic reticulum calcium ATPase (SERCA), Ca2+ activated K+ channels (SK2), and LVACC is active in dendrites of NRT neurons and shapes rhythmic oscillations. The aim of our study was to find out (i) if and how Ca2+-induced Ca2+ release (CICR) via ryanodine receptors (RyR) can be evoked in NRT neurons and (ii) how the released Ca2+ affects burst activity. Combining electrophysiological, immunohistochemical, and two-photon Ca2+ imaging techniques, we show that CICR in NRT neurons takes place by a cell-type specific coupling of LVACC and RyR. CICR could be evoked by the application of caffeine, by activation of LVACC, or by repetitive LTS generation. During the latter, CICR contributed 30% to the resulting build-up of [Ca2+]i. CICR was abolished by cyclopiazonic acid, a specific blocker for SERCA, or by high concentrations of ryanodine (50 microM). Unlike other thalamic nuclei, in the NRT the activation of high-voltage-activated Ca2+ channels failed to evoke CICR. While action potentials contributed little to the build-up of [Ca2+]i upon repetitive LTS generation, the Ca2+ released via RyR significantly reduced the number of action potentials during an LTS and reduced the neurons' low threshold activity, thus potentially reducing hypersynchronicity. This effect persisted in the presence of the SK2 channel blocker apamin. We conclude that the activation of LVACC specifically causes CICR via RyR in neurons of the NRT, thereby adding a Ca2+-dependent intracellular route to the mechanisms determining rhythmic oscillatory bursting in this nucleus.

Immunohistochemical evidence for the involvement of gonadotropin releasing hormone in neuroleptic and cataleptic effects of haloperidol in mice.

PubMed

Fegade, Harshal A; Umathe, Sudhir N

2016-04-01

Blockade of dopamine D2 receptor by haloperidol is attributed for neuroleptic and cataleptic effects; and also for the release of gonadotropin releasing hormone (GnRH) from the hypothalamus. GnRH agonist is reported to exhibit similar behavioural effects as that of haloperidol, and pre-treatment with GnRH antagonist is shown to attenuate the effects of haloperidol, suggesting a possibility that GnRH might mediate the effects of haloperidol. To substantiate such possibility, the influence of haloperidol on GnRH immunoreactivity (GnRH-ir) in the brain was studied in vehicle/antide pre-treated mice by peroxidase-antiperoxidase method. Initially, an earlier reported antide-haloperidol interaction in rat was confirmed in mice, wherein haloperidol (250μg/kg, i.p.) exhibited suppression of conditioned avoidance response (CAR) on two-way shuttle box, and induced catalepsy in bar test; and pre-treatment with antide (50μg/kg, s.c., GnRH antagonist) attenuated both effects of haloperidol. Immunohistochemical study was carried out to identify GnRH-ir in the brain, isolated 1h after haloperidol treatment to mice pre-treated with vehicle/antide. The morphometric analysis of microphotographs of brain sections revealed that haloperidol treatment increased integrated density units of GnRH-ir in various regions of the limbic system. Considering basal GnRH-ir in vehicle treated group as 100%, the increase in GnRH-ir after haloperidol treatment was by 100.98% in the medial septum; 54.26% in the bed nucleus of the stria terminalis; 1152.85% in the anteroventral periventricular nucleus; 120.79% in the preoptic area-organum vasculosum of the lamina terminalis and 138.82% in the arcuate nucleus. Antide did not influence basal and haloperidol induced increase in GnRH-ir in any of the regions. As significant increase in GnRH-ir after haloperidol treatment was observed in such regions of the brain which are reported to directly or indirectly communicate with the hippocampus and basal ganglia, the regions respectively responsible for neuroleptic and cataleptic effects; and as GnRH antagonist eliminated the effects of haloperidol without affecting GnRH-ir, it appears that GnRH released by haloperidol mediates its neuroleptic and cataleptic effects. Copyright © 2015 Elsevier Ltd. All rights reserved.

Overexpression of corticotropin-releasing factor receptor type 2 in the bed nucleus of stria terminalis improves posttraumatic stress disorder-like symptoms in a model of incubation of fear.

PubMed

Elharrar, Einat; Warhaftig, Gal; Issler, Orna; Sztainberg, Yehezkel; Dikshtein, Yahav; Zahut, Roy; Redlus, Lior; Chen, Alon; Yadid, Gal

2013-12-01

Posttraumatic stress disorder (PTSD) is a severe, persistent psychiatric disorder in response to a traumatic event, causing intense anxiety and fear. These responses may increase over time upon conditioning with fear-associated cues, a phenomenon termed fear incubation. Corticotropin-releasing factor receptor type 1 (CRFR1) is involved in activation of the central stress response, while corticotropin-releasing factor receptor type 2 (CRFR2) has been suggested to mediate termination of this response. Corticotropin-releasing factor (CRF) receptors are found in stress-related regions, including the bed nucleus of stria terminalis (BNST), which is implicated in sustained fear. Fear-related behaviors were analyzed in rats exposed to predator-associated cues, a model of psychological trauma, over 10 weeks. Rats were classified as susceptible (PTSD-like) or resilient. Expression levels of CRF receptors were measured in the amygdala nuclei and BNST of the two groups. In addition, lentiviruses overexpressing CRFR2 were injected into the medial division, posterointermediate part of the BNST (BSTMPI) of susceptible and resilient rats and response to stress cues was measured. We found that exposure to stress and stress-associated cues induced a progressive increase in fear response of susceptible rats. The behavioral manifestations of these rats were correlated both with sustained elevation in CRFR1 expression and long-term downregulation in CRFR2 expression in the BSTMPI. Intra-BSTMPI injection of CRFR2 overexpressing lentiviruses attenuated behavioral impairments of susceptible rats. These results implicate the BNST CRF receptors in the mechanism of coping with stress. Our findings suggest increase of CRFR2 levels as a new approach for understanding stress-related atypical psychiatric syndromes such as PTSD. © 2013 Society of Biological Psychiatry.

Molecular Dynamics Simulations of Membrane-Bound STIM1 to Investigate Conformational Changes during STIM1 Activation upon Calcium Release.

PubMed

Mukherjee, Sreya; Karolak, Aleksandra; Debant, Marjolaine; Buscaglia, Paul; Renaudineau, Yves; Mignen, Olivier; Guida, Wayne C; Brooks, Wesley H

2017-02-27

Calcium is involved in important intracellular processes, such as intracellular signaling from cell membrane receptors to the nucleus. Typically, calcium levels are kept at less than 100 nM in the nucleus and cytosol, but some calcium is stored in the endoplasmic reticulum (ER) lumen for rapid release to activate intracellular calcium-dependent functions. Stromal interacting molecule 1 (STIM1) plays a critical role in early sensing of changes in the ER's calcium level, especially when there is a sudden release of stored calcium from the ER. Inactive STIM1, which has a bound calcium ion, is activated upon ion release. Following activation of STIM1, there is STIM1-assisted initiation of extracellular calcium entry through channels in the cell membrane. This extracellular calcium entering the cell then amplifies intracellular calcium-dependent actions. At the end of the process, ER levels of stored calcium are reestablished. The main focus of this work was to study the conformational changes accompanying homo- or heterodimerization of STIM1. For this purpose, the ER luminal portion of STIM1 (residues 58-236), which includes the sterile alpha motif (SAM) domain plus the calcium-binding EF-hand domains 1 and 2 attached to the STIM1 transmembrane region (TM), was modeled and embedded in a virtual membrane. Next, molecular dynamics simulations were performed to study the conformational changes that take place during STIM1 activation and subsequent protein-protein interactions. Indeed, the simulations revealed exposure of residues in the EF-hand domains, which may be important for dimerization steps. Altogether, understanding conformational changes in STIM1 can help in drug discovery when targeting this key protein in intracellular calcium functions.

Delivering growth factors through a polymeric scaffold to cell cultures containing both nucleus pulposus and annulus fibrosus.

PubMed

Akyuva, Yener; Kaplan, Necati; Yilmaz, Ibrahim; Ozbek, Hanefi; Sirin, Duygu Yasar; Karaaslan, Numan; Guler, Olcay; Ateş, Özkan

2018-04-09

The aim of this in vitro experimental study was to design a novel, polyvinyl alcohol(PVA)-basedpolymericscaffold that permits the controlled release of insulin-likegrowthfactor1(IGF-1)/bonemorphogenetic protein-2(BMP-2) following intervertebral disc administration. The drug delivery system was composed of two different solutions that formed a scaffold within seconds after coming into contact with each other. We performed swelling,pH,temperature tests and analysis of the controlled release of growth factors from this system.The release kinetics of the growth factors was determined through enzyme linked immunosorbent assay(ELISA). Cell proliferation and viability was monitored with microscopy and analyzed using an MTT assay and acridine orange/propidium iodide(AO/PI) staining. Chondroadherin(CHAD), hypoxiainduciblefactor-1alpha(HIF-1α),collagentypeII(COL2A1) gene expressions were determined with quantitative real-timepolymerasechainreaction(qRT-PCR) analysis to show the effects of IGF-1/BMP-2 administration on annulus fibrosus cell(AFC)/nucleus pulposus cell(NPC) cultures. The scaffold allowed for the controlled release of IGF-1 and BMP-2 in different time intervals. It was observed that as the application time increased, the number of cells and the degree of extracellular matrix development increased in AFC/NPC cultures. AO/PI staining and an MTT analysis showed that cells retained their specific morphology and continued to proliferate. It was observed that HIF-1α and CHAD expression increased in a time-dependent manner, and there wasn't any COL2A1 expression in the AFC/NPC cultures. The designed scaffold may be used as an alternative method for intervertebral disc administration of growth factors after further in vivo studies. We believe that such prototype scaffolds may be an innovative technology in targeted drug therapies after reconstructive neurosurgeries.

Hydraulic Pressure during Fluid Flow Regulates Purinergic Signaling and Cytoskeleton Organization of Osteoblasts.

PubMed

Gardinier, Joseph D; Gangadharan, Vimal; Wang, Liyun; Duncan, Randall L

2014-06-01

During physiological activities, osteoblasts experience a variety of mechanical forces that stimulate anabolic responses at the cellular level necessary for the formation of new bone. Previous studies have primarily investigated the osteoblastic response to individual forms of mechanical stimuli. However in this study, we evaluated the response of osteoblasts to two simultaneous, but independently controlled stimuli; fluid flow-induced shear stress (FSS) and static or cyclic hydrostatic pressure (SHP or CHP, respectively). MC3T3-E1 osteoblasts-like cells were subjected to 12dyn/cm 2 FSS along with SHP or CHP of varying magnitudes to determine if pressure enhances the anabolic response of osteoblasts during FSS. For both SHP and CHP, the magnitude of hydraulic pressure that induced the greatest release of ATP during FSS was 15 mmHg. Increasing the hydraulic pressure to 50 mmHg or 100 mmHg during FSS attenuated the ATP release compared to 15 mmHg during FSS. Decreasing the magnitude of pressure during FSS to atmospheric pressure reduced ATP release to that of basal ATP release from static cells and inhibited actin reorganization into stress fibers that normally occurred during FSS with 15 mmHg of pressure. In contrast, translocation of nuclear factor kappa B (NFκB) to the nucleus was independent of the magnitude of hydraulic pressure and was found to be mediated through the activation of phospholipase-C (PLC), but not src kinase. In conclusion, hydraulic pressure during FSS was found to regulate purinergic signaling and actin cytoskeleton reorganization in the osteoblasts in a biphasic manner, while FSS alone appeared to stimulate NFκB translocation. Understanding the effects of hydraulic pressure on the anabolic responses of osteoblasts during FSS may provide much needed insights into the physiologic effects of coupled mechanical stimuli on osteogenesis.

Hydraulic Pressure during Fluid Flow Regulates Purinergic Signaling and Cytoskeleton Organization of Osteoblasts

PubMed Central

Gardinier, Joseph D.; Gangadharan, Vimal; Wang, Liyun; Duncan, Randall L.

2014-01-01

During physiological activities, osteoblasts experience a variety of mechanical forces that stimulate anabolic responses at the cellular level necessary for the formation of new bone. Previous studies have primarily investigated the osteoblastic response to individual forms of mechanical stimuli. However in this study, we evaluated the response of osteoblasts to two simultaneous, but independently controlled stimuli; fluid flow-induced shear stress (FSS) and static or cyclic hydrostatic pressure (SHP or CHP, respectively). MC3T3-E1 osteoblasts-like cells were subjected to 12dyn/cm2 FSS along with SHP or CHP of varying magnitudes to determine if pressure enhances the anabolic response of osteoblasts during FSS. For both SHP and CHP, the magnitude of hydraulic pressure that induced the greatest release of ATP during FSS was 15 mmHg. Increasing the hydraulic pressure to 50 mmHg or 100 mmHg during FSS attenuated the ATP release compared to 15 mmHg during FSS. Decreasing the magnitude of pressure during FSS to atmospheric pressure reduced ATP release to that of basal ATP release from static cells and inhibited actin reorganization into stress fibers that normally occurred during FSS with 15 mmHg of pressure. In contrast, translocation of nuclear factor kappa B (NFκB) to the nucleus was independent of the magnitude of hydraulic pressure and was found to be mediated through the activation of phospholipase-C (PLC), but not src kinase. In conclusion, hydraulic pressure during FSS was found to regulate purinergic signaling and actin cytoskeleton reorganization in the osteoblasts in a biphasic manner, while FSS alone appeared to stimulate NFκB translocation. Understanding the effects of hydraulic pressure on the anabolic responses of osteoblasts during FSS may provide much needed insights into the physiologic effects of coupled mechanical stimuli on osteogenesis. PMID:24910719

Single nucleon emission in relativistic nucleus-nucleus reactions

NASA Technical Reports Server (NTRS)

Norbury, John W.; Townsend, Lawrence W.

1992-01-01

Significant discrepancies between theory and experiment have previously been noted for nucleon emission via electromagnetic processes in relativistic nucleus-nucleus collisions. The present work investigates the hypothesis that these discrepancies have arisen due to uncertainties about how to deduce the experimental electromagnetic cross section from the total measured cross section. An optical-model calculation of single neutron removal is added to electromagnetic cross sections and compared to the total experimental cross sections. Good agreement is found thereby resolving some of the earlier noted discrepancies. A detailed comparison to the recent work of Benesh, Cook, and Vary is made for both the impact parameter and the nuclear cross section. Good agreement is obtained giving an independent confirmation of the parameterized formulas developed by those authors.

The International VEGA "Venus-Halley" (1984-1986) Experiment: Description and Scientific Objectives

NASA Technical Reports Server (NTRS)

1985-01-01

The Venus-Halley (Vega) project will provide a unique opportunity to combine a mission over Venus with a transfer flight to Halley's comet. This project is based on three research goals: (1) to study the surface of Venus; (2) to study the air circulation on Venus and its meteorological parameters; and (3) to study Halley's comet. The objective of the study of Halley's comet is to: determine the physical characteristics of its nucleus; define the structure and dynamics of the coma around the nucleus; define the gas composition near the nucleus; investigate the dust particle distribution as a function of mass at various distances from the nucleus; and investigate the solar wind interaction with the atmosphere and ionosphere of the comet.

GABA and NMDA receptors in CRF neurons have opposing effects in fear acquisition and anxiety in central amygdala vs. bed nucleus of the stria terminalis.

PubMed

Gafford, Georgette M; Ressler, Kerry J

2015-11-01

This article is part of a Special Issue "SBN 2014". Beginning with Vale and Colleagues in 1981, corticotropin releasing factor (CRF) also called corticotropin releasing hormone (CRH) has repeatedly been identified as an important contributor to fear and anxiety behavior. These findings have proven useful to further our understanding of disorders that have significant fear-dysregulation, such as post-traumatic stress, as well as other stress- and anxiety-related disorders. Unfortunately, the data are not all in agreement. In particular the role of CRF in fear learning is controversial, with studies pointing to contradictory effects from CRF manipulation even within the same brain structure. Further, very few studies address the potentially promising role of CRF manipulation in fear extinction behavior. Here, we briefly review the role of CRF in anxiety, fear learning and extinction, focusing on recent cell-type and neurotransmitter-specific studies in the amygdala and bed nucleus of the stria terminalis (BNST) that may help to synthesize the available data on the role of CRF in fear and anxiety-related behaviors. Copyright © 2015. Published by Elsevier Inc.

Emerging role for corticotropin releasing factor signaling in the bed nucleus of the stria terminalis at the intersection of stress and reward.

PubMed

Silberman, Yuval; Winder, Danny G

2013-01-01

Stress and anxiety play an important role in the development and maintenance of drug and alcohol addiction. The bed nucleus of the stria terminalis (BNST), a brain region involved in the production of long-term stress-related behaviors, plays an important role in animal models of relapse, such as reinstatement to previously extinguished drug-seeking behaviors. While a number of neurotransmitter systems have been suggested to play a role in these behaviors, recent evidence points to the neuropeptide corticotropin releasing factor (CRF) as being critically important in BNST-mediated reinstatement behaviors. Although numerous studies indicate that the BNST is a complex brain region with multiple afferent and efferent systems and a variety of cell types, there has only been limited work to determine how CRF modulates this complex neuronal system at the circuit level. Recent work from our lab and others have begun to unravel these BNST neurocircuits and explore their roles in CRF-related reinstatement behaviors. This review will examine the role of CRF signaling in drug addiction and reinstatement with an emphasis on critical neurocircuitry within the BNST that may offer new insights into treatments for addiction.

Noradrenergic synaptic function in the bed nucleus of the stria terminalis varies in animal models of anxiety and addiction.

PubMed

McElligott, Zoé A; Fox, Megan E; Walsh, Paul L; Urban, Daniel J; Ferrel, Martilias S; Roth, Bryan L; Wightman, R Mark

2013-08-01

Lewis rats show increased anxiety-like behaviors and drug consumption compared with Sprague-Dawley rats. Prior work suggests norepinephrine (NE) signaling in the bed nucleus of the stria terminalis (BNST) could have a role in mediating these phenotypes. Here, we investigated NE content and dynamics in the ventral BNST (vBNST) using fast-scan cyclic voltammetry in these two rat strains. We found that NE release evoked by electrical stimulus and its subsequent uptake was dysregulated in the more anxious Lewis rats. Because addiction is a multifaceted disease influenced by both genetic and environmental factors, we hypothesized NE dynamics would vary in these strains after the induction of a physical dependence on morphine. Following naloxone-precipitated morphine withdrawal, NE release and uptake dynamics were not changed in Lewis rats but were significantly altered in Sprague-Dawley rats. The alterations in Sprague-Dawley rats were accompanied by an increase in anxiety-like behavior in those animals as measured with the elevated plus maze. These studies suggest novel mechanisms involved in the development of affective disorders, and highlight the noradrenergic system in the vBNST as a common substrate for the manifestation of pathological anxiety and addiction.

Purinergic signaling in hypothalamic tanycytes: potential roles in chemosensing.

PubMed

Dale, Nicholas

2011-04-01

Hypothalamic tanycytes are cells that line the walls of the 3rd ventricle. Their cell bodies contact the cerebrospinal fluid and give rise to an inwardly directed process. The more dorsally located (α1 and α2) tanycytes project to areas of the brain involved in the control of feeding and energy balance (the arcuate nucleus and ventromedial hypothalamic nucleus). Although their functions are poorly understood, they have some similarities to glial cells. Recent evidence shows that they express key molecules involved in purinergic signaling and at least some tanycytes may act as adult multipotent stem cells. Emerging evidence suggests that tanycytes signal through changes in intracellular Ca(2+) and that they can respond with large Ca(2+) signals to ATP and transmitters associated with wakefulness and the drive to feed. They are also glucosensitive and this response is dependent on release of ATP from tanycytes and the activation of P2Y1 receptors. Their ability to release ATP gives potential for their integration into the hypothalamic circuitry controlling energy balance and feeding, but many fundamental questions about their possible functions and roles remain unanswered. Copyright © 2011 Elsevier Ltd. All rights reserved.

Sex- and brain region-specific patterns of gene expression associated with socially-mediated puberty in a eusocial mammal

PubMed Central

Monks, D. Ashley; Zovkic, Iva B.; Holmes, Melissa M.

2018-01-01

The social environment can alter pubertal timing through neuroendocrine mechanisms that are not fully understood; it is thought that stress hormones (e.g., glucocorticoids or corticotropin-releasing hormone) influence the hypothalamic-pituitary-gonadal axis to inhibit puberty. Here, we use the eusocial naked mole-rat, a unique species in which social interactions in a colony (i.e. dominance of a breeding female) suppress puberty in subordinate animals. Removing subordinate naked mole-rats from this social context initiates puberty, allowing for experimental control of pubertal timing. The present study quantified gene expression for reproduction- and stress-relevant genes acting upstream of gonadotropin-releasing hormone in brain regions with reproductive and social functions in pre-pubertal, post-pubertal, and opposite sex-paired animals (which are in various stages of pubertal transition). Results indicate sex differences in patterns of neural gene expression. Known functions of genes in brain suggest stress as a key contributing factor in regulating male pubertal delay. Network analysis implicates neurokinin B (Tac3) in the arcuate nucleus of the hypothalamus as a key node in this pathway. Results also suggest an unappreciated role for the nucleus accumbens in regulating puberty. PMID:29474488

Frequency specific activity in subthalamic nucleus correlates with hand bradykinesia in Parkinson's disease.

PubMed

Tan, Huiling; Pogosyan, Alek; Anzak, Anam; Foltynie, Thomas; Limousin, Patricia; Zrinzo, Ludvic; Ashkan, Keyoumars; Bogdanovic, Marko; Green, Alexander L; Aziz, Tipu; Brown, Peter

2013-02-01

Local field potential recordings made from the basal ganglia of patients undergoing deep brain stimulation have suggested that frequency specific activity is involved in determining the rate of force development and the peak force at the outset of a movement. However, the extent to which the basal ganglia might be involved in motor performance later on in a sustained contraction is less clear. We therefore recorded from the subthalamic nucleus region (STNr) in patients with Parkinson's disease (PD) as they made maximal voluntary grips. Relative to age-matched controls they had more rapid force decrement when contraction was meant to be sustained and prolonged release reaction time and slower rate of force offset when they were supposed to release the grip. These impairments were independent from medication status. Increased STNr power over 5-12 Hz (in the theta/alpha band) independently predicted better performance-reduced force decrement, shortened release reaction time and faster rate of force offset. In contrast, lower mean levels and progressive reduction of STNr power over 55-375 Hz (high gamma/high frequency) over the period when contraction was meant to be sustained were both strongly associated with greater force decrement over time. Higher power over 13-23 Hz (low beta) was associated with more rapid force decrement during the period when grip should have been sustained, and with a paradoxical shortening of the release reaction time. These observations suggest that STNr activities at 5-12 Hz and 55-375 Hz are necessary for optimal grip performance and that deficiencies of such activities lead to motor impairments. In contrast, increased levels of 13-25 Hz activity both promote force decrement and shorten the release reaction time, consistent with a role in antagonising (and terminating) voluntary movement. Frequency specific oscillatory activities in the STNr impact on motor performance from the beginning to the end of a voluntary grip. Copyright © 2012 Elsevier Inc. All rights reserved.

Frequency specific activity in subthalamic nucleus correlates with hand bradykinesia in Parkinson's disease

PubMed Central

Tan, Huiling; Pogosyan, Alek; Anzak, Anam; Foltynie, Thomas; Limousin, Patricia; Zrinzo, Ludvic; Ashkan, Keyoumars; Bogdanovic, Marko; Green, Alexander L.; Aziz, Tipu; Brown, Peter

2013-01-01

Local field potential recordings made from the basal ganglia of patients undergoing deep brain stimulation have suggested that frequency specific activity is involved in determining the rate of force development and the peak force at the outset of a movement. However, the extent to which the basal ganglia might be involved in motor performance later on in a sustained contraction is less clear. We therefore recorded from the subthalamic nucleus region (STNr) in patients with Parkinson's disease (PD) as they made maximal voluntary grips. Relative to age-matched controls they had more rapid force decrement when contraction was meant to be sustained and prolonged release reaction time and slower rate of force offset when they were supposed to release the grip. These impairments were independent from medication status. Increased STNr power over 5–12 Hz (in the theta/alpha band) independently predicted better performance—reduced force decrement, shortened release reaction time and faster rate of force offset. In contrast, lower mean levels and progressive reduction of STNr power over 55–375 Hz (high gamma/high frequency) over the period when contraction was meant to be sustained were both strongly associated with greater force decrement over time. Higher power over 13–23 Hz (low beta) was associated with more rapid force decrement during the period when grip should have been sustained, and with a paradoxical shortening of the release reaction time. These observations suggest that STNr activities at 5–12 Hz and 55–375 Hz are necessary for optimal grip performance and that deficiencies of such activities lead to motor impairments. In contrast, increased levels of 13–25 Hz activity both promote force decrement and shorten the release reaction time, consistent with a role in antagonising (and terminating) voluntary movement. Frequency specific oscillatory activities in the STNr impact on motor performance from the beginning to the end of a voluntary grip. PMID:23178580

The 5-HT1A/1B-receptor agonist eltoprazine increases both catecholamine release in the prefrontal cortex and dopamine release in the nucleus accumbens and decreases motivation for reward and "waiting" impulsivity, but increases "stopping" impulsivity.

PubMed

Korte, S Mechiel; Prins, Jolanda; Van den Bergh, Filip S; Oosting, Ronald S; Dupree, Rudy; Korte-Bouws, Gerdien A H; Westphal, Koen G C; Olivier, Berend; Denys, Damiaan A; Garland, Alexis; Güntürkün, Onur

2017-01-05

The 5-HT 1A/1B -receptor agonist eltoprazine has a behavioral drug signature that resembles that of a variety of psychostimulant drugs, despite the differences in receptor binding profile. These psychostimulants are effective in treating impulsivity disorders, most likely because they increase norepinephrine (NE) and dopamine (DA) levels in the prefrontal cortex. Both amphetamine and methylphenidate, however, also increase dopamine levels in the nucleus accumbens (NAc), which has a significant role in motivation, pleasure, and reward. How eltoprazine affects monoamine release in the medial prefrontal cortex (mPFC), the orbitofrontal cortex (OFC), and the NAc is unknown. It is also unknown whether eltoprazine affects different forms of impulsivity and brain reward mechanisms. Therefore, in the present study, we investigate the effects of eltoprazine in rats in the following sequence: 1) the activity of the monoaminergic systems using in vivo microdialysis, 2) motivation for reward measured using the intracranial self-stimulation (ICSS) procedure, and finally, 3) "waiting" impulsivity in the delay-aversion task, and the "stopping" impulsivity in the stop-signal task. The microdialysis studies clearly showed that eltoprazine increased DA and NE release in both the mPFC and OFC, but only increased DA concentration in the NAc. In contrast, eltoprazine decreased 5-HT release in the mPFC and NAc (undetectable in the OFC). Remarkably, eltoprazine decreased impulsive choice, but increased impulsive action. Furthermore, brain stimulation was less rewarding following eltoprazine treatment. These results further support the long-standing hypothesis that "waiting" and "stopping" impulsivity are regulated by distinct neural circuits, because 5-HT 1A/1B -receptor activation decreases impulsive choice, but increases impulsive action. Copyright © 2016 Elsevier B.V. All rights reserved.

Cocaine- and amphetamine-regulated transcript is present in hypothalamic neuroendocrine neurones and is released to the hypothalamic-pituitary portal circuit.

PubMed

Larsen, P J; Seier, V; Fink-Jensen, A; Holst, J J; Warberg, J; Vrang, N

2003-03-01

Cocaine- and amphetamine-regulated transcript (CART) is present in a number of hypothalamic nuclei. Besides actions in circuits regulating feeding behaviour and stress responses, the hypothalamic functions of CART are largely unknown. We report that CART immunoreactivity is present in hypothalamic neuroendocrine neurones. Adult male rats received a systemic injection of the neuronal tracer Fluorogold (FG) 2 days before fixation, and subsequent double- and triple-labelling immunoflourescence analysis demonstrated that neuroendocrine CART-containing neurones were present in the anteroventral periventricular, supraoptic, paraventricular (PVN) and periventricular nuclei of the hypothalamus. In the PVN, CART-positive neuroendocrine neurones were found in all of cytoarchitectonically identified nuclei. In the periventricular nucleus, approximately one-third of somatostatin cells were also CART-immunoreactive. In the medial parvicellular subnucleus of the PVN, CART and FG coexisted with thyrotrophin-releasing hormone, whereas very few of the corticotrophin-releasing hormone containing cells were CART-immunoreactive. In the arcuate nucleus, CART was extensively colocalized with pro-opiomelanocortin in the ventrolateral part, but completely absent from neuroendocrine neurones of the dorsomedial part. To assess the possible role of CART as a hypothalamic-releasing factor, immunoreactive CART was measured in blood samples from the long portal vessels connecting the median eminence with the anterior pituitary gland. Adult male rats were anaesthetized and the infundibular stalk exposed via a transpharyngeal approach. The long portal vessels were transected and blood collected in 30-min periods (one prestimulatory and three poststimulatory periods). Compared to systemic venous plasma samples, baseline concentrations of immunoreactive CART were elevated in portal plasma. Exposure to sodium nitroprusside hypotension triggered a two-fold elevation of portal CART42-89 immunoreactivity throughout the 90-min stimulation period. In contrast, the concentration of portal plasma CART immunoreactivity dropped in the vehicle infused rats. The current study provides further evidence that CART is a neuroendocrine-releasing factor with a possible impact on anterior pituitary function during states of haemodynamic stress.

TNF{alpha} release from peripheral blood leukocytes depends on a CRM1-mediated nuclear export

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miskolci, Veronika; Department of Pediatrics, Feinstein Institute for Medical Research at the North Shore-Long Island Jewish Health System, New Hyde Park, NY 11040; Ghosh, Chandra C.

2006-12-15

Tumor necrosis factor-{alpha} (TNF{alpha}) is a potent pro-inflammatory cytokine that plays a major role in the pathogenesis of acute and chronic inflammatory disorders such as septic shock and arthritis, respectively. Leukocytes stimulated with inflammatory signals such as lipopolysaccharide (LPS) are the predominant producers of TNF{alpha}, and thus control of TNF{alpha} release from stimulated leukocytes represents a potential therapeutic target. Here, we report that leptomycin B (LMB), a specific inhibitor of CRM1-dependent nuclear protein export, inhibits TNF{alpha} release from LPS-stimulated human peripheral blood neutrophils and mononuclear cells. In addition, immunofluorescence confocal microscopy and immunoblotting analysis indicate that TNF{alpha} is localized inmore » the nucleus of human neutrophils and mononuclear cells. This study demonstrates that the cellular release of TNF{alpha} from stimulated leukocytes is mediated by the CRM1-dependent nuclear export mechanism. Inhibition of CRM1-dependent cellular release of TNF{alpha} could thus provide a novel therapeutic approach for disorders involving excessive TNF{alpha} release.« less

Site-specific activation of dopamine and serotonin transmission by aniracetam in the mesocorticolimbic pathway of rats.

PubMed

Nakamura, K; Shirane, M; Koshikawa, N

2001-04-06

The effects of aniracetam on extracellular levels of dopamine (DA), serotonin (5-HT) and their metabolites were examined in five brain regions in freely moving stroke-prone spontaneously hypertensive rats (SHRSP) using in vivo microdialysis. Basal DA release in SHRSP was uniformly lower in all regions tested than that in age-matched control Wistar Kyoto rats. 3,4-Dihydroxyphenylacetic acid and homovanillic acid levels were altered in the basolateral amygdala, dorsal hippocampus and prefrontal cortex of SHRSP. While basal 5-HT release decreased in the striatum and increased in the basolateral amygdala, there was no associated change in 5-hydroxyindoleacetic acid levels. Systemic administration of aniracetam to SHRSP enhanced both DA and 5-HT release with partly associated change in their metabolite levels in the prefrontal cortex, basolateral amygdala and dorsal hippocampus, but not in the striatum and nucleus accumbens shell, in a dose-dependent manner (30 and/or 100 mg/kg p.o.). Microinjection (1 and 10 ng) of aniracetam or its metabolites (N-anisoyl-GABA and 2-pyrrolidinone) into the nucleus accumbens shell produced no turning behavior. These findings indicate that SHRSP have a dopaminergic hypofunction throughout the brain and that aniracetam elicits a site-specific activation in mesocorticolimbic dopaminergic and serotonergic pathways in SHRSP, possibly via nicotinic acetylcholine receptors in the ventral tegmental area and raphe nuclei. The physiological roles in the aniracetam-sensitive brain regions may closely link with their clinical efficacy towards emotional disturbances appearing after cerebral infarction.

Involvement of the oxytocin system in the bed nucleus of the stria terminalis in the sex-specific regulation of social recognition.

PubMed

Dumais, Kelly M; Alonso, Andrea G; Immormino, Marisa A; Bredewold, Remco; Veenema, Alexa H

2016-02-01

Sex differences in the oxytocin (OT) system in the brain may explain why OT often regulates social behaviors in sex-specific ways. However, a link between sex differences in the OT system and sex-specific regulation of social behavior has not been tested. Here, we determined whether sex differences in the OT receptor (OTR) or in OT release in the posterior bed nucleus of the stria terminalis (pBNST) mediates sex-specific regulation of social recognition in rats. We recently showed that, compared to female rats, male rats have a three-fold higher OTR binding density in the pBNST, a sexually dimorphic area implicated in the regulation of social behaviors. We now demonstrate that OTR antagonist (5 ng/0.5 μl/side) administration into the pBNST impairs social recognition in both sexes, while OT (100 pg/0.5 μl/side) administration into the pBNST prolongs the duration of social recognition in males only. These effects seem specific to social recognition, as neither treatment altered total social investigation time in either sex. Moreover, baseline OT release in the pBNST, as measured with in vivo microdialysis, did not differ between the sexes. However, males showed higher OT release in the pBNST during social recognition compared to females. These findings suggest a sex-specific role of the OT system in the pBNST in the regulation of social recognition. Copyright © 2015 Elsevier Ltd. All rights reserved.

Involvement of the oxytocin system in the bed nucleus of the stria terminalis in the sex-specific regulation of social recognition

PubMed Central

Dumais, Kelly M.; Alonso, Andrea G.; Immormino, Marisa A.; Bredewold, Remco; Veenema, Alexa H.

2015-01-01

Sex differences in the oxytocin (OT) system in the brain may explain why OT often regulates social behaviors in sex-specific ways. However, a link between sex differences in the OT system and sex-specific regulation of social behavior has not been tested. Here, we determined whether sex differences in the OT receptor (OTR) or in OT release in the posterior bed nucleus of the stria terminalis (pBNST) mediates sex-specific regulation of social recognition in rats. We recently showed that, compared to female rats, male rats have a three-fold higher OTR binding density in the pBNST, a sexually dimorphic area implicated in the regulation of social behaviors. We now demonstrate that OTR antagonist (5 ng/0.5 μl/side) administration into the pBNST impairs social recognition in both sexes, while OT (100 pg/0.5 μl/side) administration into the pBNST prolongs the duration of social recognition in males only. These effects seem specific to social recognition, as neither treatment altered total social investigation time in either sex. Moreover, baseline OT release in the pBNST, as measured with in vivo microdialysis, did not differ between the sexes. However, males showed higher OT release in the pBNST during social recognition compared to females. These findings suggest a sex-specific role of the OT system in the pBNST in the regulation of social recognition. PMID:26630388

Co-delivery of pemetrexed and miR-21 antisense oligonucleotide by lipid-polymer hybrid nanoparticles and effects on glioblastoma cells.

PubMed

Küçüktürkmen, Berrin; Devrim, Burcu; Saka, Ongun M; Yilmaz, Şükran; Arsoy, Taibe; Bozkir, Asuman

2017-01-01

Combination therapy using anticancer drugs and nucleic acid is a more promising strategy to overcome multidrug resistance in cancer and to enhance apoptosis. In this study, lipid-polymer hybrid nanoparticles (LPNs), which contain both pemetrexed and miR-21 antisense oligonucleotide (anti-miR-21), have been developed for treatment of glioblastoma, the most aggressive type of brain tumor. Prepared LPNs have been well characterized by particle size distribution and zeta potential measurements, determination of encapsulation efficiency, and in vitro release experiments. Morphology of LPNs was determined by transmission electron microscopy. LPNs had a hydrodynamic size below 100 nm and exhibited sustained release of pemetrexed up to 10 h. Encapsulation of pemetrexed in LPNs increased cellular uptake from 6% to 78%. Results of confocal microscopy analysis have shown that co-delivery of anti-miR-21 significantly improved accumulation of LPNs in the nucleus of U87MG cells. Nevertheless, more effective cytotoxicity results could not be obtained due to low concentration of anti-miR-21, loaded in LPNs. We expect that the effective drug delivery systems can be obtained with higher concentration of anti-miR-21 for the treatment of glioblastoma.

A role of nucleus accumbens dopamine receptors in the nucleus accumbens core, but not shell, in fear prediction error.

PubMed

Li, Susan S Y; McNally, Gavan P

2015-08-01

Two experiments used an associative blocking design to study the role of dopamine receptors in the nucleus accumbens shell (AcbSh) and core (AcbC) in fear prediction error. Rats in the experimental groups were trained to a visual fear-conditioned stimulus (conditional stimulus [CS]) A in Stage I, whereas rats in the control groups were not. In Stage II, all rats received compound fear conditioning of the visual CSA and an auditory CSB. Rats were later tested for their fear responses to CSB. All rats received microinjections of saline or the D1-D2 receptor antagonist cis-(z)-flupenthixol prior to Stage II. These microinjections targeted either the AcbSh (Experiment 1) or the AcbC (Experiment 2). In each experiment, Stage I fear conditioning of CSA blocked fear learning to CSB. Microinjection of cis-(z)-flupenthixol (10 or 20 μg) into the AcbSh (Experiment 1) had no effect on fear learning or associative blocking. In contrast, microinjection of cis-(z)-flupenthixol (10 or 20 μg) into the AcbC (Experiment 2) attenuated blocking and so enabled fear learning to CSB. These results identify the AcbC as the critical locus for dopamine receptor contributions to fear prediction error and the associative blocking of fear learning. (c) 2015 APA, all rights reserved).

Accelerator and reactor complementarity in coherent neutrino-nucleus scattering

NASA Astrophysics Data System (ADS)

Dent, James B.; Dutta, Bhaskar; Liao, Shu; Newstead, Jayden L.; Strigari, Louis E.; Walker, Joel W.

2018-02-01

We study the complementarity between accelerator and reactor coherent elastic neutrino-nucleus elastic scattering (CE ν NS ) experiments for constraining new physics in the form of nonstandard neutrino interactions (NSI). First, considering just data from the recent observation by the Coherent experiment, we explore interpretive degeneracies that emerge when activating either two or four unknown NSI parameters. Next, we demonstrate that simultaneous treatment of reactor and accelerator experiments, each employing at least two distinct target materials, can break a degeneracy between up and down flavor-diagonal NSI terms that survives analysis of neutrino oscillation experiments. Considering four flavor-diagonal (e e /μ μ ) up- and down-type NSI parameters, we find that all terms can be measured with high local precision (to a width as small as ˜5 % in Fermi units) by next-generation experiments, although discrete reflection ambiguities persist.

Vacuum low-temperature superconductivity is the essence of superconductivity - Atomic New Theory

NASA Astrophysics Data System (ADS)

Yongquan, Han

2010-10-01

The universe when the temperature closest to the Big Bang the temperature should be nuclear. Because, after the big bang, instant formation of atoms, nuclei and electrons between the absolute vacuum, the nucleus can not emit energy. (Radioactive elements, except in fact, radiation Yuan Su limited power emitted) which causes atomic nuclei and external temperature difference are so enormous that a large temperature difference reasons, all external particles became closer to the nucleus, affect the motion of electrons. When the conductor conductivity and thus affect the conductivity, the formation of resistance. Assumption that no particles affect the motion of electrons (except outside the nucleus) to form a potential difference will not change after the vector form, is now talking about the phenomenon of superconductivity, and then to introduce general, the gap between atoms in molecules or between small, valence electron number of high temperature superconducting conductors. This theory of atomic nuclei, but also explain the atomic and hydrogen bombs can remain after an explosion Why can release enormous energy reasons. Can also explain the ``super flow'' phenomenon. natural world. Tel 13241375685

On the CO and N2 abundance in Comet Halley

NASA Technical Reports Server (NTRS)

Eberhardt, P.; Krankowsky, D.; Schulte, W.; Dolder, U.; Laemmerzahl, P.; Berthelier, J. J.; Woweries, J.; Stubbemann, U.; Hodges, R. R.; Hoffmann, J. H.

1986-01-01

The mass 28 amu/e signal observed in the neutral mode of the Giotto neutral gas mass spectrometer (NMS) is evaluated. At 1000 km from the nucleus number density n(CO)/ n(H2O) is less than or = 0.07. The production rate of CO as a parent molecule directly from the nucleus is thus less than 7% of the H2O production rate. However, CO is also produced from an extended source in the inner coma (r is less than 20,000 km) and at 20,000 km from the nucleus, for the total equivalent CO production rate 0.05 is less than or = Q(CO)/Q(H2O) is less than or = 0.15. For N2 an upper limit Q(N2)/Q(H2O) is less than or = 0.1 is derived. No parent molecule for the CO is identified in agreement with the NMS measurements. It is proposed that CO or a very short-lived parent is released in the coma from cometary dust grains, such as the CHON particles.

Selectivity Mechanism of the Nuclear Pore Complex Characterized by Single Cargo Tracking

PubMed Central

Lowe, Alan R.; Siegel, Jake J.; Kalab, Petr; Siu, Merek; Weis, Karsten; Liphardt, Jan T.

2010-01-01

The Nuclear Pore Complex (NPC) mediates all exchange between the cytoplasm and the nucleus. Small molecules can passively diffuse through the NPC, while larger cargos require transport receptors to translocate1. How the NPC facilitates the translocation of transport receptor/cargo complexes remains unclear. Here, we track single protein-functionalized Quantum Dot (QD) cargos as they translocate the NPC. Import proceeds by successive sub-steps comprising cargo capture, filtering and translocation, and release into the nucleus. The majority of QDs are rejected at one of these steps and return to the cytoplasm including very large cargos that abort at a size-selective barrier. Cargo movement in the central channel is subdiffusive and cargos that can bind more transport receptors diffuse more freely. Without Ran, cargos still explore the entire NPC, but have a markedly reduced probability of exit into the nucleus, suggesting that NPC entry and exit steps are not equivalent and that the pore is functionally asymmetric to importing cargos. The overall selectivity of the NPC appears to arise from the cumulative action of multiple reversible sub-steps and a final irreversible exit step. PMID:20811366

Spectroscopic Research of Lambda Hypdernuclei at JLab Hall C

NASA Astrophysics Data System (ADS)

Gogami, T.; Achenbach, P.; Ahmidouch, A.; Albayrak, I.; Androic, D.; Asaturyan, A.; Asaturyan, R.; Ates, O.; Baturin, P.; Badui, R.; Boeglin, W.; Bono, J.; Brash, E.; Carter, P.; Chen, C.; Chiba, A.; Christy, E.; Dalton, M.; Danagoulian, S.; De Leo, R.; Doi, D.; Elaasar, M.; Ent, R.; Fujii, Y.; Furic, M.; Gabrielyan, M.; Gan, L.; Garibaldi, F.; Gaskell, D.; Gasparian, A.; Hashimoto, O.; Horn, T.; Hu, B.; Hungerford, Ed. V.; Jones, M.; Kanda, H.; Kaneta, M.; Kato, S.; Kawai, M.; Kawama, D.; Khanal, H.; Kohl, M.; Liyanage, A.; Luo, W.; Maeda, K.; Margaryan, A.; Markowitz, P.; Maruta, T.; Matsumura, A.; Maxwell, V.; Mkrtchyan, A.; Mkrtchyan, H.; Nagao, S.; Nakamura, S. N.; Narayan, A.; Neville, C.; Niculescu, G.; Niculescu, M. I.; Nunez, A.; Nuruzzaman; Okayasu, Y.; Petkovic, T.; Pochodzalla, J.; Qiu, X.; Reinhold, J.; Rodriguez, V. M.; Samanta, C.; Sawatzky, B.; Seva, T.; Shichijo, A.; Tadevosyan, V.; Tang, L.; Taniya, N.; Tsukada, K.; Veilleux, M.; Vulcan, W.; Wesselmann, F. R.; Wood, S. A.; Yamamoto, T.; Ya, L.; Ye, Z.; Yokota, K.; Yuan, L.; Zhamkochyan, S.; Zhu, L.

A Λ hyperon which has a strangeness can be bound in deep inside of a nucleus since a Λ does not suffer from the Pauli exclusion principle from nucleons. Thus, a Λ could be a useful tool to investigate inside of a nucleus. Since 2000, Λ hypernuclear spectroscopic experiments by the (e,e'k) reaction have been performed at the experimental hall C in Thomas Jefferson National Accelerator Facility (JLab Hall C). An experiment, JLab E05-115 was carried out to investigate Λ hypernuclei with a wide mass range (the mass number, A = 7, 9, 10, 12, 52). The latest analysis status of JLab E05-115 experiment is discussed in the present article.

Frequency response of pig intervertebral disc cells subjected to dynamic hydrostatic pressure.

PubMed

Kasra, Mehran; Merryman, W David; Loveless, Kristen N; Goel, Vijay K; Martin, James D; Buckwalter, Joseph A

2006-10-01

The pathogenesis of vibration-induced disorders of intervertebral disc at the cellular level is largely unknown. Dynamic loads with frequencies close to that of the in vivo human spine resonant frequency (4-6 Hz) have a destructive effect, which may induce extracellular disc matrix (ECM) degradation. To investigate this issue, three-dimensional (3D) alginate cultures of normal pig intervertebral disc nucleus and inner annulus cells were tested under dynamic hydrostatic loading. Alginate cultures of each region were divided into six groups; five groups were exposed to cyclic hydrostatic pressures of frequencies 1, 3, 5, 8, and 10 Hz with the same amplitude (1 MPa), and group 6 was the control group (no loading). Cultures of different groups were loaded for 3 days (30 min daily) in a hydraulic chamber. Effects of loading frequency on disc collagen and protein metabolism were investigated by measuring 3H-proline-labeled proteins associated with the cells in the extracellular matrix and release of 3H-proline-labeled molecules into culture medium. The results indicated a poor synthesis rate and more degradation near the 5 Hz frequency. The repeatability of experiments was verified by performing two experiments with the same protocol. Both experiments indicated that a threshold frequency of around 5 Hz disrupted protein metabolism. Copyright (c) 2006 Orthopaedic Research Society.

A simple polymeric model describes cell nuclear mechanical response

NASA Astrophysics Data System (ADS)

Banigan, Edward; Stephens, Andrew; Marko, John

The cell nucleus must continually resist inter- and intracellular mechanical forces, and proper mechanical response is essential to basic cell biological functions as diverse as migration, differentiation, and gene regulation. Experiments probing nuclear mechanics reveal that the nucleus stiffens under strain, leading to two characteristic regimes of force response. This behavior depends sensitively on the intermediate filament protein lamin A, which comprises the outer layer of the nucleus, and the properties of the chromatin interior. To understand these mechanics, we study a simulation model of a polymeric shell encapsulating a semiflexible polymer. This minimalistic model qualitatively captures the typical experimental nuclear force-extension relation and observed nuclear morphologies. Using a Flory-like theory, we explain the simulation results and mathematically estimate the force-extension relation. The model and experiments suggest that chromatin organization is a dominant contributor to nuclear mechanics, while the lamina protects cell nuclei from large deformations.

Elucidation of the anatomy of a satiety network: Focus on connectivity of the parabrachial nucleus in the adult rat.

PubMed

Zséli, Györgyi; Vida, Barbara; Martinez, Anais; Lechan, Ronald M; Khan, Arshad M; Fekete, Csaba

2016-10-01

We hypothesized that brain regions showing neuronal activation after refeeding comprise major nodes in a satiety network, and tested this hypothesis with two sets of experiments. Detailed c-Fos mapping comparing fasted and refed rats was performed to identify candidate nodes of the satiety network. In addition to well-known feeding-related brain regions such as the arcuate, dorsomedial, and paraventricular hypothalamic nuclei, lateral hypothalamic area, parabrachial nucleus (PB), nucleus of the solitary tract and central amygdalar nucleus, other refeeding activated regions were also identified, such as the parastrial and parasubthalamic nuclei. To begin to understand the connectivity of the satiety network, the interconnectivity of PB with other refeeding-activated neuronal groups was studied following administration of anterograde or retrograde tracers into the PB. After allowing for tracer transport time, the animals were fasted and then refed before sacrifice. Refeeding-activated neurons that project to the PB were found in the agranular insular area; bed nuclei of terminal stria; anterior hypothalamic area; arcuate, paraventricular, and dorsomedial hypothalamic nuclei; lateral hypothalamic area; parasubthalamic nucleus; central amygdalar nucleus; area postrema; and nucleus of the solitary tract. Axons originating from the PB were observed to closely associate with refeeding-activated neurons in the agranular insular area; bed nuclei of terminal stria; anterior hypothalamus; paraventricular, arcuate, and dorsomedial hypothalamic nuclei; lateral hypothalamic area; central amygdalar nucleus; parasubthalamic nucleus; ventral posterior thalamic nucleus; area postrema; and nucleus of the solitary tract. These data indicate that the PB has bidirectional connections with most refeeding-activated neuronal groups, suggesting that short-loop feedback circuits exist in this satiety network. J. Comp. Neurol. 524:2803-2827, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Social defeat in adolescent mice increases vulnerability to alcohol consumption.

PubMed

Rodriguez-Arias, Marta; Navarrete, Francisco; Blanco-Gandia, Maria Carmen; Arenas, Maria Carmen; Bartoll-Andrés, Adrián; Aguilar, Maria A; Rubio, Gabriel; Miñarro, José; Manzanares, Jorge

2016-01-01

This study employs an oral operant conditioning paradigm to evaluate the effects of repeated social defeat during adolescence on the reinforcing and motivational actions of ethanol in adult OF1 mice. Social interaction, emotional and cognitive behavioral aspects were also analyzed, and real-time polymerase chain reaction (PCR) experiments were performed to study gene expression changes in the mesocorticolimbic and hypothalamus-hypophysis-adrenal (HHA) axis. Social defeat did not alter anxiety-like behavior in the elevated plus maze or cognitive performance in the passive avoidance and Hebb-Williams tests. A social interaction test revealed depression-like symptoms and social subordination behavior in defeated OF1 mice. Interestingly, social defeat in adolescence significantly increased the number of effective responses, ethanol consumption values and motivation to drink. Finally, real-time PCR analyses revealed that social defeat significantly increased tyrosine hydroxylase and corticotropin-releasing hormone in the ventral tegmental area and paraventricular nucleus, respectively. In contrast, mu-opioid receptor gene expression was decreased in the nucleus accumbens of socially defeated mice. In summary, these findings suggest that exposure to social defeat during adolescence increases vulnerability to the rewarding effects of ethanol without affecting emotional or cognitive performance. The gene expression alterations we have observed in the mesocorticolimbic and HHA axis systems of defeated mice could be related with their increased ethanol consumption. These results endorse future research into pharmacological strategies that modulate these systems for the treatment of social stress-related alcohol consumption problems. © 2014 Society for the Study of Addiction.

Central administration of the anorexigenic peptide neuromedin U decreases alcohol intake and attenuates alcohol-induced reward in rodents.

PubMed

Vallöf, Daniel; Ulenius, Lisa; Egecioglu, Emil; Engel, Jörgen A; Jerlhag, Elisabet

2017-05-01

By investigating the neurochemical mechanisms through which alcohol activates the brain reward systems, novel treatment strategies for alcohol use disorder (AUD), a chronic relapsing disease, can be developed. In contrast to the common view of the function of gut-brain peptides, such as neuromedin U (NMU), to regulate food intake and appetite, a novel role in reinforcement mediation has been implied. The anorexigenic effects of NMU are mediated via NMU2 receptors, preferably in the arcuate nucleus and paraventricular nucleus. The expression of NMU2 receptors is also expressed in several reward-related areas in the brain, suggesting a role in reward regulation. The present experiments were therefore set up to investigate the effect of intracerebroventricular administration of NMU on alcohol-mediated behaviors in rodents. We found that central administration of NMU attenuated alcohol-induced locomotor stimulation, accumbal dopamine release and the expression of conditioned place preference in mice. In addition, NMU dose dependently decreased alcohol intake in high, but not in low, alcohol-consuming rats. Central NMU administration did not alter the blood alcohol concentrations nor change the corticosterone levels in rodents. Given that AUD is a major health-care challenge causing an enormous cost to society and novel treatment strategies are warranted, our data suggest that NMU analogues deserve to be evaluated as novel treatment of AUD in humans. © 2016 The Authors Addiction Biology published by John Wiley & Sons Ltd.

Modulating dopamine release by optogenetics in transgenic mice reveals terminal dopaminergic dynamics

PubMed Central

Lu, Yao; Driscoll, Nicolette; Ozden, Ilker; Yu, Zeyang; Nurmikko, Arto V.

2015-01-01

Abstract. Dopamine (DA) release and uptake dynamics in the nucleus accumbens (NAc) have important implications for neurological diseases and mammalian animal behaviors. We demonstrate here the use of cell-type-specific optogenetic targeting in conjunction with fast-scan cyclic voltammetry applied to brain slices prepared from specifically tailored transgenic mice, which conditionally express channelrhodopsin-2 (ChR2) through dopamine transporter (DAT)-Cre. Terminal dopaminergic dynamics and the direct manipulation of induced DA release level by controlling light intensity, pulse width, and the shape of stimulation waveforms were studied. Effective cell terminal-targeting optogenetic induction of DA release at physiological levels in NAc is demonstrated and discussed. It was found that delivering more light energy by increasing stimulation intensity and length is not the only way to control DA release; the temporal shape of the stimulus waveform at light onset is also critically related to induced DA concentrations. In addition, DA uptake dynamics as well as the recovery of the presynaptic releasable DA pool are studied and modeled. More broadly, our experimental findings provide important further evidence for effectively applying optogenetics to induce neurotransmitter release in the behaviorally relevant region of the brain in a highly cell-type selective context. PMID:26171413

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.

From the Vega mission to comet Halley to the Rosetta mission to comet 67/P Churyumov-Gerasimenko

NASA Astrophysics Data System (ADS)

Zelenyi, L. M.; Ksanfomality, L. V.

2016-12-01

The data acquired by the Vega and Giotto spacecraft, while investigating comet 1P/Halley in 1986, are compared to the results of the first phase of exploration of the nucleus of comet 67P/Churyumov-Gerasimenko performed with the Rosetta and Philae modules. The course of the Rosetta mission activity and the status of the modules after the Philae probe landing on the comet's nucleus are overviewed. Since some elements of the touchdown equipment failed, a number of in-situ experiments on the comet's nucleus were not carried out.

Red nucleus and rubrospinal tract disorganization in the absence of Pou4f1

PubMed Central

Martinez-Lopez, Jesus E.; Moreno-Bravo, Juan A.; Madrigal, M. Pilar; Martinez, Salvador; Puelles, Eduardo

2015-01-01

The red nucleus (RN) is a neuronal population that plays an important role in forelimb motor control and locomotion. Histologically it is subdivided into two subpopulations, the parvocellular RN (pRN) located in the diencephalon and the magnocellular RN (mRN) in the mesencephalon. The RN integrates signals from motor cortex and cerebellum and projects to spinal cord interneurons and motor neurons through the rubrospinal tract (RST). Pou4f1 is a transcription factor highly expressed in this nucleus that has been related to its specification. Here we profoundly analyzed consequences of Pou4f1 loss-of-function in development, maturation and axonal projection of the RN. Surprisingly, RN neurons are specified and maintained in the mutant, no cell death was detected. Nevertheless, the nucleus appeared disorganized with a strong delay in radial migration and with a wider neuronal distribution; the neurons did not form a compacted population as they do in controls, Robo1 and Slit2 were miss-expressed. Cplx1 and Npas1, expressed in the RN, are transcription factors involved in neurotransmitter release, neuronal maturation and motor function processes among others. In our mutant mice, both transcription factors are lost, suggesting an abnormal maturation of the RN. The resulting altered nucleus occupied a wider territory. Finally, we examined RST development and found that the RN neurons were able to project to the spinal cord but their axons appeared defasciculated. These data suggest that Pou4f1 is necessary for the maturation of RN neurons but not for their specification and maintenance. PMID:25698939

Nucleus incertus inactivation impairs spatial learning and memory in rats.

PubMed

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

2015-02-01

Nucleus incertus (NI) is a pontine nucleus which releases mainly GABA and relaxin-3 in rats. Its suggested functions include response to stress, arousal, and modulation of hippocampal theta rhythm. Since the role of NI in learning and memory has not been well characterized, therefore the involvement of this nucleus in spatial learning and memory and the aftermath hippocampal levels of c-fos and pCREB were evaluated. NI was targeted by implanting cannula in male rats. For reference memory, NI was inactivated by lidocaine (0.4 μl, 4%) at three stages of acquisition, consolidation and retrieval in Morris water maze paradigm. For working memory, NI was inactivated in acquisition and retrieval phases. Injection of lidocaine prior to the first training session of reference memory significantly increased the distance moved, suggesting that inactivation of NI delays acquisition in this spatial task. Inactivation also interfered with the retrieval phase of spatial reference memory, as the time in target quadrant for lidocaine group was less, and the escape latency was higher compared to the control group. However, no difference was observed in the consolidation phase. In the working memory task, with inter-trial intervals of 75 min, the escape latency was higher when NI was inactivated in the retrieval phase. In addition, c-fos and pCREB/CREB levels decreased in NI-inhibited rats. This study suggests that nucleus incertus might participate in acquisition of spatial reference, and retrieval of both spatial reference and working memory. Further studies should investigate possible roles of NI in the hippocampal plasticity. Copyright © 2014 Elsevier Inc. All rights reserved.

A short‐term extremely low frequency electromagnetic field exposure increases circulating leukocyte numbers and affects HPA‐axis signaling in mice

PubMed Central

de Kleijn, Stan; Ferwerda, Gerben; Wiese, Michelle; Trentelman, Jos; Cuppen, Jan; Kozicz, Tamas; de Jager, Linda; Hermans, Peter W. M.

2016-01-01

There is still uncertainty whether extremely low frequency electromagnetic fields (ELF‐EMF) can induce health effects like immunomodulation. Despite evidence obtained in vitro, an unambiguous association has not yet been established in vivo. Here, mice were exposed to ELF‐EMF for 1, 4, and 24 h/day in a short‐term (1 week) and long‐term (15 weeks) set‐up to investigate whole body effects on the level of stress regulation and immune response. ELF‐EMF signal contained multiple frequencies (20–5000 Hz) and a magnetic flux density of 10 μT. After exposure, blood was analyzed for leukocyte numbers (short‐term and long‐term) and adrenocorticotropic hormone concentration (short‐term only). Furthermore, in the short‐term experiment, stress‐related parameters, corticotropin‐releasing hormone, proopiomelanocortin (POMC) and CYP11A1 gene‐expression, respectively, were determined in the hypothalamic paraventricular nucleus, pituitary, and adrenal glands. In the short‐term but not long‐term experiment, leukocyte counts were significantly higher in the 24 h‐exposed group compared with controls, mainly represented by increased neutrophils and CD4 ± lymphocytes. POMC expression and plasma adrenocorticotropic hormone were significantly lower compared with unexposed control mice. In conclusion, short‐term ELF‐EMF exposure may affect hypothalamic‐pituitary‐adrenal axis activation in mice. Changes in stress hormone release may explain changes in circulating leukocyte numbers and composition. Bioelectromagnetics. 37:433–443, 2016. © 2016 The Authors. Bioelectromagnetics Published by Wiley Periodicals, Inc. PMID:27553635

Effects of Nucleus Basalis Magnocellularis Stimulation on a Socially Transmitted Food Preference and c-Fos Expression

ERIC Educational Resources Information Center

Boix-Trelis, Nuria; Vale-Martinez, Anna; Guillazo-Blanch, Gemma; Costa-Miserachs, David; Marti-Nicolovius, Margarita

2006-01-01

Experiment 1 examined the effects of electrical stimulation of nucleus basalis magnocellularis (NBM) on a relational odor-association task--the social transmission of food preference (STFP). Rats were stimulated unilaterally in the NBM for 20 min (100 [mu]A, 1 Hz) immediately before the social training. They were tested on their ability to…

The Atom in a Molecule: Implications for Molecular Structure and Properties

DTIC Science & Technology

2016-05-23

unlimited. PA Clearance #16075.” Atomic- Product Representations of Molecules Employ “van der Waals” products of atomic states to represent molecules...representation the electrons “stay home” with each nucleus. Atomic fragment operators are well-defined over product representations. Expectation values of...release; distribution unlimited. PA Clearance #16075.” Hamiltonian Matrix in the Atomic- Product Basis Technical Questions Addressed: J. Chem. Phys

The Maryland Large-Scale Integrated Neurocognitive Architecture

DTIC Science & Technology

2008-03-01

Visual input enters the network through the lateral geniculate nucleus (LGN) and is passed forward through visual brain regions (V1, V2, and V4...University of Maryland Sponsored by Defense Advanced Research Projects Agency DARPA Order No. V029 APPROVED FOR PUBLIC RELEASE...interpreted as necessarily representing the official policies, either expressed or implied, of the Defense Advanced Research Projects Agency or the U.S

Differential co-localisation of the P2X7 receptor subunit with vesicular glutamate transporters VGLUT1 and VGLUT2 in rat CNS.

PubMed

Atkinson, L; Batten, T F C; Moores, T S; Varoqui, H; Erickson, J D; Deuchars, J

2004-01-01

Presynaptic P2X(7) receptors are thought to play a role in the modulation of transmitter release and have been localised to terminals with the location and morphology typical of excitatory boutons. To test the hypothesis that this receptor is preferentially associated with excitatory terminals we combined immunohistochemistry for the P2X(7) receptor subunit (P2X(7)R) with that for two vesicular glutamate transporters (VGLUT1 and VGLUT2) in the rat CNS. This confirmed that P2X(7)R immunoreactivity (IR) is present in glutamatergic terminals; however, whether it was co-localised with VGLUT1-IR or VGLUT2-IR depended on the CNS region examined. In the spinal cord, P2X(7)R-IR co-localised with VGLUT2-IR. In the brainstem, co-localisation of P2X(7)R-IR with VGLUT2-IR was widespread, but co-localisation with VGLUT1-IR was seen only in the external cuneate nucleus and spinocerebellar tract region of the ventral medulla. In the cerebellum, P2X(7)R-IR co-localised with both VGLUT1 and VGLUT2-IR in the granular layer. In the hippocampus it was co-localised only with VGLUT1-IR, including in the polymorphic layer of the dentate gyrus and the substantia radiatum of the CA3 region. In other forebrain areas, P2X(7)R-IR co-localised with VGLUT1-IR throughout the amygdala, caudate putamen, striatum, reticular thalamic nucleus and cortex and with VGLUT2-IR in the dorsal lateral geniculate nucleus, amygdala and hypothalamus. Dual labelling studies performed using markers for cholinergic, monoaminergic, GABAergic and glycinergic terminals indicated that in certain brainstem and spinal cord nuclei the P2X(7)R is also expressed by subpopulations of cholinergic and GABAergic/glycinergic terminals. These data support our previous hypothesis that the P2X(7)R may play a role in modulating glutamate release in functionally different systems throughout the CNS but further suggest a role in modulating release of inhibitory transmitters in some regions.

Nociceptive vocalization response in guinea pigs modulated by opioidergic, GABAergic and serotonergic neurotransmission in the dorsal raphe nucleus.

PubMed

Ferreira, Mateus Dalbem; Menescal-de-Oliveira, Leda

2014-07-01

The dorsal raphe nucleus (DRN) is involved in the control of several physiological functions, including nociceptive modulation. This nucleus is one of the main sources of serotonin to the CNS and neuromodulators such as opioids and GABA may be are important for its release. This study evaluated the influence of serotonergic, GABAergic and opioidergic stimulation, as well as their interactions in the DRN, on vocalization nociceptive response during a peripheral noxious stimulus application in guinea pigs. Morphine (1.1 nmol), bicuculline (0.50 nmol) and alpha-methyl-5-HT (1.6 nmol) microinjection on the DRN produces antinociception. The antinociception produced by morphine (1.1 nmol) and alpha-methyl-5-HT (1.6 nmol) into the DRN was blocked by prior microinjection of naloxone (0.7 nmol). The alpha-methyl-5-HT effect blocked by naloxone may indicate the existence of 5-HT2A receptors on enkephalinergic interneurons within the dorsal raphe. Pretreatment with muscimol (0.26 nmol) also prevented the antinociceptive effect caused by morphine (1.1 nmol) when administered alone at the same site, indicating an interaction between GABAergic and opioidergic interneurons. The antinociception produced by bicuculline (0.5 nmol) in the DRN was blocked by prior administration of 8-OH-DPAT (0.5 nmol), a 5-HT1A agonist. This may indicate that the 5-HT autoreceptor activation by 8-OH-DPAT at DRN effector neurons can oppose the bicuculline disinhibition effect applied to the same effectors. Thus, we suggest that 5-HT2 receptor activation in the DRN promotes endorphin/enkephalin release that may disinhibit efferent serotonergic neurons of this present structure by inhibiting GABAergic interneurons, resulting in antinociception. Copyright © 2014 Elsevier Inc. All rights reserved.

The anorectic hormone amylin contributes to feeding-related changes of neuronal activity in key structures of the gut-brain axis.

PubMed

Riediger, T; Zuend, D; Becskei, C; Lutz, T A

2004-01-01

Amylin is a peptide hormone that is cosecreted with insulin from the pancreas during and after food intake. Peripherally injected amylin potently inhibits feeding by acting on the area postrema (AP), a circumventricular organ lacking a functional blood-brain barrier. We recently demonstrated that AP neurons are excited by a near physiological concentration of amylin. However, the subsequent neuronal mechanisms and the relevance of endogenously released amylin for the regulation of food intake are poorly understood. Therefore, we investigated 1) amylin's contribution to feeding-induced c-Fos expression in the rat AP and its ascending projection sites, and 2) amylin's ability to reverse fasting-induced c-Fos expression in the lateral hypothalamic area (LHA). Similar to amylin (20 microg/kg sc), refeeding of 24-h food-deprived rats induced c-Fos expression in the AP, the nucleus of the solitary tract, the lateral parabrachial nucleus, and the central nucleus of the amygdala. In AP-lesioned rats, the amylin-induced c-Fos expression in each of these sites was blunted, indicating an AP-mediated activation of these structures. Pretreatment with the amylin antagonist AC-187 (1 mg/kg sc) inhibited feeding-induced c-Fos expression in the AP. Food deprivation activated LHA neurons, a response known to be associated with hunger. This effect was reversed within 2 h after refeeding and also in nonrefed animals that received amylin. In summary, our data provide the first evidence that feeding-induced amylin release activates AP neurons projecting to subsequent relay stations known to transmit meal-related signals to the forebrain. Activation of this pathway seems to coincide with an inhibition of LHA neurons.

Physiological correlates of comodulation masking release in the mammalian ventral cochlear nucleus.

PubMed

Pressnitzer, D; Meddis, R; Delahaye, R; Winter, I M

2001-08-15

Comodulation masking release (CMR) enhances the detection of signals embedded in wideband, amplitude-modulated maskers. At least part of the CMR is attributable to across-frequency processing, however, the relative contribution of different stages in the auditory system to across-frequency processing is unknown. We have measured the responses of single units from one of the earliest stages in the ascending auditory pathway, the ventral cochlear nucleus, where across frequency processing may take place. A sinusoidally amplitude-modulated tone at the best frequency of each unit was used as a masker. A pure tone signal was added in the dips of the masker modulation (reference condition). Flanking components (FCs) were then added at frequencies remote from the unit best frequency. The FCs were pure tones amplitude modulated either in phase (comodulated) or out of phase (codeviant) with the on-frequency component. Psychophysically, this CMR paradigm reduces within-channel cues while producing an advantage of approximately 10 dB for the comodulated condition in comparison with the reference condition. Some of the recorded units showed responses consistent with perceptual CMR. The addition of the comodulated FCs produced a strong reduction in the response to the masker modulation, making the signal more salient in the poststimulus time histograms. A decision statistic based on d' showed that threshold was reached at lower signal levels for the comodulated condition than for reference or codeviant conditions. The neurons that exhibited such a behavior were mainly transient chopper or primary-like units. The results obtained from a subpopulation of transient chopper units are consistent with a possible circuit in the cochlear nucleus consisting of a wideband inhibitor contacting a narrowband cell. A computational model was used to confirm the feasibility of such a circuit.

Hypothalamic supraoptic but not paraventricular nucleus is involved in cardiovascular responses to carbachol microinjected into the bed nucleus of stria terminalis of unanesthetized rats.

PubMed

Alves, Fernando H F; Crestani, Carlos C; Busnardo, Cristiane; Antunes-Rodrigues, José; Gomes, Felipe V; Resstel, Leonardo B M; Corrêa, Fernando M A

2011-06-01

Microinjection of the cholinergic agonist carbachol into the bed nucleus of the stria terminalis (BST) has been reported to cause pressor response in unanesthetized rats, which was shown to be mediated by an acute release of vasopressin into the systemic circulation and followed by baroreflex-mediated bradycardia. In the present study, we tested the possible involvement of the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei in the pressor response evoked by carbachol microinjection into the BST of unanesthetized rats. For this, cardiovascular responses following carbachol (1 nmol/100 nL) microinjection into the BST were studied before and after PVN or SON pretreatment, either ipsilateral or contralateral in relation to BST microinjection site, with the nonselective neurotransmission blocker cobalt chloride (CoCl₂, 1 mM/100 nL). Carbachol microinjection into the BST evoked pressor response. Moreover, BST treatment with carbachol significantly increased plasma vasopressin levels, thus confirming previous evidences that carbachol microinjection into the BST evokes pressor response due to vasopressin release into the circulation. SON pretreatment with CoCl₂, either ipsilateral or contralateral in relation to BST microinjection site, inhibited the pressor response to carbachol microinjection into the BST. However, CoCl₂ microinjection into the ipsilateral or contralateral PVN did not affect carbachol-evoked pressor response. In conclusion, our results suggest that pressor response to carbachol microinjection into the BST is mediated by SON magnocellular neurons, without significant involvement of those in the PVN. The results also indicate that responses to carbachol microinjection into the BST are mediated by a neural pathway that depends on the activation of both ipsilateral and contralateral SON. Copyright © 2011 Elsevier B.V. All rights reserved.

Peptides and neurotransmitters that affect renin secretion

NASA Technical Reports Server (NTRS)

Ganong, W. F.; Porter, J. P.; Bahnson, T. D.; Said, S. I.

1984-01-01

Substance P inhibits renin secretion. This polypeptide is a transmitter in primary afferent neurons and is released from the peripheral as well as the central portions of these neurons. It is present in afferent nerves from the kidneys. Neuropeptide Y, which is a cotransmitter with norepinephrine and epinephrine, is found in sympathetic neurons that are closely associated with and presumably innervate the juxtagolmerular cells. Its effect on renin secretion is unknown, but it produces renal vasoconstriction and natriuresis. Vasoactive intestinal polypeptide (VIP) is a cotransmitter with acetylocholine in cholinergic neurons, and this polypeptide stimulates renin secretion. We cannot find any evidence for its occurence in neurons in the kidneys, but various stimuli increase plasma VIP to levels comparable to those produced by doses of exogenous VIP which stimulated renin secretion. Neostigmine increases plasma VIP and plasma renin activity, and the VIP appears to be responsible for the increase in renin secretion, since the increase is not blocked by renal denervation or propranolol. Stimulation of various areas in the brain produces sympathetically mediated increases in plasma renin activity associated with increases in blood pressure. However, there is pharmacological evidence that the renin response can be separated from the blood pressure response. In anaesthetized dogs, drugs that increase central serotonergic discharge increase renin secretion without increasing blood pressure. In rats, activation of sertonergic neurons in the dorsal raphe nucleus increases renin secretion by a pathway that projects from this nucleus to the ventral hypothalamus, and from there to the kidneys via the sympathetic nervous system. The serotonin releasing drug parachloramphetamine also increases plasma VIP, but VIP does not appear to be the primary mediator of the renin response. There is preliminary evidence that the serotonergic neurons in the dorsal raphe nucleus are part of the pathway by which psychosocial stimuli increase renin secretion.

Pair production in classical Stueckelberg-Horwitz-Piron electrodynamics

NASA Astrophysics Data System (ADS)

Land, Martin

2015-05-01

We calculate pair production from bremsstrahlung as a classical effect in Stueckelberg-Horwitz electrodynamics. In this framework, worldlines are traced out dynamically through the evolution of events xμ(τ) parameterized by a chronological time τ that is independent of the spacetime coordinates. These events, defined in an unconstrained 8D phase space, interact through five τ-dependent gauge fields induced by the event evolution. The resulting theory differs in its underlying mechanics from conventional electromagnetism, but coincides with Maxwell theory in an equilibrium limit. In particular, the total mass-energy-momentum of particles and fields is conserved, but the mass-shell constraint is lifted from individual interacting events, so that the Feynman-Stueckelberg interpretation of pair creation/annihilation is implemented in classical mechanics. We consider a three-stage interaction which when parameterized by the laboratory clock x0 appears as (1) particle-1 scatters on a heavy nucleus to produce bremsstrahlung, (2) the radiation field produces a particle/antiparticle pair, (3) the antiparticle is annihilated with particle-2 in the presence of a second heavy nucleus. When parameterized in chronological time τ, the underlying process develops as (1) particle-2 scatters on the second nucleus and begins evolving backward in time with negative energy, (2) particle-1 scatters on the first nucleus and releases bremsstrahlung, (3) particle-2 absorbs radiation which returns it to forward time evolution with positive energy.

The nucleus parvocellularis reticularis regulates submandibular-sublingual salivary secretion in the rat: a pharmacological study.

PubMed

Ramos, J M; Puerto, A

1988-09-01

This experiment shows that activation of the nucleus parvocellularis reticularis in the rat brainstem provokes salivary hypersecretion by the submandibular-sublingual glands. The secretory effect is mediated by cholinergic mechanisms, as the administration of atropine blocked the flow of saliva evoked by stimulation of the nucleus parvocellularis. In contrast, injection of dihydroergotamine (an alpha-blocker) and/or propranolol (a beta-blocker) failed to significantly reduce submandibular and sublingual salivary secretion when compared to a control group injected with distilled water. The cholinergic nature of the salivary response suggests that the nucleus parvocellularis reticularis exerts its secretory effect on the salivary glands parasympathetically rather than through mechanisms associated with sympathetic pathways. The area of the brainstem activated in the present study closely overlaps the region in which cell bodies of superior salivatory neurons have recently been identified with retrograde transport of peroxidase. The data presented herein represent functional proof in support of the location of the superior salivatory nucleus within the parvocellularis reticular formation.

Spectroscopic Research of Lambda Hypdernuclei at JLab Hall C

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gogami, Toshiyuki; et. al.,

2014-03-01

A Lambda hyperon which has a strangeness can be bound in deep inside of a nucleus since a Λ does not suffer from the Pauli exclusion principle from nucleons. Thus, a Λ could be a useful tool to investigate inside of a nucleus. Since 2000, Lambda hypernuclear spectroscopic experiments by the (e,e'k) reaction have been performed at the experimental hall C in Thomas Jefferson National Accelerator Facility (JLab Hall C). An experiment, JLab E05-115 was carried out to investigate Lambda hypernuclei with a wide mass range (the mass number, A = 7, 9, 10, 12, 52). The latest analysis statusmore » of JLab E05-115 experiment is discussed in the present article.« less

Subjective effects of slow-release bupropion versus caffeine as determined in a quasi-naturalistic setting.

PubMed

Zernig, Gerald; De Wit, Harriet; Telser, Stefan; Nienhusmeier, Matthias; Wakonigg, Gudrun; Sturm, Katja; Berger, Iris; Kemmler, Georg; Saria, Alois

2004-04-01

Bupropion (BUP), which in its slow-release formulation (Zyban) is used as a smoking-cessation drug, increases dopamine overflow in the nucleus accumbens and serves as a reinforcer in animal experiments, both suggesting that BUP may possess some abuse liability. The present study examined if BUP produced subjective effects indicative of abuse liability in a quasi-naturalistic setting, with caffeine (CAF) serving as a positive control. In a randomized double-blind crossover design, male smokers (n = 50) ingested two doses (interdosing interval, 6 h) of placebo (PLC), 178 mg CAF, or 150 mg slow-release BUP in their normal mid-week work environment. They completed questionnaires administered by telephone at regular intervals. CAF significantly increased ratings of 'pleasant effects' (p = 0.008) and 'high' (p = 0.03), whereas BUP produced a 'high' of only very moderate size (p = 0.02). In 3 subjects each, BUP or CAF produced ratings of 'pleasant effects' that were >9-fold higher than those for PLC. Finally, BUP increased the number of cigarettes smoked by 29% (i.e., from 24 to 31 per day; p = 0.004) only in those subjects who were unable to report any effect of either BUP or CAF. CAF had no effect on cigarette consumption. These findings suggest that BUP, like CAF, might be of some abuse liability in a small subgroup of smokers (i.e., 6% each of the present sample), and it may transiently increase, rather than decrease, smoking during early phases of treatment in continuing smokers. Copyright 2004 S. Karger AG, Basel

Action at a Distance in the Cell's Nucleus

NASA Astrophysics Data System (ADS)

Kondev, Jane

Various functions performed by chromosomes involve long-range communication between DNA sequences that are tens of thousands of bases apart along the genome, and microns apart in the nucleus. In this talk I will discuss experiments and theory relating to two distinct modes of long-range communication in the nucleus, chromosome looping and protein hopping along the chromosome, both in the context of DNA-break repair in yeast. Yeast is an excellent model system for studies that link chromosome conformations to their function as there is ample experimental evidence that yeast chromosome conformations are well described by a simple, random-walk polymer model. Using a combination of polymer physics theory and experiments on yeast cells, I will demonstrate that loss of polymer entropy due to chromosome looping is the driving force for homology search during repair of broken DNA by homologous recombination. I will also discuss the spread of histone modifications along the chromosome and away from the DNA break point in the context of simple physics models based on chromosome looping and kinase hopping, and show how combining physics theory and cell-biology experiment can be used to dissect the molecular mechanism of the spreading process. These examples demonstrate how combined theoretical and experimental studies can reveal physical principles of long-range communication in the nucleus, which play important roles in regulation of gene expression, DNA recombination, and chromatin modification. This work was supported by the NSF DMR-1206146.

Comparison of Hi-C results using in-solution versus in-nucleus ligation.

PubMed

Nagano, Takashi; Várnai, Csilla; Schoenfelder, Stefan; Javierre, Biola-Maria; Wingett, Steven W; Fraser, Peter

2015-08-26

Chromosome conformation capture and various derivative methods such as 4C, 5C and Hi-C have emerged as standard tools to analyze the three-dimensional organization of the genome in the nucleus. These methods employ ligation of diluted cross-linked chromatin complexes, intended to favor proximity-dependent, intra-complex ligation. During development of single-cell Hi-C, we devised an alternative Hi-C protocol with ligation in preserved nuclei rather than in solution. Here we directly compare Hi-C methods employing in-nucleus ligation with the standard in-solution ligation. We show in-nucleus ligation results in consistently lower levels of inter-chromosomal contacts. Through chromatin mixing experiments we show that a significantly large fraction of inter-chromosomal contacts are the result of spurious ligation events formed during in-solution ligation. In-nucleus ligation significantly reduces this source of experimental noise, and results in improved reproducibility between replicates. We also find that in-nucleus ligation eliminates restriction fragment length bias found with in-solution ligation. These improvements result in greater reproducibility of long-range intra-chromosomal and inter-chromosomal contacts, as well as enhanced detection of structural features such as topologically associated domain boundaries. We conclude that in-nucleus ligation captures chromatin interactions more consistently over a wider range of distances, and significantly reduces both experimental noise and bias. In-nucleus ligation creates higher quality Hi-C libraries while simplifying the experimental procedure. We suggest that the entire range of 3C applications are likely to show similar benefits from in-nucleus ligation.

Pure uptake blockers of dopamine can reduce prolactin secretion: studies with diclofensine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Di Renzo, G.; Amoroso, S.; Taglialatela, M.

1988-01-01

The effects of diclofensine, a pure dopamine (DA) uptake inhibitor on 1) /sup 3/H-DA uptake in rat arcuate-periventricular nucleus-median eminence synaptosomes, 2) basal and K+-evoked endogenous DA release from tuberoinfundibular dopaminergic (TIDA) neurons and 3) in vivo prolactin (PRL) secretion were studied. Diclofensine, in concentrations of 0.01, 0.1 and 1 ..mu..M caused a marked decrease of /sup 3/H-DA uptake. In addition, it was unable to stimulate basal endogenous DA release which, on the contrary, was elicited by d-amphetamine in the same concentration. On the other hand, diclofensine caused a 3 fold enhancement on K+-evoked DA release. Finally, the compound, whenmore » administered in vivo to male rats, significantly reduced basal serum PRL levels. The results of the present study seem to indicate that the pharmacological blockade of DA uptake in TIDA neurons is a condition sufficient to cause a reduction of PRL release.« less

Dynamic NETosis is Carried Out by Live Neutrophils in Human and Mouse Bacterial Abscesses and During Severe Gram-Positive Infection

PubMed Central

Yipp, Bryan G.; Petri, Björn; Salina, Davide; Jenne, Craig N.; Scott, Brittney N. V.; Zbytnuik, Lori D.; Pittman, Keir; Asaduzzaman, Muhammad; Wu, Kaiyu; Meijndert, H. Christopher; Malawista, Stephen E.; de Boisfleury Chevance, Anne; Zhang, Kunyan; Conly, John; Kubes, Paul

2013-01-01

Neutrophil extracellular traps (NETs) are released, as neutrophils die in vitro, in a process requiring hours, leaving a temporal gap for invasive microbes to exploit. Functional neutrophils undergoing NETosis have not been documented. During Gram-positive skin infections, we directly visualized live PMN in vivo rapidly releasing NETs, which prevented bacterial dissemination. NETosis occurred during crawling thereby casting large areas of NETs. NET-releasing PMN developed diffuse decondensed nuclei ultimately becoming devoid of DNA. Cells with abnormal nuclei displayed unusual crawling behavior highlighted by erratic pseudopods and hyperpolarization consistent with the nucleus being a fulcrum for crawling. A combined requirement of Tlr2 and complement mediated opsonization tightly regulated NET release. Additionally live human PMN developed decondensed nuclei and formed NETS in vivo and intact anuclear neutrophils were abundant in Gram-positive human abscesses. Therefore early in infection, non-cell death NETosis occurs in vivo during Gram-positive infection in mice and humans. PMID:22922410

The behavioral effects of the destruction of the magnocellular basal nucleus of the forebrain of cats.

PubMed

Nabieva, T N

1993-01-01

Behavioral experiments were carried out in cats following methodology which simulates complexly organized, nonautomatized behavior with elements of generalization and abstraction. A conclusion was reached regarding the participation of this formation in the structural-functional support of complex integrative forms of activity, cognitive and gnostic processes, was reached on the basis of the results of the performance of test tasks by the animals with partial destruction of the magnocellular basal nucleus. The proposed mechanism of the involvement of the basal nucleus in gnostic and cognitive processes is the nonspecific support of the system of structures which participate directly in thinking and learning.

PHENIX Measurements of Heavy Flavor in Small Systems

NASA Astrophysics Data System (ADS)

Lebedev, Alexandre

2018-01-01

The study of heavy flavor production in proton-nucleus and nucleus-nucleus collisions is a sensitive probe of the hot and dense matter created in such collisions. Installation of silicon vertex detectors in the PHENIX experiment, and increased performance of the BNL RHIC collider allowed collection of large amount of data on heavy flavor production in small colliding systems. In this talk we will present recent PHENIX results on open heavy flavor and quarkonia production in p+p, p+A, d+A, and He3+A colliding systems in a broad rapidity range, and discuss how these measurements help us to better understand all stages of nuclear collisions at high energy.

Loss of hypothalamic corticotropin-releasing hormone markedly reduces anxiety behaviors in mice.

PubMed

Zhang, R; Asai, M; Mahoney, C E; Joachim, M; Shen, Y; Gunner, G; Majzoub, J A

2017-05-01

A long-standing paradigm posits that hypothalamic corticotropin-releasing hormone (CRH) regulates neuroendocrine functions such as adrenal glucocorticoid release, whereas extra-hypothalamic CRH has a key role in stressor-triggered behaviors. Here we report that hypothalamus-specific Crh knockout mice (Sim1CrhKO mice, created by crossing Crhflox with Sim1Cre mice) have absent Crh mRNA and peptide mainly in the paraventricular nucleus of the hypothalamus (PVH) but preserved Crh expression in other brain regions including amygdala and cerebral cortex. As expected, Sim1CrhKO mice exhibit adrenal atrophy as well as decreased basal, diurnal and stressor-stimulated plasma corticosterone secretion and basal plasma adrenocorticotropic hormone, but surprisingly, have a profound anxiolytic phenotype when evaluated using multiple stressors including open-field, elevated plus maze, holeboard, light-dark box and novel object recognition task. Restoring plasma corticosterone did not reverse the anxiolytic phenotype of Sim1CrhKO mice. Crh-Cre driver mice revealed that PVHCrh fibers project abundantly to cingulate cortex and the nucleus accumbens shell, and moderately to medial amygdala, locus coeruleus and solitary tract, consistent with the existence of PVHCrh-dependent behavioral pathways. Although previous, nonselective attenuation of CRH production or action, genetically in mice and pharmacologically in humans, respectively, has not produced the anticipated anxiolytic effects, our data show that targeted interference specifically with hypothalamic Crh expression results in anxiolysis. Our data identify neurons that express both Sim1 and Crh as a cellular entry point into the study of CRH-mediated, anxiety-like behaviors and their therapeutic attenuation.

Activation of Supraoptic Oxytocin Neurons by Secretin Facilitates Social Recognition.

PubMed

Takayanagi, Yuki; Yoshida, Masahide; Takashima, Akihide; Takanami, Keiko; Yoshida, Shoma; Nishimori, Katsuhiko; Nishijima, Ichiko; Sakamoto, Hirotaka; Yamagata, Takanori; Onaka, Tatsushi

2017-02-01

Social recognition underlies social behavior in animals, and patients with psychiatric disorders associated with social deficits show abnormalities in social recognition. Oxytocin is implicated in social behavior and has received attention as an effective treatment for sociobehavioral deficits. Secretin receptor-deficient mice show deficits in social behavior. The relationship between oxytocin and secretin concerning social behavior remains to be determined. Expression of c-Fos in oxytocin neurons and release of oxytocin from their dendrites after secretin application were investigated. Social recognition was examined after intracerebroventricular or local injection of secretin, oxytocin, or an oxytocin receptor antagonist in rats, oxytocin receptor-deficient mice, and secretin receptor-deficient mice. Electron and light microscopic immunohistochemical analysis was also performed to determine whether oxytocin neurons extend their dendrites into the medial amygdala. Supraoptic oxytocin neurons expressed the secretin receptor. Secretin activated supraoptic oxytocin neurons and facilitated oxytocin release from dendrites. Secretin increased acquisition of social recognition in an oxytocin receptor-dependent manner. Local application of secretin into the supraoptic nucleus facilitated social recognition, and this facilitation was blocked by an oxytocin receptor antagonist injected into, but not outside of, the medial amygdala. In the medial amygdala, dendrite-like thick oxytocin processes were found to extend from the supraoptic nucleus. Furthermore, oxytocin treatment restored deficits of social recognition in secretin receptor-deficient mice. The results of our study demonstrate that secretin-induced dendritic oxytocin release from supraoptic neurons enhances social recognition. The newly defined secretin-oxytocin system may lead to a possible treatment for social deficits. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Loss of hypothalamic corticotropin-releasing hormone markedly reduces anxiety behaviors in mice

PubMed Central

Zhang, Rong; Asai, Masato; Mahoney, Carrie E; Joachim, Maria; Shen, Yuan; Gunner, Georgia; Majzoub, Joseph A

2016-01-01

A long-standing paradigm posits that hypothalamic corticotropin-releasing hormone (CRH) regulates neuroendocrine functions such as adrenal glucocorticoid release, while extra-hypothalamic CRH plays a key role in stressor-triggered behaviors. Here we report that hypothalamus-specific Crh knockout mice (Sim1CrhKO mice, created by crossing Crhflox with Sim1Cre mice) have absent Crh mRNA and peptide mainly in the paraventricular nucleus of the hypothalamus (PVH) but preserved Crh expression in other brain regions including amygdala and cerebral cortex. As expected, Sim1CrhKO mice exhibit adrenal atrophy as well as decreased basal, diurnal and stressor-stimulated plasma corticosterone secretion and basal plasma ACTH, but surprisingly, have a profound anxiolytic phenotype when evaluated using multiple stressors including open field, elevated plus maze, holeboard, light-dark box, and novel object recognition task. Restoring plasma corticosterone did not reverse the anxiolytic phenotype of Sim1CrhKO mice. Crh-Cre driver mice revealed that PVHCrh fibers project abundantly to cingulate cortex and the nucleus accumbens shell, and moderately to medial amygdala, locus coeruleus, and solitary tract, consistent with the existence of PVHCrh-dependent behavioral pathways. Although previous, nonselective attenuation of CRH production or action, genetically in mice and pharmacologically in humans, respectively, has not produced the anticipated anxiolytic effects, our data show that targeted interference specifically with hypothalamic Crh expression results in anxiolysis. Our data identify neurons that express both Sim1 and Crh as a cellular entry point into the study of CRH-mediated, anxiety-like behaviors and their therapeutic attenuation. PMID:27595593

Involvement of Prolactin-Releasing Peptide in the Activation of Oxytocin Neurones in Response to Food Intake

PubMed Central

Yamashita, M; Takayanagi, Y; Yoshida, M; Nishimori, K; Kusama, M; Onaka, T

2013-01-01

Food intake activates neurones expressing prolactin-releasing peptide (PrRP) in the medulla oblongata and oxytocin neurones in the hypothalamus. Both PrRP and oxytocin have been shown to have an anorexic action. In the present study, we investigated whether the activation of oxytocin neurones following food intake is mediated by PrRP. We first examined the expression of PrRP receptors (also known as GPR10) in rats. Immunoreactivity of PrRP receptors was observed in oxytocin neurones and in vasopressin neurones in the paraventricular and supraoptic nuclei of the hypothalamus and in the bed nucleus of the stria terminalis. Application of PrRP to isolated supraoptic nuclei facilitated the release of oxytocin and vasopressin. In mice, re-feeding increased the expression of Fos protein in oxytocin neurones of the hypothalamus and bed nucleus of the stria terminalis. The increased expression of Fos protein in oxytocin neurones following re-feeding or i.p. administration of cholecystokinin octapeptide (CCK), a peripheral satiety factor, was impaired in PrRP-deficient mice. CCK-induced oxytocin increase in plasma was also impaired in PrRP-deficient mice. Furthermore, oxytocin receptor-deficient mice showed an increased meal size, as reported in PrRP-deficient mice and in CCKA receptor-deficient mice. These findings suggest that PrRP mediates, at least in part, the activation of oxytocin neurones in response to food intake, and that the CCK–PrRP–oxytocin pathway plays an important role in the control of the termination of each meal. PMID:23363338

GOTHiC, a probabilistic model to resolve complex biases and to identify real interactions in Hi-C data.

PubMed

Mifsud, Borbala; Martincorena, Inigo; Darbo, Elodie; Sugar, Robert; Schoenfelder, Stefan; Fraser, Peter; Luscombe, Nicholas M

2017-01-01

Hi-C is one of the main methods for investigating spatial co-localisation of DNA in the nucleus. However, the raw sequencing data obtained from Hi-C experiments suffer from large biases and spurious contacts, making it difficult to identify true interactions. Existing methods use complex models to account for biases and do not provide a significance threshold for detecting interactions. Here we introduce a simple binomial probabilistic model that resolves complex biases and distinguishes between true and false interactions. The model corrects biases of known and unknown origin and yields a p-value for each interaction, providing a reliable threshold based on significance. We demonstrate this experimentally by testing the method against a random ligation dataset. Our method outperforms previous methods and provides a statistical framework for further data analysis, such as comparisons of Hi-C interactions between different conditions. GOTHiC is available as a BioConductor package (http://www.bioconductor.org/packages/release/bioc/html/GOTHiC.html).

The mini-CIDEX GC/IMS: Analysis of cometary ice and dust

NASA Technical Reports Server (NTRS)

Kojiro, Daniel R.; Carle, Glenn C.; Humphry, Donald E.; Shao, Maxine; Takeuchi, Nori

1995-01-01

Comets are recognized as among the most scientifically important objects in the solar system. They are presumed relics of the early primitive material in the solar nebula and are believed to have provided a general enrichment of volatiles to the inner solar system. The Cometary Coma Chemical Composition (C4) Mission, a proposed Discovery-Class Mission, will analyze materials released into the coma, providing information leading to the understanding of the chemical composition and make-up of the cometary nucleus. As one of two scientific instruments in the C4 spacecraft, an advanced and streamlined version of the Cometary Ice and Dust Experiment (CIDEX), a mini-CIDEX, will employ an X-Ray Fluorescence (XRF) spectrometer to determine bulk elemental composition of cometary dust grains and a Gas Chromatograph/Ion Mobility Spectrometer (GC/IMS) for determination of the molecular composition of dust and ices following stepwise pyrolysis and combustion. A description of the mini-CIDEX IMS will be provided as well as data from analyses conducted using the mini-CIDEX breadboard instrument.

Membrane-tethered transcription factors provide a connection between stress response and developmental pathways

PubMed Central

Slabaugh, Erin

2011-01-01

Membrane-tethered transcription factors (MTTFs) are proteins that are targeted to membranes and are capable of regulating gene expression. In this way, they are physically restrained from entering the nucleus and are innately dormant. Upon specific signal recognition cues, MTTFs are activated through cleavage by a protease that releases the transcription factor domain into the cytosol thus allowing it to translocate to the nucleus where it can regulate gene expression. MTTFs are classically thought to provide an advantage to an organism by allowing for rapid signal transduction in response to cellular and environmental stresses. However, recent findings suggest that MTTFs may not only act as a means to respond quickly to stress but also are able to regulate developmental pathways, illustrating a point of interaction between stress and development. PMID:21758012

Efferent connections of the olfactory bulb in the opossum (Didelphis marsupialis aurita): a Fink-Heimer study.

PubMed

Shammah-Lagnado, S J; Negrão, N

1981-09-01

The efferent concentrations of the olfactory bulb (OB) in the opossum (Didelphis marsupialis aurita) were studied by the aid of the Fink-Heimer technique. Following lesions restricted to the OB, ipsilateral degenerating fibers entered the lateral olfactory tract and were treated to terminal fields essentially limited to the outer portion of the plexiform layer (sublamina IA) of the following structures: all the subdivisions of the anterior olfactory nucleus, the rostroventral tenia tecta, the full extent of the olfactory tubercle, the nucleus of the lateral olfactory tract, the anterior portion of the medial amygdaloid nucleus, the whole cortical amygdaloid nucleus (in the posteromedial subdivision of this structure the degeneration was very scanty), and the sulcal, piriform, and lateral entorhinal cortices. Some degree of topographical organization in the OB projections was noticed in the rostral portion of the lateral olfactory tract and within the external and lateral subdivisions of the anterior olfactory nucleus. In another series of experiments, when the lesion also involved the accessory olfactory bulb, heavy terminal degeneration occurred along the whole extent of the medial amygdaloid nucleus and in the posteromedial subdivision of the cortical amygdaloid nucleus. These findings indicate that, although very similar to those described in other mammals, the OB efferent connections in the opossum present some peculiarities; namely, the existence of dense terminal fields in the sulcal cortex and in the rostral district of the medial amygdaloid nucleus.

The prediction of the gas environment of the PHILAE probe during its 2014 descent to the nucleus of the comet 67P

NASA Astrophysics Data System (ADS)

Crifo, J.-F.; Zakharov, V. V.; Rodionov, A. V.; Lukyanov, G. A.

2016-11-01

One of the objectives of the ESA "ROSETTA" mission to the comet 67P was to insert, in August 2014, an orbiter probe around the so-called nucleus of the comet, and to deposit the "PHILAE" lander at the surface of the nucleus in November 2014. The selection of the landing site and the definition of the release point and initial descent velocity vector were made in the period August to October 2014 on the basis of simulations of the descent trajectory. This requested an assessment of the gravitational and aerodynamic forces on PHILAE. We here describe the so-called RZC model developed to predict the gas environment of 67P in November 2014 and compute the aerodynamic force. We first outline the unusual diffculties resulting from (1) the complexity of the nucleus surface on all scales, (2) the absence of direct measurements of the gas flux at the surface itself, (3) the time-dependence of the gas production induced by the fast nucleus rotation, (4) the need to perform the whole program within less than three months. Then we outline the physical approach adopted to overcome these diffculties, and describe the RZC model which included three differing tools: (1) a set of gasdynamic/gaskinetic codes to compute the vacuum outflow of a rarefied gas mixture from a highly aspherical rotating solid source; (2) an heuristic approach to deal with the solid/gas initial boundary conditions, and (3) an iterative procedure to derive the gas production parameters on the nucleus surface from the observational data acquired from the orbiter probe. The satisfactory operation of the RZC code in the weeks preceding the November 2014 PHILAE descent is shown, and the forecasted aerodynamic force during the PHILAE descent is compared to the gravitational force.

Picrotoxin antagonism of γ aminobutyric acid inhibitory responses and synaptic inhibition in the rat substantia nigra

PubMed Central

Crossman, A. R.; Walker, R. J.; Woodruff, G. N.

1973-01-01

Neurones in the substantia nigra of the rat, anaesthetized with urethane, are inhibited both by electrical stimulation of the ipsilateral caudate nucleus and by iontophoretically applied γ-aminobutyric acid (GABA). Iontophoretically applied picrotoxin reversibly blocks both of these inhibitory responses. These results are consistent with the hypothesis that GABA is the transmitter released by the inhibitory striato-nigral pathway. PMID:4362811

Cannabis and alcohol--a close friendship.

PubMed

Mechoulam, Raphael; Parker, Linda

2003-06-01

Cannabinoids and alcohol activate the same reward pathways, and the cannabinoid CB(1) receptor system plays an important role in regulating the positive reinforcing properties of alcohol. Indeed, both cannabinoids and alcohol cause the release of dopamine in the nucleus accumbens. Recent research suggests that ethanol preference, which is dependent on CB(1) receptors, is higher in young mice than in old mice, and higher in female mice than in male mice.

Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala.

PubMed

Marcinkiewcz, Catherine A; Mazzone, Christopher M; D'Agostino, Giuseppe; Halladay, Lindsay R; Hardaway, J Andrew; DiBerto, Jeffrey F; Navarro, Montserrat; Burnham, Nathan; Cristiano, Claudia; Dorrier, Cayce E; Tipton, Gregory J; Ramakrishnan, Charu; Kozicz, Tamas; Deisseroth, Karl; Thiele, Todd E; McElligott, Zoe A; Holmes, Andrew; Heisler, Lora K; Kash, Thomas L

2016-09-01

Serotonin (also known as 5-hydroxytryptamine (5-HT)) is a neurotransmitter that has an essential role in the regulation of emotion. However, the precise circuits have not yet been defined through which aversive states are orchestrated by 5-HT. Here we show that 5-HT from the dorsal raphe nucleus (5-HT DRN ) enhances fear and anxiety and activates a subpopulation of corticotropin-releasing factor (CRF) neurons in the bed nucleus of the stria terminalis (CRF BNST ) in mice. Specifically, 5-HT DRN projections to the BNST, via actions at 5-HT 2C receptors (5-HT 2C Rs), engage a CRF BNST inhibitory microcircuit that silences anxiolytic BNST outputs to the ventral tegmental area and lateral hypothalamus. Furthermore, we demonstrate that this CRF BNST inhibitory circuit underlies aversive behaviour following acute exposure to selective serotonin reuptake inhibitors (SSRIs). This early aversive effect is mediated via the corticotrophin-releasing factor type 1 receptor (CRF 1 R, also known as CRHR1), given that CRF 1 R antagonism is sufficient to prevent acute SSRI-induced enhancements in aversive learning. These results reveal an essential 5-HT DRN →CRF BNST circuit governing fear and anxiety, and provide a potential mechanistic explanation for the clinical observation of early adverse events to SSRI treatment in some patients with anxiety disorders.

MCT2 Expression and Lactate Influx in Anorexigenic and Orexigenic Neurons of the Arcuate Nucleus

PubMed Central

Cortes-Campos, Christian; Elizondo, Roberto; Carril, Claudio; Martínez, Fernando; Boric, Katica; Nualart, Francisco; Garcia-Robles, Maria Angeles

2013-01-01

Hypothalamic neurons of the arcuate nucleus control food intake, releasing orexigenic and anorexigenic neuropeptides in response to changes in glucose concentration. Several studies have suggested that the glucosensing mechanism is governed by a metabolic interaction between neurons and glial cells via lactate flux through monocarboxylate transporters (MCTs). Hypothalamic glial cells (tanycytes) release lactate through MCT1 and MCT4; however, similar analyses in neuroendocrine neurons have yet to be undertaken. Using primary rat hypothalamic cell cultures and fluorimetric assays, lactate incorporation was detected. Furthermore, the expression and function of MCT2 was demonstrated in the hypothalamic neuronal cell line, GT1-7, using kinetic and inhibition assays. Moreover, MCT2 expression and localization in the Sprague Dawley rat hypothalamus was analyzed using RT-PCR, in situ hybridization and Western blot analyses. Confocal immunohistochemistry analyses revealed MCT2 localization in neuronal but not glial cells. Moreover, MCT2 was localized to ∼90% of orexigenic and ∼60% of anorexigenic neurons as determined by immunolocalization analysis of AgRP and POMC with MCT2-positives neurons. Thus, MCT2 distribution coupled with lactate uptake by hypothalamic neurons suggests that hypothalamic neurons control food intake using lactate to reflect changes in glucose levels. PMID:23638108

Elastic Network Model of a Nuclear Transport Complex

NASA Astrophysics Data System (ADS)

Ryan, Patrick; Liu, Wing K.; Lee, Dockjin; Seo, Sangjae; Kim, Young-Jin; Kim, Moon K.

2010-05-01

The structure of Kap95p was obtained from the Protein Data Bank (www.pdb.org) and analyzed RanGTP plays an important role in both nuclear protein import and export cycles. In the nucleus, RanGTP releases macromolecular cargoes from importins and conversely facilitates cargo binding to exportins. Although the crystal structure of the nuclear import complex formed by importin Kap95p and RanGTP was recently identified, its molecular mechanism still remains unclear. To understand the relationship between structure and function of a nuclear transport complex, a structure-based mechanical model of Kap95p:RanGTP complex is introduced. In this model, a protein structure is simply modeled as an elastic network in which a set of coarse-grained point masses are connected by linear springs representing biochemical interactions at atomic level. Harmonic normal mode analysis (NMA) and anharmonic elastic network interpolation (ENI) are performed to predict the modes of vibrations and a feasible pathway between locked and unlocked conformations of Kap95p, respectively. Simulation results imply that the binding of RanGTP to Kap95p induces the release of the cargo in the nucleus as well as prevents any new cargo from attaching to the Kap95p:RanGTP complex.

Social Laughter Triggers Endogenous Opioid Release in Humans.

PubMed

Manninen, Sandra; Tuominen, Lauri; Dunbar, Robin I; Karjalainen, Tomi; Hirvonen, Jussi; Arponen, Eveliina; Hari, Riitta; Jääskeläinen, Iiro P; Sams, Mikko; Nummenmaa, Lauri

2017-06-21

The size of human social networks significantly exceeds the network that can be maintained by social grooming or touching in other primates. It has been proposed that endogenous opioid release after social laughter would provide a neurochemical pathway supporting long-term relationships in humans (Dunbar, 2012), yet this hypothesis currently lacks direct neurophysiological support. We used PET and the μ-opioid-receptor (MOR)-specific ligand [ 11 C]carfentanil to quantify laughter-induced endogenous opioid release in 12 healthy males. Before the social laughter scan, the subjects watched laughter-inducing comedy clips with their close friends for 30 min. Before the baseline scan, subjects spent 30 min alone in the testing room. Social laughter increased pleasurable sensations and triggered endogenous opioid release in thalamus, caudate nucleus, and anterior insula. In addition, baseline MOR availability in the cingulate and orbitofrontal cortices was associated with the rate of social laughter. In a behavioral control experiment, pain threshold-a proxy of endogenous opioidergic activation-was elevated significantly more in both male and female volunteers after watching laughter-inducing comedy versus non-laughter-inducing drama in groups. Modulation of the opioidergic activity by social laughter may be an important neurochemical pathway that supports the formation, reinforcement, and maintenance of human social bonds. SIGNIFICANCE STATEMENT Social contacts are vital to humans. The size of human social networks significantly exceeds the network that can be maintained by social grooming in other primates. Here, we used PET to show that endogenous opioid release after social laughter may provide a neurochemical mechanism supporting long-term relationships in humans. Participants were scanned twice: after a 30 min social laughter session and after spending 30 min alone in the testing room (baseline). Endogenous opioid release was stronger after laughter versus the baseline scan. Opioid receptor density in the frontal cortex predicted social laughter rates. Modulation of the opioidergic activity by social laughter may be an important neurochemical mechanism reinforcing and maintaining social bonds between humans. Copyright © 2017 the authors 0270-6474/17/376125-07$15.00/0.

A Single Brain-Derived Neurotrophic Factor Infusion into the Dorsomedial Prefrontal Cortex Attenuates Cocaine Self-Administration-Induced Phosphorylation of Synapsin in the Nucleus Accumbens during Early Withdrawal

PubMed Central

Sun, Wei-Lun; Eisenstein, Sarah A.; Zelek-Molik, Agnieszka

2015-01-01

Background: Dysregulation in the prefrontal cortex-nucleus accumbens pathway has been implicated in cocaine addiction. We have previously demonstrated that one intra-dorsomedial prefrontal cortex brain-derived neurotrophic factor (BDNF) infusion immediately following the last cocaine self-administration session caused a long-lasting inhibition of cocaine-seeking and normalized the cocaine-induced disturbance of glutamate transmission in the nucleus accumbens after extinction and a cocaine prime. However, the molecular mechanism mediating the brain-derived neurotrophic factor effect on cocaine-induced alterations in extracellular glutamate levels is unknown. Methods: In the present study, we determined the effects of brain-derived neurotrophic factor on cocaine-induced changes in the phosphorylation of synapsin (p-synapsin), a family of presynaptic proteins that mediate synaptic vesicle mobilization, in the nucleus accumbens during early withdrawal. Results: Two hours after cocaine self-administration, p-synapsin Ser9 and p-synapsin Ser62/67, but not p-synapsin Ser603, were increased in the nucleus accumbens. At 22 hours, only p-synapsin Ser9 was still elevated. Elevations at both time points were attenuated by an intra-dorsomedial prefrontal cortex brain-derived neurotrophic factor infusion immediately after the end of cocaine self-administration. Brain-derived neurotrophic factor also reduced cocaine self-administration withdrawal-induced phosphorylation of the protein phosphatase 2A C-subunit, suggesting that brain-derived neurotrophic factor disinhibits protein phosphatase 2A C-subunit, consistent with p-synapsin Ser9 dephosphorylation. Further, co-immunoprecipitation demonstrated that protein phosphatase 2A C-subunit and synapsin are associated in a protein-protein complex that was reduced after 2 hours of withdrawal from cocaine self-administration and reversed by brain-derived neurotrophic factor. Conclusions: Taken together, these findings demonstrate that brain-derived neurotrophic factor normalizes the cocaine self-administration–induced elevation of p-synapsin in nucleus accumbens that may underlie a disturbance in the probability of neurotransmitter release or represent a compensatory neuroadaptation in response to the hypofunction within the prefrontal cortex-nucleus accumbens pathway during cocaine withdrawal. PMID:25522393

A novel central pathway links arterial baroreceptors and pontine parasympathetic neurons in cerebrovascular control.

PubMed

Agassandian, Khristofor; Fazan, Valeria P S; Margaryan, Naira; Dragon, Deidre Nitschke; Riley, Jeffrey; Talman, William T

2003-10-01

1. We tested the hypothesis that arterial baroreceptor reflexes modulate cerebrovascular tone through a pathway that connects the cardiovascular nucleus tractus solitarii with parasympathetic preganglionic neurons in the pons. 2. Anesthetized rats were used in all studies. Laser flowmetry was used to measure cerebral blood flow. We assessed cerebrovascular responses to increases in arterial blood pressure in animals with lesions of baroreceptor nerves, the nucleus tractus solitarii itself, the pontine preganglionic parasympathetic neurons, or the parasympathetic ganglionic nerves to the cerebral vessels. Similar assessments were made in animals after blockade of synthesis of nitric oxide, which is released by the parasympathetic nerves from the pterygopalatine ganglia. Finally the effects on cerebral blood flow of glutamate stimulation of pontine preganglionic parasympathetic neurons were evaluated. 3. We found that lesions at any one of the sites in the putative pathway or interruption of nitric oxide synthesis led to prolongation of autoregulation as mean arterial pressure was increased to levels as high as 200 mmHg. Conversely, stimulation of pontine parasympathetic preganglionic neurons led to cerebral vasodilatation. The second series of studies utilized classic anatomical tracing methods to determine at the light and electron microscopic level whether neurons in the cardiovascular nucleus tractus solitarii, the site of termination of baroreceptor afferents, projected to the pontine preganglionic neurons. Fibers were traced with anterograde tracer from the nucleus tractus solitarii to the pons and with retrograde tracer from the pons to the nucleus tractus solitarii. Using double labeling techniques we further studied synapses made between labeled projections from the nucleus tractus solitarii and preganglionic neurons that were themselves labeled with retrograde tracer placed into the pterygopalatine ganglion. 4. These anatomical studies showed that the nucleus tractus solitarii directly projects to pontine preganglionic neurons and makes asymmetric, seemingly excitatory, synapses with those neurons. These studies provide strong evidence that arterial baroreceptors may modulate cerebral blood flow through direct connections with pontine parasympathetic neurons. Further study is needed to clarify the role this pathway plays in integrative physiology.

The C Terminus of the Herpes Simplex Virus UL25 Protein Is Required for Release of Viral Genomes from Capsids Bound to Nuclear Pores

PubMed Central

Huffman, Jamie B.; Daniel, Gina R.; Falck-Pedersen, Erik; Huet, Alexis

2017-01-01

ABSTRACT The herpes simplex virus (HSV) capsid is released into the cytoplasm after fusion of viral and host membranes, whereupon dynein-dependent trafficking along microtubules targets it to the nuclear envelope. Binding of the capsid to the nuclear pore complex (NPC) is mediated by the capsid protein pUL25 and the capsid-tethered tegument protein pUL36. Temperature-sensitive mutants in both pUL25 and pUL36 dock at the NPC but fail to release DNA. The uncoating reaction has been difficult to study due to the rapid release of the genome once the capsid interacts with the nuclear pore. In this study, we describe the isolation and characterization of a truncation mutant of pUL25. Live-cell imaging and immunofluorescence studies demonstrated that the mutant was not impaired in penetration of the host cell or in trafficking of the capsid to the nuclear membrane. However, expression of viral proteins was absent or significantly delayed in cells infected with the pUL25 mutant virus. Transmission electron microscopy revealed capsids accumulated at nuclear pores that retained the viral genome for at least 4 h postinfection. In addition, cryoelectron microscopy (cryo-EM) reconstructions of virion capsids did not detect any obvious differences in the location or structural organization for the pUL25 or pUL36 proteins on the pUL25 mutant capsids. Further, in contrast to wild-type virus, the antiviral response mediated by the viral DNA-sensing cyclic guanine adenine synthase (cGAS) was severely compromised for the pUL25 mutant. These results demonstrate that the pUL25 capsid protein has a critical role in releasing viral DNA from NPC-bound capsids. IMPORTANCE Herpes simplex virus 1 (HSV-1) is the causative agent of several pathologies ranging in severity from the common cold sore to life-threatening encephalitic infection. Early steps in infection include release of the capsid into the cytoplasm, docking of the capsid at a nuclear pore, and release of the viral genome into the nucleus. A key knowledge gap is how the capsid engages the NPC and what triggers release of the viral genome into the nucleus. Here we show that the C-terminal region of the HSV-1 pUL25 protein is required for releasing the viral genome from capsids docked at nuclear pores. The significance of our research is in identifying pUL25 as a key viral factor for genome uncoating. pUL25 is found at each of the capsid vertices as part of the capsid vertex-specific component and implicates the importance of this complex for NPC binding and genome release. PMID:28490590

Beyond the Classic VTA: Extended Amygdala Projections to DA-Striatal Paths in the Primate

PubMed Central

Fudge, Julie L; Kelly, Emily A; Pal, Ria; Bedont, Joseph L; Park, Lydia; Ho, Brian

2017-01-01

The central extended amygdala (CEA) has been conceptualized as a ‘macrosystem’ that regulates various stress-induced behaviors. Consistent with this, the CEA highly expresses corticotropin-releasing factor (CRF), an important modulator of stress responses. Stress alters goal-directed responses associated with striatal paths, including maladaptive responses such as drug seeking, social withdrawal, and compulsive behavior. CEA inputs to the midbrain dopamine (DA) system are positioned to influence striatal functions through mesolimbic DA-striatal pathways. However, the structure of this amygdala-CEA-DA neuron path to the striatum has been poorly characterized in primates. In primates, we combined neuronal tracer injections into various arms of the circuit through specific DA subpopulations to assess: (1) whether the circuit connecting amygdala, CEA, and DA cells follows CEA intrinsic organization, or a more direct topography involving bed nucleus vs central nucleus divisions; (2) CRF content of the CEA-DA path; and (3) striatal subregions specifically involved in CEA-DA-striatal loops. We found that the amygdala-CEA-DA path follows macrostructural subdivisions, with the majority of input/outputs converging in the medial central nucleus, the sublenticular extended amygdala, and the posterior lateral bed nucleus of the stria terminalis. The proportion of CRF+ outputs is >50%, and mainly targets the A10 parabrachial pigmented nucleus (PBP) and A8 (retrorubal field, RRF) neuronal subpopulations, with additional inputs to the dorsal A9 neurons. CRF-enriched CEA-DA projections are positioned to influence outputs to the ‘limbic-associative’ striatum, which is distinct from striatal regions targeted by DA cells lacking CEA input. We conclude that the concept of the CEA is supported on connectional grounds, and that CEA termination over the PBP and RRF neuronal populations can influence striatal circuits involved in associative learning. PMID:28220796

Beyond the Classic VTA: Extended Amygdala Projections to DA-Striatal Paths in the Primate.

PubMed

Fudge, Julie L; Kelly, Emily A; Pal, Ria; Bedont, Joseph L; Park, Lydia; Ho, Brian

2017-07-01

The central extended amygdala (CEA) has been conceptualized as a 'macrosystem' that regulates various stress-induced behaviors. Consistent with this, the CEA highly expresses corticotropin-releasing factor (CRF), an important modulator of stress responses. Stress alters goal-directed responses associated with striatal paths, including maladaptive responses such as drug seeking, social withdrawal, and compulsive behavior. CEA inputs to the midbrain dopamine (DA) system are positioned to influence striatal functions through mesolimbic DA-striatal pathways. However, the structure of this amygdala-CEA-DA neuron path to the striatum has been poorly characterized in primates. In primates, we combined neuronal tracer injections into various arms of the circuit through specific DA subpopulations to assess: (1) whether the circuit connecting amygdala, CEA, and DA cells follows CEA intrinsic organization, or a more direct topography involving bed nucleus vs central nucleus divisions; (2) CRF content of the CEA-DA path; and (3) striatal subregions specifically involved in CEA-DA-striatal loops. We found that the amygdala-CEA-DA path follows macrostructural subdivisions, with the majority of input/outputs converging in the medial central nucleus, the sublenticular extended amygdala, and the posterior lateral bed nucleus of the stria terminalis. The proportion of CRF+ outputs is >50%, and mainly targets the A10 parabrachial pigmented nucleus (PBP) and A8 (retrorubal field, RRF) neuronal subpopulations, with additional inputs to the dorsal A9 neurons. CRF-enriched CEA-DA projections are positioned to influence outputs to the 'limbic-associative' striatum, which is distinct from striatal regions targeted by DA cells lacking CEA input. We conclude that the concept of the CEA is supported on connectional grounds, and that CEA termination over the PBP and RRF neuronal populations can influence striatal circuits involved in associative learning.

Exploring the fission and reconfiguration cycle of comet 67P/Churyumov-Gerasimenko

NASA Astrophysics Data System (ADS)

Scheeres, Daniel J.; Hirabayashi, Masatoshi; Chesley, Steven R.; McMahon, Jay W.

2016-10-01

In Hirabayashi et al. (Nature, 2016) the nucleus of comet 67P/Churyumov-Gerasimenko (67P) is studied with a focus on the straight cracks observed on the Hapi region. These cracks were shown to have formed during a period of fast rotation and led to a proposed evolutionary scenario in which the nuclei may eventually split into two components and recombine to create a new bilobate configuration. Other bilobate nuclei should be subject to such a reconfiguration process, based on the relative sizes of the components, suggesting that this evolutionary scenario may be common for bilobate nuclei which comprise the majority of comet nuclei observed at high spatial resolution. Such reconfigurations could explain the observed occurrence of comet nucleus splitting and brightening events, which still lack a definitive geophysical understanding. Motivated by the proposed theory in Hirabayashi et al., the current work explores the dynamics of the 67P nucleus' rotation rate, fission limits, and subsequent dynamics. One aspect of the theory posits that the comet's distant Jupiter flybys will cause the latitude of the sub-solar point at perihelion to vary chaotically, leading to periods of net positive and negative torques and causing the nucleus to spin-up and spin-down in a random fashion. We analyze the current 67P nucleus shape and orbit to estimate the characteristic time-scale of this rotational evolution, providing an estimate of the current nucleus lifetime in its current configuration. Once the nucleus reaches a spin period shorter than ~7 hours the components will fission into a bound orbit, with the components subsequently reimpacting at speeds less than local escape speed (about 0.4 m/s). The current study extends Hirabayashi et al., explicitly modeling the mutual gravity and orbital dynamics of the head and body, assuming that the head and body rest on each other with the current shape of the 67P nucleus. The results show that when the components are released at a spin period between 6.5 hr and 7 hr, the components will separate and subsequently collide with a low impact speed. The orbital and rotational dynamics of the system components after fission are explored as a function of the initial spin rate at fission.

Distribution of Off-Diagonal Cross Sections in Quantum Chaotic Scattering: Exact Results and Data Comparison.

PubMed

Kumar, Santosh; Dietz, Barbara; Guhr, Thomas; Richter, Achim

2017-12-15

The recently derived distributions for the scattering-matrix elements in quantum chaotic systems are not accessible in the majority of experiments, whereas the cross sections are. We analytically compute distributions for the off-diagonal cross sections in the Heidelberg approach, which is applicable to a wide range of quantum chaotic systems. Thus, eventually, we fully solve a problem that already arose more than half a century ago in compound-nucleus scattering. We compare our results with data from microwave and compound-nucleus experiments, particularly addressing the transition from isolated resonances towards the Ericson regime of strongly overlapping ones.

Distribution of Off-Diagonal Cross Sections in Quantum Chaotic Scattering: Exact Results and Data Comparison

NASA Astrophysics Data System (ADS)

Kumar, Santosh; Dietz, Barbara; Guhr, Thomas; Richter, Achim

2017-12-01

The recently derived distributions for the scattering-matrix elements in quantum chaotic systems are not accessible in the majority of experiments, whereas the cross sections are. We analytically compute distributions for the off-diagonal cross sections in the Heidelberg approach, which is applicable to a wide range of quantum chaotic systems. Thus, eventually, we fully solve a problem that already arose more than half a century ago in compound-nucleus scattering. We compare our results with data from microwave and compound-nucleus experiments, particularly addressing the transition from isolated resonances towards the Ericson regime of strongly overlapping ones.

A method for calculating proton-nucleus elastic cross-sections

NASA Technical Reports Server (NTRS)

Tripathi, R. K.; Wilson, J. W.; Cucinotta, F. A.

2002-01-01

Recently [Nucl. Instr. and Meth. B 145 (1998) 277; Extraction of in-medium nucleon-nucleon amplitude from experiment, NASA-TP, 1998], we developed a method of extracting nucleon-nucleon (N-N) cross-sections in the medium directly from experiment. The in-medium N-N cross-sections form the basic ingredients of several heavy-ion scattering approaches including the coupled-channel approach developed at the NASA Langley Research Center. We investigated [Proton-nucleus total cross-sections in coupled-channel approach, NASA/TP, 2000; Nucl. Instr. and Meth. B 173-174 (2001) 391] the ratio of real to imaginary part of the two body scattering amplitude in the medium. These ratios are used in combination with the in-medium N-N cross-sections to calculate proton-nucleus elastic cross-sections. The agreement is excellent with the available experimental data. These cross-sections are needed for the radiation risk assessment of space missions. c2002 Elsevier Science B.V. All rights reserved.

Lesions of the amygdala central nucleus abolish lipoprivic-enhanced responding during oil-predicting conditioned stimuli.

PubMed

Benoit, S C; Morell, J R; Davidson, T L

1999-12-01

T. L. Davidson, A. M. Altizer, S. C. Benoit, E. K. Walls, and T. L. Powley (1997) reported that rats show facilitated responding to conditioned stimuli (CSs) that predict oil, after administration of the lipoprivic agent, Na-2-mercaptoacetate (MA). This facilitation was blocked by vagal deafferentation. The present article extends that investigation to another structure, the amygdala central nucleus (CN). The CN receives inputs from dorsal vagal nuclei, and neurotoxic lesions of this nucleus are reported to abolish feeding in response to lipoprivic challenges. In Experiment 1, rats with ibotenic acid (IBO) lesions of the CN failed to show enhanced appetitive responding during oil-predicting CSs after administration of MA. Experiment 2 used a conditioned taste-aversion procedure to establish that rats with IBO lesions of the CN were able to discriminate the tastes of sucrose and peanut oil and had intact CS-US representations. It is concluded that the amygdala CN is a necessary structure for the detection of lipoprivic challenges.

Mapping the dynamical organization of the cell nucleus through fluorescence correlation spectroscopy.

PubMed

Stortz, Martin; Angiolini, Juan; Mocskos, Esteban; Wolosiuk, Alejandro; Pecci, Adali; Levi, Valeria

2018-05-01

The hierarchical organization of the cell nucleus into specialized open reservoirs and the nucleoplasm overcrowding impose restrictions to the mobility of biomolecules and their interactions with nuclear targets. These properties determine that many nuclear functions such as transcription, replication, splicing or DNA repair are regulated by complex, dynamical processes that do not follow simple rules. Advanced fluorescence microscopy tools and, in particular, fluorescence correlation spectroscopy (FCS) provide complementary and exquisite information on the dynamics of fluorescent labeled molecules moving through the nuclear space and are helping us to comprehend the complexity of the nuclear structure. Here, we describe how FCS methods can be applied to reveal the dynamical organization of the nucleus in live cells. Specifically, we provide instructions for the preparation of cellular samples with fluorescent tagged proteins and detail how FCS can be easily instrumented in commercial confocal microscopes. In addition, we describe general rules to set the parameters for one and two-color experiments and the required controls for these experiments. Finally, we review the statistical analysis of the FCS data and summarize the use of numerical simulations as a complementary approach that helps us to understand the complex matrix of molecular interactions network within the nucleus. Copyright © 2017 Elsevier Inc. All rights reserved.

The “ram effect”: new insights into neural modulation of the gonadotropic axis by male odors and socio-sexual interactions

PubMed Central

Fabre-Nys, Claude; Kendrick, Keith M.; Scaramuzzi, Rex J.

2015-01-01

Reproduction in mammals is controlled by the hypothalamo-pituitary-gonadal (HPG) axis under the influence of external and internal factors such as photoperiod, stress, nutrition, and social interactions. Sheep are seasonal breeders and stop mating when day length is increasing (anestrus). However, interactions with a sexually active ram during this period can override the steroid negative feedback responsible for the anoestrus state, stimulate luteinizing hormone (LH) secretion and eventually reinstate cyclicity. This is known as the “ram effect” and research into the mechanisms underlying it is shedding new light on HPG axis regulation. The first step in the ram effect is increased LH pulsatile secretion in anestrus ewes exposed to a sexually active male or only to its fleece, the latter finding indicating a “pheromone-like” effect. Estradiol secretion increases in all ewes and this eventually induces a LH surge and ovulation, just as during the breeding season. An exception is a minority of ewes that exhibit a precocious LH surge (within 4 h) with no prior increase in estradiol. The main olfactory system and the cortical nucleus of the amygdala are critical brain structures in mediating the ram effect since it is blocked by their inactivation. Sexual experience is also important since activation (increased c-fos expression) in these and other regions is greatly reduced in sexually naïve ewes. In adult ewes kisspeptin neurons in both arcuate and preoptic regions and some preoptic GnRH neurons are activated 2 h after exposure to a ram. Exposure to rams also activates noradrenergic neurons in the locus coeruleus and A1 nucleus and increased noradrenalin release occurs in the posterior preoptic area. Pharmacological modulation of this system modifies LH secretion in response to the male or his odor. Together these results show that the ram effect can be a fruitful model to promote both a better understanding of the neural and hormonal regulation of the HPG axis in general and also the specific mechanisms by which male cues can overcome negative steroid feedback and trigger LH release and ovulatory cycles. PMID:25914614

Where and what is the paralaminar nucleus? A review on a unique and frequently overlooked area of the primate amygdala

PubMed Central

deCampo, Danielle; Fudge, Julie

2011-01-01

The primate amygdala is composed of multiple subnuclei that play distinct roles in amygdala function. While some nuclei have been areas of focused investigation, others remain virtually unknown. One of the more obscure regions of the amygdala is the paralaminar nucleus (PL). The PL in humans and non-human primates is relatively expanded compared to lower species. Long considered to be part of the basal nucleus, the PL has several interesting features that make it unique. These features include a dense concentration of small cells, high concentrations of receptors for corticotropin releasing hormone and benzodiazepines, and dense innervation of serotonergic fibers. More recently, high concentrations of immature-appearing cells have been noted in the primate PL, suggesting special mechanisms of neural plasticity. Following a brief overview of amygdala structure and function, this review will provide an introduction to the history, embryology, anatomical connectivity, immunohistochemical and cytoarchitectural properties of the PL. Our conclusion based on the following information, is that the PL is a unique subregion of the amygdala that may yield important clues about the normal growth and function of the amygdala, particularly in higher species. PMID:21906624

[Concentration of monoamines and activity of several enzymes in the arcuate nucleus of the hypothalamus in young and aging rats during the estrous cycle].

PubMed

Grantyn', V A

1976-07-01

The arcuate nucleus (AN) and the median eminence (ME) of the hypothalamus were investigated in young and ageing female rats. During the estral cycle (EC) the monoamine (MA) content, the monoaminoxidase (MAO), NADP and NAD-diaphorase activities were determined in the AN, and the MA content and the activity of alkaline phosphatase (AP) -- in the ME. In young rats in the proestrus-estrus there was an increase in the activity of the NADP and NAD-diaphorase and of the MA content, but a decrease of the MAO activity. This indicated an intensified function of the nucleus at these stages of the EC. Accumulation of the MA in the ME was noted in the diestrus, while in the proestrus their concentration sharply fell; on the other hand, the activity of the AP was considerably increased. In the ageing rats the dynamics of the indices under study during the EC were largely unchanged. However, the functional activity of the AN proved to increase, and in the ME and elevation of the MA concentration and disturbance of its release from the nerve terminals was seen.

REM Sleep at its Core – Circuits, Neurotransmitters, and Pathophysiology

PubMed Central

Fraigne, Jimmy J.; Torontali, Zoltan A.; Snow, Matthew B.; Peever, John H.

2015-01-01

Rapid eye movement (REM) sleep is generated and maintained by the interaction of a variety of neurotransmitter systems in the brainstem, forebrain, and hypothalamus. Within these circuits lies a core region that is active during REM sleep, known as the subcoeruleus nucleus (SubC) or sublaterodorsal nucleus. It is hypothesized that glutamatergic SubC neurons regulate REM sleep and its defining features such as muscle paralysis and cortical activation. REM sleep paralysis is initiated when glutamatergic SubC cells activate neurons in the ventral medial medulla, which causes release of GABA and glycine onto skeletal motoneurons. REM sleep timing is controlled by activity of GABAergic neurons in the ventrolateral periaqueductal gray and dorsal paragigantocellular reticular nucleus as well as melanin-concentrating hormone neurons in the hypothalamus and cholinergic cells in the laterodorsal and pedunculo-pontine tegmentum in the brainstem. Determining how these circuits interact with the SubC is important because breakdown in their communication is hypothesized to underlie narcolepsy/cataplexy and REM sleep behavior disorder (RBD). This review synthesizes our current understanding of mechanisms generating healthy REM sleep and how dysfunction of these circuits contributes to common REM sleep disorders such as cataplexy/narcolepsy and RBD. PMID:26074874

The extended amygdala and salt appetite

NASA Technical Reports Server (NTRS)

Johnson, A. K.; de Olmos, J.; Pastuskovas, C. V.; Zardetto-Smith, A. M.; Vivas, L.

1999-01-01

Both chemo- and mechanosensitive receptors are involved in detecting changes in the signals that reflect the status of body fluids and of blood pressure. These receptors are located in the systemic circulatory system and in the sensory circumventricular organs of the brain. Under conditions of body fluid deficit or of marked changes in fluid distribution, multiple inputs derived from these humoral and neural receptors converge on key areas of the brain where the information is integrated. The result of this central processing is the mobilization of homeostatic behaviors (thirst and salt appetite), hormone release, autonomic changes, and cardiovascular adjustments. This review discusses the current understanding of the nature and role of the central and systemic receptors involved in the facilitation and inhibition of thirst and salt appetite and on particular components of the central neural network that receive and process input derived from fluid- and cardiovascular-related sensory systems. Special attention is paid to the structures of the lamina terminalis, the area postrema, the lateral parabrachial nucleus, and their association with the central nucleus of the amygdala and the bed nucleus of the stria terminalis in controlling the behaviors that participate in maintaining body fluid and cardiovascular homeostasis.

Inhibitory effects of acetylcholine on neurones in the feline nucleus reticularis thalami.

PubMed

Ben-Ari, Y; Dingledine, R; Kanazawa, I; Kelly, J S

1976-10-01

1. Short iontophoretic pulses of acetylcholine (ACh) inhibited almost every spontaneously active cell encountered in the nucleus reticularis thalami of cats anaesthetized with a mixture of halothane, nitrous oxide and oxygen. On 200 cells the mean current needed to eject an effective inhibitory dose of ACh was 67 +/- 2 nA. When the ACh-evoked inhibition was mimicked by gamma-aminobutyric acid (GABA) or glycine on the same cell, the current required to release ACh was found to be approximately twice as great as that required to release an equally effective dose of GABA or glycine. 2. ACh inhibitions developed with a latency which was very much shorter than that for ACh excitation in cells of the ventrobasal complex. The latency of the ACh-evoked inhibition was as rapid as the onset and offset of the excitation of the same cells glutamate and their inhibition by GABA or glycine. 3. The firing pattern of ACh-inhibited neurones in the nucleus reticularis was characterized by periods of prolonged, high frequency bursts, and their mean firing frequency was 22 Hz. Raster dot displays and interspike interval histograms showed that whereas ACh suppressed the spikes that occurred between bursts much more readily than those that occurred during bursts, all spikes were equally sensitive to the depressant action of GABA and glycine. Large doses of ACh provoked or exaggerated burst activity. 4. ACh-evoked inhibition was extremely sensitive to blockade by short iontophoretic applications of atropine, which had no effect on the inhibitions evoked on the same cell equipotent doses of GABA or glycine. The ACh-evoked inhibitions were also antagonized by dihydro-beta-erythroidine released with slightly larger currents. When tested on the same cell, small iontophoretic applications of picrotoxin and bicuculline methoiodide blocked the inhibition evoked by GABA but had no effect on that evoked by ACh. Iontophoretic strychnine only rarely affected the inhibition evoked by ACh, while readily blocking the inhibition evoked on the same cell by an equipotent dose of glycine. In two cats, intravenous strychnine (1-2 mg/kg) had no effect on the ACh-evoked inhibition, while greatly reducing the sensitivity of the cell under study to glycine. 5. Only four out of forty-eight ACh-inhibted cells tested were inhibited by iontophoretic applications of either guanosine or adenosine 3':5'-phosphate. 6. Cells of the nucleus reticularis have been shown to have an inhibitory action on the thalamic relay cells, which are excited by ACh. It is suggested that the presence of both ACh excited and inhibited cells in different nuclei of the thalamus could be of considerable functional significance in gating sensory transmission through the thalamus.

Reward system and addiction: what dopamine does and doesn't do.

PubMed

Di Chiara, Gaetano; Bassareo, Valentina

2007-02-01

Addictive drugs share with palatable food the property of increasing extracellular dopamine (DA), preferentially in the nucleus accumbens shell rather than in the core. However, by acting directly on the brain, drugs bypass the adaptive mechanisms (habituation) that constrain the responsiveness of accumbens shell DA to food reward, abnormally facilitating Pavlovian incentive learning and promoting the acquisition of abnormal DA-releasing properties by drug conditioned stimuli. Thus, whereas Pavlovian food conditioned stimuli release core but not shell DA, drug conditioned stimuli do the opposite, releasing shell but not core DA. This process, which results in the acquisition of excessive incentive-motivational properties by drug conditioned stimuli, initiates the drug addiction process. Neuroadaptive processes related to the chronic influence of drugs on subcortical DA might secondarily impair the function of prefronto-striatal loops, resulting in impairments in impulse control and decision making that form the basis for the compulsive feature of drug seeking and its relapsing character.

Streaming Clumps Ejection Model and the Heterogeneous Inner Coma of Comet Wild 2

NASA Technical Reports Server (NTRS)

Clark, B. C.; Economou, T. E.; Green, S. F.; Sandford, S. A.; Zolensky, M. E.

2004-01-01

The conventional concept of cometary comae is that they are dominated by fine particulates released individually by sublimation of surface volatiles and subsequent entrainment in the near-surface gas. It has long been recognized that such particulates could be relatively large, with early estimates that objects perhaps up to one meter in size may be levitated from the surface of the typical cometary nucleus. However, the general uniformity and small average particulate size of observed comae and the relatively smooth, monotonic increases and decreases in particle density during the Giotto flythrough of comet Halley s coma in 1986 reinforced the view that the bulk of the particles are released at the surface, are fine-sized and inert. Jets have been interpreted as geometrically constrained release of these particulates. With major heterogeneities observed during the recent flythrough of the inner coma of comet Wild 2, these views deserve reconsideration.

Inositol trisphosphate receptor mediated spatiotemporal calcium signalling.

PubMed

Miyazaki, S

1995-04-01

Spatiotemporal Ca2+ signalling in the cytoplasm is currently understood as an excitation phenomenon by analogy with electrical excitation in the plasma membrane. In many cell types, Ca2+ waves and Ca2+ oscillations are mediated by inositol 1,4,5-trisphosphate (IP3) receptor/Ca2+ channels in the endoplasmic reticulum membrane, with positive feedback between cytosolic Ca2+ and IP3-induced Ca2+ release creating a regenerative process. Remarkable advances have been made in the past year in the analysis of subcellular Ca2+ microdomains using confocal microscopy and of Ca2+ influx pathways that are functionally coupled to IP3-induced Ca2+ release. Ca2+ signals can be conveyed into the nucleus and mitochondria. Ca2+ entry from outside the cell allows repetitive Ca2+ release by providing Ca2+ to refill the endoplasmic reticulum stores, thus giving rise to frequency-encoded Ca2+ signals.

Investigation of a central nucleus of the amygdala/dorsal raphe nucleus serotonergic circuit implicated in fear-potentiated startle

PubMed Central

Spannuth, Benjamin M.; Hale, Matthew W.; Evans, Andrew K.; Lukkes, Jodi L.; Campeau, Serge; Lowry, Christopher A.

2011-01-01

Serotonergic systems are thought to play an important role in control of motor activity and emotional states. We used a fear-potentiated startle paradigm to investigate the effects of a motor-eliciting stimulus in the presence or absence of induction of an acute fear state on serotonergic neurons in the dorsal raphe nucleus (DR) and cells in subdivisions of the central amygdaloid nucleus (CE), a structure that plays an important role in fear responses, using induction of the protein product of the immediate-early gene, c-fos. In Experiment 1 we investigated the effects of fear conditioning training, by training rats to associate a light cue (conditioned stimulus, CS; 1000 lx, 2 sec) with foot shock (0.5 s, 0.5 mA) in a single session. In Experiment 2 rats were given two training sessions identical to Experiment 1 on days 1 and 2, then tested in one of four conditions on day 3: 1) placement in the training context without exposure to either the CS or acoustic startle (AS), 2) exposure to 10 trials of the 2 s CS, 3) exposure to 40 110 dB AS trials, or 4) exposure to 40 110 dB AS trials with 10 of the trials preceded by and co-terminating with the CS. All treatments were conducted during a 20 min session. Fear conditioning training, by itself, increased c-Fos expression in multiple subdivisions of the CE and throughout the DR. In contrast, fear-potentiated startle selectively increased c-Fos expression in the medial subdivision of the CE and in serotonergic neurons in the dorsal part of the dorsal raphe nucleus (DRD). These data are consistent with previous studies demonstrating that fear-related stimuli selectively activate DRD serotonergic neurons. Further studies of this mesolimbocortical serotonergic system could have important implications for understanding mechanisms underlying vulnerability to stress-related psychiatric disorders, including anxiety and affective disorders. PMID:21277950

One pot synthesis of highly luminescent polyethylene glycol anchored carbon dots functionalized with a nuclear localization signal peptide for cell nucleus imaging.

PubMed

Yang, Lei; Jiang, Weihua; Qiu, Lipeng; Jiang, Xuewei; Zuo, Daiying; Wang, Dongkai; Yang, Li

2015-04-14

Strong blue fluorescent polyethylene glycol (PEG) anchored carbon nitride dots (CDs@PEG) with a high quantum yield (QY) of 75.8% have been synthesized by a one step hydrothermal treatment. CDs with a diameter of ca. 6 nm are well dispersed in water and present a graphite-like structure. Photoluminescence (PL) studies reveal that CDs display excitation-dependent behavior and are stable under various test conditions. Based on the as-prepared CDs, we designed novel cell nucleus targeting imaging carbon dots functionalized with a nuclear localization signal (NLS) peptide. The favourable biocompatibilities of CDs and NLS modified CDs (NLS-CDs) are confirmed by in vitro cytotoxicity assays. Importantly, intracellular localization experiments in MCF7 and A549 cells demonstrate that NLS-CDs could be internalized in the nucleus and show blue light, which indicates that CDs may serve as cell nucleus imaging probes.

Photo nuclear energy loss term for muon-nucleus interactions based on xi scaling model of QCD

NASA Technical Reports Server (NTRS)

Roychoudhury, R.

1985-01-01

Extensive air showers (EMC) experiments discovered a significant deviation of the ratio of structure functions of iron and deuteron from unity. It was established that the quark parton distribution in nuclei are different from the corresponding distribution in the nucleus. It was examined whether these results have an effect on the calculation of photo nucleus energy loss term for muon-nucleus nuclear interaction. Though the EMC and SLAC data were restricted to rather large q sq region it is expected that the derivation would persist even in the low q sq domain. For the ratio of iron and deuteron structure function a rather naive least square fit of the form R(x) = a + bx was taken and it is assumed that the formula is valid for the whole q sq region the absence of any knowledge of R(x) for small q sq.

Differences in the motility of Amoeba proteus isolated fragments are determined by F-actin arrangement and cell nucleus presence.

PubMed

Grebecka, L; Pomorski, P; Lopatowska, A

1995-10-01

Isolated fragments produced by bisection of Amoeba proteus differ by their position in the original cell and by the presence or absence of the cell nucleus. Immediately after the operation, both types of anterior fragments preserve the former motory polarity, and do not interrupt locomotion. In the same time, all posterior fragments stop, round up and fail to react stimuli. In the second phase of experiment, these anterior fragments, which had no nucleus ceased to move, whereas the nucleated posterior ones resumed locomotion. It was demonstrated, that the behaviour of a fragment is primarily determined by the peripheral F-actin distribution, which is different depending on the origin of the fragment either from the anterior or from the posterior cell region. Later, the "inherited" F-actin distribution may be stabilized or reorganized in the presence of the nucleus, or desorganized in its absence.

Analysis of the nuclear dependence of the νμ charged current inclusive cross section with MINERvA

NASA Astrophysics Data System (ADS)

Ransome, Ronald

2014-03-01

Neutrino experiments use heavy nuclei (Fe, Pb, C) to achieve necessary statistics. However, the use of heavy nuclei exposes these experiments to the nuclear dependence of neutrino-nucleus cross sections, which are poorly known and difficult to model. The MINERvA (Main INjector ExpeRiment for ?-A), a few-GeV neutrino nucleus scattering experiment at Fermilab, seeks to remedy the situation by directly studying the A-dependence of exclusive and inclusive channels. The MINERvA detector contains an 8 ton fully active fine-grained scintillator tracking core and targets of carbon, iron, lead, water and liquid helium which sit upstream of the tracking core. We present results from our analysis using the nuclear targets: ratios of the ?? charged-current inclusive cross section in carbon, iron, lead and plastic scintillator (CH). Supported in part by the US National Science Foundation and the Dept. of Energy.

A novel method for morphological pleomorphism and heterogeneity quantitative measurement: Named cell feature level co-occurrence matrix.

PubMed

Saito, Akira; Numata, Yasushi; Hamada, Takuya; Horisawa, Tomoyoshi; Cosatto, Eric; Graf, Hans-Peter; Kuroda, Masahiko; Yamamoto, Yoichiro

2016-01-01

Recent developments in molecular pathology and genetic/epigenetic analysis of cancer tissue have resulted in a marked increase in objective and measurable data. In comparison, the traditional morphological analysis approach to pathology diagnosis, which can connect these molecular data and clinical diagnosis, is still mostly subjective. Even though the advent and popularization of digital pathology has provided a boost to computer-aided diagnosis, some important pathological concepts still remain largely non-quantitative and their associated data measurements depend on the pathologist's sense and experience. Such features include pleomorphism and heterogeneity. In this paper, we propose a method for the objective measurement of pleomorphism and heterogeneity, using the cell-level co-occurrence matrix. Our method is based on the widely used Gray-level co-occurrence matrix (GLCM), where relations between neighboring pixel intensity levels are captured into a co-occurrence matrix, followed by the application of analysis functions such as Haralick features. In the pathological tissue image, through image processing techniques, each nucleus can be measured and each nucleus has its own measureable features like nucleus size, roundness, contour length, intra-nucleus texture data (GLCM is one of the methods). In GLCM each nucleus in the tissue image corresponds to one pixel. In this approach the most important point is how to define the neighborhood of each nucleus. We define three types of neighborhoods of a nucleus, then create the co-occurrence matrix and apply Haralick feature functions. In each image pleomorphism and heterogeneity are then determined quantitatively. For our method, one pixel corresponds to one nucleus feature, and we therefore named our method Cell Feature Level Co-occurrence Matrix (CFLCM). We tested this method for several nucleus features. CFLCM is showed as a useful quantitative method for pleomorphism and heterogeneity on histopathological image analysis.

The organization of the lateral geniculate nucleus and of the geniculocortical pathway that develops without retinal afferents.

PubMed

Guillery, R W; Ombrellaro, M; LaMantia, A L

1985-06-01

The fine structure and cortical connections of the dorsal lateral geniculate nucleus have been studied in postnatal (3.5-14-month-old) ferrets in which all retinal afferents had been removed prenatally at the time these fibers are first starting to invade the nucleus. The synaptic profiles in the mature nucleus show the cytological characteristics and arrangements that would remain if the retinal afferents were removed, with no significant compensatory ingrowth of foreign specific afferents. The nucleus is reduced in overall volume, but the geniculocortical and corticogeniculate interconnections show an essentially normal topography. Although in these experiments the geniculocortical projections can establish a normal topographic pattern in the absence of retinal afferents an accompanying paper shows that this topographic pattern can also be modified in the presence of abnormal retinogeniculate inputs. We conclude that two separate mechanisms contribute to the formation of retinal maps within the geniculocortical pathways and that different interactions between these two mechanisms produce the different patterns of abnormal geniculocortical pathways that have been described in pigment-deficient cats, mink and ferrets.

Ultrasound-triggered drug delivery using acoustic droplet vaporization

NASA Astrophysics Data System (ADS)

Fabiilli, Mario Leonardo

The goal of targeted drug delivery is the spatial and temporal localization of a therapeutic agent and its associated bioeffects. One method of drug localization is acoustic droplet vaporization (ADV), whereby drug-laden perfluorocarbon (PFC) emulsions are vaporized into gas bubbles using ultrasound, thereby releasing drug locally. Transpulmonary droplets are converted into bubbles that occlude capillaries, sequestering the released drug within an organ or tumor. This research investigates the relationship between the ADV and inertial cavitation (IC) thresholds---relevant for drug delivery due to the bioffects generated by IC---and explores the delivery of lipophilic and hydrophilic compounds using PFC double emulsions. IC can positively and negatively affect ultrasound mediated drug delivery. The ADV and IC thresholds were determined for various bulk fluid, droplet, and acoustic parameters. At 3.5 MHz, the ADV threshold occurred at a lower rarefactional pressure than the IC threshold. The results suggest that ADV is a distinct phenomenon from IC, the ADV nucleus is internal to the droplet, and the IC nucleus is the bubble generated by ADV. The ADV triggered release of a lipophilic chemotherapeutic agent, chlorambucil (CHL), from a PFC-in-oil-in-water emulsion was explored using plated cells. Cells exposed to a CHL-loaded emulsion, without ADV, displayed 44% less growth inhibition than cells exposed to an equal concentration of CHL in solution. Upon ADV of the CHL-loaded emulsion, the growth inhibition increased to the same level as cells exposed to CHL in solution. A triblock copolymer was synthesized which enabled the formulation of stable water-in-PFC-in-water (W1/PFC/W2) emulsions. The encapsulation of fluorescein in the W1 phase significantly decreased the mass flux of fluorescein; ADV was shown to completely release the fluorescein from the emulsions. ADV was also shown to release thrombin, dissolved in the W1 phase, which could be used in vivo to extend synergistically the duration of ADV-generated, microbubble-based embolizations. Overall, the results suggest that PFC double emulsions can be used as an ultrasound-triggered drug delivery system. Compared to traditional drug delivery systems, ADV could be used to increase the therapeutic efficacy and decrease the systemic toxicity of drug therapy.

Implications for glycine receptors and astrocytes in ethanol-induced elevation of dopamine levels in the nucleus accumbens.

PubMed

Adermark, Louise; Clarke, Rhona B C; Olsson, Torsten; Hansson, Elisabeth; Söderpalm, Bo; Ericson, Mia

2011-01-01

Elevated dopamine levels are believed to contribute to the rewarding sensation of ethanol (EtOH), and previous research has shown that strychnine-sensitive glycine receptors in the nucleus accumbens (nAc) are involved in regulating dopamine release and in mediating the reinforcing effects of EtOH. Furthermore, the osmoregulator taurine, which is released from astrocytes treated with EtOH, can act as an endogenous ligand for the glycine receptor, and increase extracellular dopamine levels. The aim of this study was to address if EtOH-induced swelling of astrocytes could contribute to elevated dopamine levels by increasing the extracellular concentration of taurine. Cell swelling was estimated by optical sectioning of fluorescently labeled astrocytes in primary cultures from rat, and showed that EtOH (25-150 mM) increased astrocyte cell volumes in a concentration- and ion-dependent manner. The EtOH-induced cell swelling was inhibited in cultures treated with the Na(+) /K(+) /2Cl⁻ cotransporter blocker furosemide (1 mM), Na(+) /K(+) -ATPase inhibitor ouabain (0.1 mM), potassium channel inhibitor BaCl₂ (50 µM) and in cultures containing low extracellular sodium concentration (3 mM). In vivo microdialysis performed in the nAc of awake and freely moving rats showed that local treatment with EtOH enhanced the concentrations of dopamine and taurine in the microdialysate, while glycine and β-alanine levels were not significantly modulated. EtOH-induced dopamine release was antagonized by local treatment with the glycine receptor antagonist strychnine (20 µM) or furosemide (100 µM or 1 mM). Furosemide also prevented EtOH-induced taurine release in the nAc. In conclusion, our data suggest that extracellular concentrations of dopamine and taurine are interconnected and that swelling of astrocytes contributes to the acute rewarding sensation of EtOH. © 2010 The Authors, Addiction Biology © 2010 Society for the Study of Addiction.

Phasic dopamine release in the nucleus accumbens in response to pro-social 50 kHz ultrasonic vocalizations in rats.

PubMed

Willuhn, Ingo; Tose, Amanda; Wanat, Matthew J; Hart, Andrew S; Hollon, Nick G; Phillips, Paul E M; Schwarting, Rainer K W; Wöhr, Markus

2014-08-06

Rats emit ultrasonic vocalizations (USVs) that are thought to serve as situation-dependent affective signals and accomplish important communicative functions. In appetitive situations, rats produce 50 kHz USVs, whereas 22 kHz USVs occur in aversive situations. Reception of 50 kHz USVs induces social approach behavior, while 22 kHz USVs lead to freezing behavior. These opposite behavioral responses are paralleled by distinct brain activation patterns, with 50 kHz USVs, but not 22 kHz USVs, activating neurons in the nucleus accumbens (NAcc). The NAcc mediates appetitive behavior and is critically modulated by dopaminergic afferents that are known to encode the value of reward. Therefore, we hypothesized that 50 kHz USVs, but not 22 kHz USVs, elicit NAcc dopamine release. While recording dopamine signaling with fast-scan cyclic voltammetry, freely moving rats were exposed to playback of four acoustic stimuli via an ultrasonic speaker in random order: (1) 50 kHz USVs, (2) 22 kHz USVs, (3) time- and amplitude-matched white noise, and (4) background noise. Only presentation of 50 kHz USVs induced phasic dopamine release and elicited approach behavior toward the speaker. Both of these effects, neurochemical and behavioral, were most pronounced during initial playback, but then declined rapidly with subsequent presentations, indicating a close temporal relationship between the two measures. Moreover, the magnitudes of these effects during initial playback were significantly correlated. Collectively, our findings show that NAcc dopamine release encodes pro-social 50 kHz USVs, but not alarming 22 kHz USVs. Thus, our results support the hypothesis that these call types are processed in distinct neuroanatomical regions and establish a functional link between pro-social communicative signals and reward-related neurotransmission. Copyright © 2014 the authors 0270-6474/14/3410616-08$15.00/0.

The effects of reserpine and 6-hydroxydopamine on the concentrations of some arylakylamines in rat brain.

PubMed Central

Boulton, A A; Juorio, A V; Philips, S R; Wu, P H

1977-01-01

1 The concentrations of p- and m-tyramine were measured in the caudate nucleus of the rat brain following subcutaneous injection of reserpine or intraventricular injection of 6-hydroxydopamine, beta-Phenylethylamine was analysed in the hypothalamus after reserpine. 2 Endogenous levels of p-tyramine and m-tyramine in the caudate nucleus, and beta-phenylethylamine in the hypothalamus were 8.02, 2.25 and 2.52 ng/g respectively. 3 Tyramine concentrations were reduced to less than 20% of control values one day after a reserpine injection of 1 or 10 mg/kg. A single dose of reserpine (0.4 mg/kg) significantly decreased the content of both tyramines in the caudate nucleus. The effects became apparent as early as 45 min after drug case of m-tyramine. 4 The hypothalamic content of beta-phenylethylamine was unaffected by reserpine. 5 Ten days after an intraventricular injection of 6-hydroxydopamine (250 mug), p- and m-tyramine concentrations in the caudate nucleus were significantly below control levels. 6 The results suggest that p- and m-tyramine may be stored by an intraneuronal reserpine-sensitive storage mechanism. Alternatively, the tyramines may replace some of the catecholamines from their storage granules and then be released as false transmitters by the nervous impulse. The observed changes in tyramine levels might also the fact that these amines may be metabolically related to another amine which is stored in reserpine-sensitive granules. PMID:837000

Evidence that metyrapone can act as a stressor: effect on pituitary-adrenal hormones, plasma glucose and brain c-fos induction.

PubMed

Rotllant, David; Ons, Sheila; Carrasco, Javier; Armario, Antonio

2002-08-01

Metyrapone, a 11-beta steroid hydroxylase inhibitor that blocks stress-induced glucocorticoid release, is extensively used to study the physiological and behavioural roles of glucocorticoids. However, there is circumstantial evidence suggesting that metyrapone could act as a pharmacological stressor. Thus, the effects of various doses of metyrapone on two well-characterized stress markers (ACTH and glucose) were studied in male rats. Metyrapone administration, while exerting a modest effect on plasma corticosterone levels, dose-dependently increased plasma ACTH and glucose levels. Using the highest doses previously tested (200 mg/kg) we further observed, as evaluated by fos-like immunoreactivity (FLI), a strong activation of a wide range of brain areas, including the parvocellular region of the hypothalamic paraventricular nucleus (PVNp), the origin of the main ACTH secretagogues. Metyrapone-induced FLI was observed in neocortical and allocortical areas, in several limbic, thalamic and hypothalamic nuclei and, to a lesser extent, in the brainstem. In a final experiment, a dose-response study of metyrapone-induced FLI was carried out focusing on selected brain areas. The study revealed that the paraventricular thalamic nucleus and central amygdala were the areas most sensitive to metyrapone as they responded even to the lowest dose of the drug. Most areas, among them the PVNp, only showed enhanced FLI with the two highest doses, i.e. when it was associated with ACTH and glucose responses. These data suggest that some of the effects of metyrapone could be due to its stressful properties rather than its ability to inhibit glucocorticoid synthesis. The exact mechanisms involved remain to be established.

Structure and function of the amygdaloid NPY system: NPY Y2 receptors regulate excitatory and inhibitory synaptic transmission in the centromedial amygdala.

PubMed

Wood, J; Verma, D; Lach, G; Bonaventure, P; Herzog, H; Sperk, G; Tasan, R O

2016-09-01

The amygdala is essential for generating emotional-affective behaviors. It consists of several nuclei with highly selective, elaborate functions. In particular, the central extended amygdala, consisting of the central amygdala (CEA) and the bed nucleus of the stria terminalis (BNST) is an essential component actively controlling efferent connections to downstream effectors like hypothalamus and brain stem. Both, CEA and BNST contain high amounts of different neuropeptides that significantly contribute to synaptic transmission. Among these, neuropeptide Y (NPY) has emerged as an important anxiolytic and fear-reducing neuromodulator. Here, we characterized the expression, connectivity and electrophysiological function of NPY and Y2 receptors within the CEA. We identified several NPY-expressing neuronal populations, including somatostatin- and calretinin-expressing neurons. Furthermore, in the main intercalated nucleus, NPY is expressed primarily in dopamine D1 receptor-expressing neurons but also in interspersed somatostatin-expressing neurons. Interestingly, NPY neurons did not co-localize with the Y2 receptor. Retrograde tract tracing experiments revealed that NPY neurons reciprocally connect the CEA and BNST. Functionally, the Y2 receptor agonist PYY3-36, reduced both, inhibitory as well as excitatory synaptic transmission in the centromedial amygdala (CEm). However, we also provide evidence that lack of NPY or Y2 receptors results in increased GABA release specifically at inhibitory synapses in the CEm. Taken together, our findings suggest that NPY expressed by distinct populations of neurons can modulate afferent and efferent projections of the CEA via presynaptic Y2 receptors located at inhibitory and excitatory synapses.

Neural mechanisms of sexual behavior in the male rat: emphasis on ejaculation-related circuits.

PubMed

Veening, J G; Coolen, L M

2014-06-01

Sexual behavior of the male rat can be described as a 'sequence': a series of behavioral transitions eventually leading to a consummatory act: ejaculation. A 'funnel-model' is presented to describe the behavioral progression during the sexual sequence. The ejaculation itself is extensively controlled by the 'spinal ejaculation generator', consisting of several elements with afferent sources of genitosensory information, with ascending projection fibers to inform the brainstem and forebrain as well as with descending afferent fibers providing the supraspinal control mechanisms with the opportunity to restrict ejaculations to the optimal moments and circumstances. The messages ascending from the spinal cord reach several interconnected thalamic, hypothalamic and limbic brain areas and are integrated with olfactory information. These brain areas play a role in mechanisms like 'sexual satiety' or a temporary interruption of sexual activities (post-ejaculatory interval), but the exact facilitatory and inhibitory mechanisms involved have not been elucidated yet. In the 'downward' mechanisms controlling the spinal 'release' of an ejaculation, the medial preoptic nucleus plays an important role in cooperation with a number of brainstem areas. This nucleus is also explicitly involved in the rewarding experiences coming with an ejaculation. Finally, the role of several neurotransmitters and-peptides on male sexual behavior are discussed shortly, because sometimes they show remarkable effects on specific aspects of the behavioral sequence. We conclude that, despite our increased knowledge about the brain mechanisms involved in the control of ejaculation, we are still far away from a complete understanding and quite a few questions remain to be resolved. Copyright © 2014 Elsevier Inc. All rights reserved.

Functional characterization of the essential tail anchor of the herpes simplex virus type 1 nuclear egress protein pUL34.

PubMed

Ott, Melanie; Tascher, Georg; Hassdenteufel, Sarah; Zimmermann, Richard; Haas, Jürgen; Bailer, Susanne M

2011-12-01

Release of herpes simplex virus type 1 (HSV-1) nucleocapsids from the host nucleus relies on the nuclear egress complex consisting of the two essential proteins pUL34 and pUL31. The cytoplasmically exposed N-terminal region of pUL34 interacts with pUL31, while a hydrophobic region followed by a short luminal part mediates membrane association. Based on its domain organization, pUL34 was postulated to be a tail-anchor (TA) protein. We performed a coupled in vitro transcription/translation assay to show that membrane insertion of pUL34 occurs post-translationally. Transient transfection and localization experiments in mammalian cells were combined with HSV-1 bacterial artificial chromosome mutagenesis to reveal the functional properties of the essential pUL34 TA. Our data show that a minimal tail length of 15 residues is sufficient for nuclear envelope targeting and pUL34 function. Permutations of the pUL34 TA with orthologous regions of human cytomegalovirus pUL50 or Epstein-Barr virus pBFRF1 as well as the heterologous HSV-1 TA proteins pUL56 or pUS9 or the cellular TA proteins Bcl-2 and Vamp2 revealed that nuclear egress tolerates TAs varying in sequence and hydrophobicity, while a non-α-helical membrane anchor failed to complement the pUL34 function. In conclusion, this study provides the first mechanistic insights into the particular role of the TA of pUL34 in membrane curving and capsid egress from the host nucleus.

Anatomical Evidence that the Superior Colliculus Controls Saccades through Central Mesencephalic Reticular Formation Gating of Omnipause Neuron Activity

PubMed Central

Wang, Niping; Perkins, Eddie; Zhou, Lan; Warren, Susan

2013-01-01

Omnipause neurons (OPNs) within the nucleus raphe interpositus (RIP) help gate the transition between fixation and saccadic eye movements by monosynaptically suppressing activity in premotor burst neurons during fixation, and releasing them during saccades. Premotor neuron activity is initiated by excitatory input from the superior colliculus (SC), but how the tectum's saccade-related activity turns off OPNs is not known. Since the central mesencephalic reticular formation (cMRF) is a major SC target, we explored whether this nucleus has the appropriate connections to support tectal gating of OPN activity. In dual-tracer experiments undertaken in macaque monkeys (Macaca fascicularis), cMRF neurons labeled retrogradely from injections into RIP had numerous anterogradely labeled terminals closely associated with them following SC injections. This suggested the presence of an SC–cMRF–RIP pathway. Furthermore, anterograde tracers injected into the cMRF of other macaques labeled axonal terminals in RIP, confirming this cMRF projection. To determine whether the cMRF projections gate OPN activity, postembedding electron microscopic immunochemistry was performed on anterogradely labeled cMRF terminals with antibody to GABA or glycine. Of the terminals analyzed, 51.4% were GABA positive, 35.5% were GABA negative, and most contacted glycinergic cells. In summary, a trans-cMRF pathway connecting the SC to the RIP is present. This pathway contains inhibitory elements that could help gate omnipause activity and allow other tectal drives to induce the bursts of firing in premotor neurons that are necessary for saccades. The non-GABAergic cMRF terminals may derive from fixation units in the cMRF. PMID:24107960

Single oral administration of flavan 3-ols induces stress responses monitored with stress hormone elevations in the plasma and paraventricular nucleus.

PubMed

Fujii, Yasuyuki; Suzuki, Kenta; Hasegawa, Yahiro; Nanba, Fumio; Toda, Toshiya; Adachi, Takahiro; Taira, Shu; Osakabe, Naomi

2018-06-11

We previously confirmed that postprandial alterations in the circulation and metabolism after a single oral dose of flavan 3-ols (mixture of catechin and catechin oligomers) were involved in an increase in sympathetic nervous activity. However, it is well known that, in response to various stresses, activation of the hypothalamic-pituitary-adrenal (HPA) axis occurs together with sympathetic nerve activity, which is associated with activation of the sympathetic-adrenal-medullary (SAM) axis. In this study, we examined whether the HPA axis was activated after a single dose of flavan 3-ols. We administered an oral dose of 10 or 50 mg/kg flavan 3-ols to male ICR mice, removed the brains, and fixed them in paraformaldehyde-phosphate buffer. Other animals that were treated similarly were decapitated, and blood was collected. In the paraventricular nucleus (PVN), c-fos mRNA expression increased significantly at 15 min after administration of either 10 or 50 mg/kg flavan 3-ols. Corticotropin-releasing hormone (CRH) mRNA expression levels significantly increased at 240 min after administration of 10 mg/kg flavan 3-ols, and at 60 min after administration of 50 mg/kg flavan 3-ols. Plasma corticosterone levels were also significantly increased at 240 min after ingestion of 50 mg/kg flavan 3-ols. In this experiment, we confirmed that the ingestion of flavan 3-ols acted as a stressor in mammals with activation both the SAM and HPA axes. Copyright © 2018 Elsevier B.V. All rights reserved.

Anatomical evidence that the superior colliculus controls saccades through central mesencephalic reticular formation gating of omnipause neuron activity.

PubMed

Wang, Niping; Perkins, Eddie; Zhou, Lan; Warren, Susan; May, Paul J

2013-10-09

Omnipause neurons (OPNs) within the nucleus raphe interpositus (RIP) help gate the transition between fixation and saccadic eye movements by monosynaptically suppressing activity in premotor burst neurons during fixation, and releasing them during saccades. Premotor neuron activity is initiated by excitatory input from the superior colliculus (SC), but how the tectum's saccade-related activity turns off OPNs is not known. Since the central mesencephalic reticular formation (cMRF) is a major SC target, we explored whether this nucleus has the appropriate connections to support tectal gating of OPN activity. In dual-tracer experiments undertaken in macaque monkeys (Macaca fascicularis), cMRF neurons labeled retrogradely from injections into RIP had numerous anterogradely labeled terminals closely associated with them following SC injections. This suggested the presence of an SC-cMRF-RIP pathway. Furthermore, anterograde tracers injected into the cMRF of other macaques labeled axonal terminals in RIP, confirming this cMRF projection. To determine whether the cMRF projections gate OPN activity, postembedding electron microscopic immunochemistry was performed on anterogradely labeled cMRF terminals with antibody to GABA or glycine. Of the terminals analyzed, 51.4% were GABA positive, 35.5% were GABA negative, and most contacted glycinergic cells. In summary, a trans-cMRF pathway connecting the SC to the RIP is present. This pathway contains inhibitory elements that could help gate omnipause activity and allow other tectal drives to induce the bursts of firing in premotor neurons that are necessary for saccades. The non-GABAergic cMRF terminals may derive from fixation units in the cMRF.

Exposure to retrieval cues improves retention performance and induces changes in ACTH and corticosterone release.

PubMed

Gisquet-Verrier, Pascale; Botreau, Fanny; Venero, Cesar; Sandi, Carmen

2004-05-01

Memory retrieval can be facilitated by pretest exposure to cues associated with the original training. The present series of experiments was aimed at investigating whether the effectiveness of the retrieval cues might be due to their emotional value and thus be associated to a particular pattern of activation of stress systems. Therefore, the effects of exposing rats to different cueing conditions were investigated both on retention performance and on the level of different stress hormones (ACTH, corticosterone and glucose; the latter as an indirect index of adrenergic/sympathetic nervous system activation). Rats trained in a brightness avoidance discrimination task exhibited an enhancement of the retention performance following exposure to the light discriminative stimulus when delivered 1-day after training and not after 21 days, while exposure to contextual cues led to opposite effects on the retention performance, confirming our previous results. Analyses of the level of stress hormones at the time of testing indicated that when the retrieval cues were effective at the behavioral level, cued rats exhibited higher ACTH plasmatic levels than controls, but did not differ in their glucose or corticosterone levels. Further experiments showed that one day after training, both ACTH and corticosterone levels were elevated in light-cued rats if hormone samples were taken 15 min after cueing. These results show that exposure to an effective retrieval cue is accompanied by the activation of the hypothalamus-pituitary-adrenal axis. The possible involvement of the Corticotropin Releasing Factor at the level of the hypothalamus and amygdala (particularly the central nucleus) on the facilitating effect on retention performance following exposure to aversive training-associated cues is discussed. The present results strengthen the notion that emotion can interact with retrieval processes.

Zen and the brain: mutually illuminating topics.

PubMed

Austin, James H

2013-10-24

Zen Buddhist meditative practices emphasize the long-term, mindful training of attention and awareness during one's ordinary daily-life activities, the shedding of egocentric behaviors, and the skillful application of one's innate compassionate resources of insight-wisdom toward others and oneself. This review focuses on how such a comprehensive approach to training the brain could relate to a distinctive flavor of Zen: its emphasis on direct experience, with special reference to those major acute states of awakening that create deep transformations of consciousness and behavior. In Japanese, these advanced states are called kensho and satori. Ten key concepts are reviewed. They begin by distinguishing between the concentrative and receptive forms of meditation, noticing the complementary ways that they each train our normal "top-down" and "bottom-up" modes of attentive processing. Additional concepts distinguish between our two major processing pathways. The self-centered, egocentric frame of reference processes information in relation to our body (our soma) or to our mental functions (our psyche). The other-centered frame of reference processes information anonymously. Its prefix, allo- simply means "other" in Greek. Subsequent concepts consider how these useful Greek words-ego/allo, soma/psyche-correlate with the normal functional anatomy of important thalamo ↔ cortical connections. A plausible model then envisions how a triggering stimulus that captures attention could prompt the reticular nucleus to release GABA; how its selective inhibition of the dorsal thalamus could then block both our higher somatic and psychic cortical functions; so as to: (a) delete the maladaptive aspects of selfhood, while also (b) releasing the direct, all-inclusive, globally-unified experience of other. Two final concepts consider how the long-term meditative training of intuitive functions relates to certain kinds of word-free spatial tasks that involve insightful creative problem-solving.

Zen and the brain: mutually illuminating topics

PubMed Central

Austin, James H.

2013-01-01

Zen Buddhist meditative practices emphasize the long-term, mindful training of attention and awareness during one's ordinary daily-life activities, the shedding of egocentric behaviors, and the skillful application of one's innate compassionate resources of insight-wisdom toward others and oneself. This review focuses on how such a comprehensive approach to training the brain could relate to a distinctive flavor of Zen: its emphasis on direct experience, with special reference to those major acute states of awakening that create deep transformations of consciousness and behavior. In Japanese, these advanced states are called kensho and satori. Ten key concepts are reviewed. They begin by distinguishing between the concentrative and receptive forms of meditation, noticing the complementary ways that they each train our normal “top–down” and “bottom–up” modes of attentive processing. Additional concepts distinguish between our two major processing pathways. The self-centered, egocentric frame of reference processes information in relation to our body (our soma) or to our mental functions (our psyche). The other-centered frame of reference processes information anonymously. Its prefix, allo- simply means “other” in Greek. Subsequent concepts consider how these useful Greek words—ego/allo, soma/psyche—correlate with the normal functional anatomy of important thalamo ↔ cortical connections. A plausible model then envisions how a triggering stimulus that captures attention could prompt the reticular nucleus to release GABA; how its selective inhibition of the dorsal thalamus could then block both our higher somatic and psychic cortical functions; so as to: (a) delete the maladaptive aspects of selfhood, while also (b) releasing the direct, all-inclusive, globally-unified experience of other. Two final concepts consider how the long-term meditative training of intuitive functions relates to certain kinds of word-free spatial tasks that involve insightful creative problem-solving. PMID:24187544

Periodic mechanical stress activates EGFR-dependent Rac1 mitogenic signals in rat nucleus pulpous cells via ERK1/2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gao, Gongming; Shen, Nan; Jiang, Xuefeng

2016-01-15

The mitogenic effects of periodic mechanical stress on nucleus pulpous cells have been studied extensively but the mechanisms whereby nucleus pulpous cells sense and respond to mechanical stimulation remain a matter of debate. We explored this question by performing cell culture experiments in our self-developed periodic stress field and perfusion culture system. Under periodic mechanical stress, rat nucleus pulpous cell proliferation was significantly increased (p < 0.05 for each) and was associated with increases in the phosphorylation and activation of EGFR, Rac1, and ERK1/2 (p < 0.05 for each). Pretreatment with the ERK1/2 selective inhibitor PD98059 reduced periodic mechanical stress-induced nucleus pulpous cell proliferationmore » (p < 0.05 for each), while the activation levels of EGFR and Rac1 were not inhibited. Proliferation and phosphorylation of ERK1/2 were inhibited after pretreatment with the Rac1 inhibitor NSC23766 in nucleus pulpous cells in response to periodic mechanical stress (p < 0.05 for each), while the phosphorylation site of EGFR was not affected. Inhibition of EGFR activity with AG1478 abrogated nucleus pulpous cell proliferation (p < 0.05 for each) and attenuated Rac1 and ERK1/2 activation in nucleus pulpous cells subjected to periodic mechanical stress (p < 0.05 for each). These findings suggest that periodic mechanical stress promotes nucleus pulpous cell proliferation in part through the EGFR-Rac1-ERK1/2 signaling pathway, which links these three important signaling molecules into a mitogenic cascade. - Highlights: • The mechanism involved in nucleus pulpous cells to respond to mechanical stimuli. • Periodic mechanical stress can stimulate the phosphorylation of EGFR. • EGFR activates Rac1 and leads to rat nucleus pulpous cell proliferation. • EGFR and Rac1 activate ERK1/2 mitogenic signals in nucleus pulpous cells. • EGFR-Rac1-ERK1/2 is constitutes at least one critical signal transduction pathway.« less

The Sensory Features of a Food Cue Influence Its Ability to Act as an Incentive Stimulus and Evoke Dopamine Release in the Nucleus Accumbens Core

ERIC Educational Resources Information Center

Singer, Bryan F.; Bryan, Myranda A.; Popov, Pavlo; Scarff, Raymond; Carter, Cody; Wright, Erin; Aragona, Brandon J.; Robinson, Terry E.

2016-01-01

The sensory properties of a reward-paired cue (a conditioned stimulus; CS) may impact the motivational value attributed to the cue, and in turn influence the form of the conditioned response (CR) that develops. A cue with multiple sensory qualities, such as a moving lever-CS, may activate numerous neural pathways that process auditory and visual…

Search for the Exotic Wobbling Mode in Rhenium-171

DTIC Science & Technology

2011-05-13

USB hard drive. The decay sequences mentioned above release all of their γ rays within a nanosecond (ns). Data will be recorded when multiple ...events in which multiple detectors measured γ rays within a 120 ns window. An event in which three detectors fired within the coincidence window is...spherical nuclei; however, if the nucleus is axially deformed (non-spherical), the shell model cannot accurately describe its features . The shell model

NuSTEC1 White Paper: Status and challenges of neutrino-nucleus scattering

NASA Astrophysics Data System (ADS)

Alvarez-Ruso, L.; Sajjad Athar, M.; Barbaro, M. B.; Cherdack, D.; Christy, M. E.; Coloma, P.; Donnelly, T. W.; Dytman, S.; de Gouvêa, A.; Hill, R. J.; Huber, P.; Jachowicz, N.; Katori, T.; Kronfeld, A. S.; Mahn, K.; Martini, M.; Morfín, J. G.; Nieves, J.; Perdue, G. N.; Petti, R.; Richards, D. G.; Sánchez, F.; Sato, T.; Sobczyk, J. T.; Zeller, G. P.

2018-05-01

The precise measurement of neutrino properties is among the highest priorities in fundamental particle physics, involving many experiments worldwide. Since the experiments rely on the interactions of neutrinos with bound nucleons inside atomic nuclei, the planned advances in the scope and precision of these experiments require a commensurate effort in the understanding and modeling of the hadronic and nuclear physics of these interactions, which is incorporated as a nuclear model in neutrino event generators. This model is essential to every phase of experimental analyses and its theoretical uncertainties play an important role in interpreting every result. In this White Paper we discuss in detail the impact of neutrino-nucleus interactions, especially the nuclear effects, on the measurement of neutrino properties using the determination of oscillation parameters as a central example. After an Executive Summary and a concise Overview of the issues, we explain how the neutrino event generators work, what can be learned from electron-nucleus interactions and how each underlying physics process - from quasi-elastic to deep inelastic scattering - is understood today. We then emphasize how our understanding must improve to meet the demands of future experiments. With every topic we find that the challenges can be met only with the active support and collaboration among specialists in strong interactions and electroweak physics that include theorists and experimentalists from both the nuclear and high energy physics communities.

NuSTEC White Paper: Status and Challenges of Neutrino-Nucleus Scattering

DOE Office of Scientific and Technical Information (OSTI.GOV)

Alvarez-Ruso, L.; et al.

The precise measurement of neutrino properties is among the highest priorities in fundamental particle physics, involving many experiments worldwide. Since the experiments rely on the interactions of neutrinos with bound nucleons inside atomic nuclei, the planned advances in the scope and precision of these experiments requires a commensurate effort in the understanding and modeling of the hadronic and nuclear physics of these interactions, which is incorporated as a nuclear model in neutrino event generators. This model is essential to every phase of experimental analyses and its theoretical uncertainties play an important role in interpreting every result. In this White Papermore » we discuss in detail the impact of neutrino-nucleus interactions, especially the nuclear effects, on the measurement of neutrino properties using the determination of oscillation parameters as a central example. After an Executive Summary and a concise Overview of the issues, we explain how the neutrino event generators work, what can be learned from electron-nucleus interactions and how each underlying physics process - from quasi-elastic to deep inelastic scattering - is understood today. We then emphasize how our understanding must improve to meet the demands of future experiments. With every topic we find that the challenges can be met only with the active support and collaboration among specialists in strong interactions and electroweak physics that include theorists and experimentalists from both the nuclear and high energy physics communities.« less

Universal functions of nuclear proximity potential for Skyrme nucleus-nucleus interaction in a semiclassical approach

NASA Astrophysics Data System (ADS)

Gupta, Raj K.; Singh, Dalip; Kumar, Raj; Greiner, Walter

2009-07-01

The universal function of the nuclear proximity potential is obtained for the Skyrme nucleus-nucleus interaction in the semiclassical extended Thomas-Fermi (ETF) approach. This is obtained as a sum of the spin-orbit-density-independent and spin-orbit-density-dependent parts of the Hamiltonian density, since the two terms behave differently, the spin-orbit-density-independent part mainly attractive and the spin-orbit-density-dependent part mainly repulsive. The semiclassical expansions of kinetic energy density and spin-orbit density are allowed up to second order, and the two-parameter Fermi density, with its parameters fitted to experiments, is used for the nuclear density. The universal functions or the resulting nuclear proximity potential reproduce the 'exact' Skyrme nucleus-nucleus interaction potential in the semiclassical approach, within less than ~1 MeV of difference, both at the maximum attraction and in the surface region. An application of the resulting interaction potential to fusion excitation functions shows clearly that the parameterized universal functions of nuclear proximity potential substitute completely the 'exact' potential in the Skyrme energy density formalism based on the semiclassical ETF method, including also the modifications of interaction barriers at sub-barrier energies in terms of modifying the constants of the universal functions.

Velocity-resolved observations of water in Comet Halley

NASA Technical Reports Server (NTRS)

Larson, Harold P.; Davis, D. Scott; Mumma, Michael J.; Weaver, Harold A.

1986-01-01

High resolution (lambda/delta lambda approx. = 3 x 10 to the 5th power) near-infrared observations of H2O emission from Comet Halley were acquired at the time of maximum post-perihelion geocentric Doppler shift. The observed widths and absolute positions of the H2O line profiles reveal characteristics of the molecular velocity field in the coma. These results support H2O outflow from a Sun-lit hemisphere or the entire nucleus, but not from a single, narrow jet emanating from the nucleus. The measured pre- and post-perihelion outflow velocities were 0.9 + or - 0.2 and 1.4 + or - 0.2 km/s, respectively. Temporal variations in the kinematic properties of the outflow were inferred from changes in the spectral line shapes. These results are consistent with the release of H2O into the coma from multiple jets.

Centrosome docking at the immunological synapse is controlled by Lck signaling

PubMed Central

Tsun, Andy; Qureshi, Ihjaaz; Stinchcombe, Jane C.; Jenkins, Misty R.; de la Roche, Maike; Kleczkowska, Joanna; Zamoyska, Rose

2011-01-01

Docking of the centrosome at the plasma membrane directs lytic granules to the immunological synapse. To identify signals controlling centrosome docking at the synapse, we have studied cytotoxic T lymphocytes (CTLs) in which expression of the T cell receptor–activated tyrosine kinase Lck is ablated. In the absence of Lck, the centrosome is able to translocate around the nucleus toward the immunological synapse but is unable to dock at the plasma membrane. Lytic granules fail to polarize and release their contents, and target cells are not killed. In CTLs deficient in both Lck and the related tyrosine kinase Fyn, centrosome translocation is impaired, and the centrosome remains on the distal side of the nucleus relative to the synapse. These results show that repositioning of the centrosome in CTLs involves at least two distinct steps, with Lck signaling required for the centrosome to dock at the plasma membrane. PMID:21339332

The tumor suppressor PTEN has a critical role in antiviral innate immunity.

PubMed

Li, Shun; Zhu, Mingzhu; Pan, Ruangang; Fang, Ting; Cao, Yuan-Yuan; Chen, Shuliang; Zhao, Xiaolu; Lei, Cao-Qi; Guo, Lin; Chen, Yu; Li, Chun-Mei; Jokitalo, Eija; Yin, Yuxin; Shu, Hong-Bing; Guo, Deyin

2016-03-01

The gene encoding PTEN is one of the most frequently mutated tumor suppressor-encoding genes in human cancer. While PTEN's function in tumor suppression is well established, its relationship to anti-microbial immunity remains unknown. Here we found a pivotal role for PTEN in the induction of type I interferon, the hallmark of antiviral innate immunity, that was independent of the pathway of the kinases PI(3)K and Akt. PTEN controlled the import of IRF3, a master transcription factor responsible for IFN-β production, into the nucleus. We further identified a PTEN-controlled negative phosphorylation site at Ser97 of IRF3 and found that release from this negative regulation via the phosphatase activity of PTEN was essential for the activation of IRF3 and its import into the nucleus. Our study identifies crosstalk between PTEN and IRF3 in tumor suppression and innate immunity.

Transsynaptic trophic effects of steroid hormones in an avian model of adult brain plasticity

PubMed Central

Brenowitz, Eliot A.

2014-01-01

The avian song control system provides an excellent model for studying transsynaptic trophic effects of steroid sex hormones. Seasonal changes in systemic testosterone (T) and its metabolites regulate plasticity of this system. Steroids interact with the neurotrophin brain-derived neurotrophic factor (BDNF) to influence cellular processes of plasticity in nucleus HVC of adult birds, including the addition of newborn neurons. This interaction may also occur transsynpatically; T increases the synthesis of BDNF in HVC, and BDNF protein is then released by HVC neurons on to postsynaptic cells in nucleus RA where it has trophic effects on activity and morphology. Androgen action on RA neurons increases their activity and this has a retrograde trophic effect on the addition of new neurons to HVC. The functional linkage of sex steroids to BDNF may be of adaptive value in regulating the trophic effects of the neurotrophin and coordinating circuit function in reproductively relevant contexts. PMID:25285401

Creation of an injectable in situ gelling native extracellular matrix for nucleus pulposus tissue engineering.

PubMed

Wachs, Rebecca A; Hoogenboezem, Ella N; Huda, Hammad I; Xin, Shangjing; Porvasnik, Stacy L; Schmidt, Christine E

2017-03-01

Disc degeneration is the leading cause of low back pain and is often characterized by a loss of disc height, resulting from cleavage of chondroitin sulfate proteoglycans (CSPGs) present in the nucleus pulposus. Intact CSPGs are critical to water retention and maintenance of the nucleus osmotic pressure. Decellularization of healthy nucleus pulposus tissue has the potential to serve as an ideal matrix for tissue engineering of the disc because of the presence of native disc proteins and CSPGs. Injectable in situ gelling matrices are the most viable therapeutic option to prevent damage to the anulus fibrosus and future disc degeneration. The purpose of this research was to create a gentle decellularization method for use on healthy nucleus pulposus tissue explants and to develop an injectable formulation of this matrix to enable therapeutic use without substantial tissue disruption. Porcine nuclei pulposi were isolated, decellularized, and solubilized. Samples were assessed to determine the degree of cell removal, matrix maintenance, gelation ability, cytotoxic residuals, and native cell viability. Nuclei pulposi were decellularized using serial detergent, buffer, and enzyme treatments. Decellularized nuclei pulposi were solubilized, neutralized, and buffered. The efficacy of decellularization was assessed by quantifying DNA removal and matrix preservation. An elution study was performed to confirm removal of cytotoxic residuals. Gelation kinetics and injectability were quantified. Long-term in vitro experiments were performed with nucleus pulposus cells to ensure cell viability and native matrix production within the injectable decellularized nucleus pulposus matrices. This work resulted in the creation of a robust acellular matrix (>96% DNA removal) with highly preserved sulfated glycosaminoglycans (>47%), and collagen content and microstructure similar to native nucleus pulposus, indicating preservation of disc components. Furthermore, it was possible to create an injectable formulation that gelled in situ within 45 minutes and formed fibrillar collagen with similar diameters to native nucleus pulposus. The processing did not result in any remaining cytotoxic residuals. Solubilized decellularized nucleus pulposus samples seeded with nucleus pulposus cells maintained robust viability (>89%) up to 21 days of culture in vitro, with morphology similar to native nucleus pulposus cells, and exhibited significantly enhanced sulfated glycosaminoglycans production over 21 days. A gentle decellularization of porcine nucleus pulposus followed by solubilization enabled the creation of an injectable tissue-specific matrix that is well tolerated in vitro by nucleus pulposus cells. These matrices have the potential to be used as a minimally invasive nucleus pulposus therapeutic to restore disc height. Copyright © 2016 Elsevier Inc. All rights reserved.

Mechanical and SEM analysis of artificial comet nucleus samples

NASA Technical Reports Server (NTRS)

Thiel, K.; Kochan, H.; Roessler, K.; Gruen, E.; Schwehm, G.; Hellmann, H.; Hsiung, P.; Koelzer, G.

1989-01-01

Since 1987 experiments dealing with comet nucleus phenomena have been carried out in the DFVLR space simulation chambers. The main objective of these experiments is a better understanding of thermal behavior, surface phenomena and especially the gas dust interaction. As a function of different sample compositions and exposure to solar irradiation (xenon-bulbs) crusts of different hardness and thickness were measured. The measuring device consists of a motor driven pressure foot (5 mm diameter), which is pressed into the sample. The applied compressive force is electronically monitored. The microstructure of the crust and dust residuals is investigated by scanning electron microscopy (SEM) techniques. Stress-depth profiles of an unirradiated and an irradiated model comet are given.

[Effect of caffeine and phenamin on caudate inhibition of aggressive reactions in cats].

PubMed

Belozertsev, Iu A

1975-01-01

In chronic experiments conducted on cats it was shown that caffeine (10--30 mg/kg) failed to change agressive reactions developing in stimulation of the meso- or diencephalic structures. Phenamine (1--3 mg/kg) facilitated the appearance of emotional manifestations and lowered the threshold of the agressive response. Subliminal stimulation of the caudate nucleus in control experiments caused motor tranquilization and depressed the agressive behaviour to a lesser degree when practised against the background of the caffeine action. At the same time, phenamine abolished the influence not only of the threshold, but also of the subliminal stimulation of the caudate nucleus on the spontaneous motor activity and the rage behaviour.

Nuclei pulposi formation from the embryonic notochord occurs normally in GDF-5-deficient mice.

PubMed

Maier, Jennifer A; Harfe, Brian D

2011-11-15

The transition of the mouse embryonic notochord into nuclei pulposi was determined ("fate mapped") in vivo in growth and differentiating factor-5 (GDF-5)-null mice using the Shhcre and R26R alleles. To determine whether abnormal nuclei pulposi formation from the embryonic notochord was responsible for defects present in adult nuclei pulposi of Gdf-5-null mice. The development, maintenance, and degeneration of the intervertebral disc are not understood. Previously, we demonstrated that all cells in the adult nucleus pulposus of normal mice are derived from the embryonic notochord. Gdf-5-null mice have been reported to contain intervertebral discs in which the nucleus pulposus is abnormal. It is currently unclear if disc defects in Gdf-5-null mice arise during the formation of nuclei pulposi from the notochord during embryogenesis or result from progressive postnatal degeneration of nuclei pulposi. Gdf-5 messenger RNA expression was examined in the discs of wild-type embryos by RNA in situ hybridization to determine when and where this gene was expressed. To examine nucleus pulposus formation in Gdf-5-null mice, intervertebral discs in which embryonic notochord cells were marked were analyzed in newborn and 24-week-old mice. Our Gdf-5 messenger RNA in situ experiments determined that this gene is localized to the annulus fibrosus and not the nucleus pulposus in mouse embryos. Notochord fate-mapping experiments revealed that notochord cells in Gdf-5-null mice correctly form nuclei pulposi. Our data suggest that the defects reported in the nucleus pulposus of adult Gdf-5-null mice do not result from abnormal patterning of the embryonic notochord. The use of mouse alleles to mark cells that produce all cell types that reside in the adult nucleus pulposus will allow for a detailed examination of disc formation in other mouse mutants that have been reported to contain disc defects.

Nuclei pulposi formation from the embryonic notochord occurs normally in GDF5-deficient mice

PubMed Central

Maier, Jennifer A.; Harfe, Brian D.

2011-01-01

Study Design The transition of the mouse embryonic notochord into nuclei pulposi was determined (“fate mapped”) in vivo in GDF-5 null mice using the Shhcre and R26R alleles. Objective To determine if abnormal nuclei pulposi formation from the embryonic notochord was responsible for defects present in adult nuclei pulposi of Gdf-5 null mice. Summary of Background Data The development, maintenance, and degeneration of the intervertebral disc are not understood. Previously, we demonstrated that all cells in the adult nucleus pulposus of normal mice are derived from the embryonic notochord. Gdf-5 null mice have been reported to contain intervertebral discs in which the nucleus pulposus is abnormal. It is currently unclear if disc defects in Gdf-5 null mice arise during the formation of nuclei pulposi from the notochord during embryogenesis or resulted from progressive postnatal degeneration of nuclei pulposi. Methods Gdf-5 mRNA expression was examined in the discs of wild-type embryos by RNA in situ hybridization to determine when and where this gene was expressed. To examine nucleus pulposus formation in Gdf-5 null mice, intervertebral discs in which embryonic notochord cells were marked were analyzed in newborn and 24 week old mice. Results Our Gdf-5 mRNA in situ experiments determined that this gene is localized to the annulus fibrosus and not the nucleus pulposus in mouse embryos. Notochord fate mapping experiments revealed that notochord cells in Gdf-5 null mice correctly form nuclei pulposi. Conclusion Our data suggest that the defects reported in the nucleus pulposus of adult Gdf-5 null mice do not result from abnormal patterning of the embryonic notochord. The use of mouse alleles to mark cells that produce all cell types that reside in the adult nucleus pulposus will allow for a detailed examination of disc formation in other mouse mutants that have been reported to contain disc defects. PMID:21278629

Abuse-Related Neurochemical Effects of Para-Substituted Methcathinone Analogs in Rats: Microdialysis Studies of Nucleus Accumbens Dopamine and Serotonin

PubMed Central

Suyama, Julie A.; Sakloth, Farhana; Kolanos, Renata; Glennon, Richard A.; Lazenka, Matthew F.; Negus, S. Stevens

2016-01-01

Methcathinone (MCAT) is a monoamine releaser and parent compound to a new class of designer drugs that includes the synthetic cathinones mephedrone and flephedrone. Using MCAT and a series of para-substituted (or 4-substituted) MCAT analogs, it has been previously shown that expression of abuse-related behavioral effects in rats correlates both with the volume of the para substituent and in vitro neurochemical selectivity to promote monoamine release via the dopamine (DA) versus serotonin (5-HT) transporters in rat brain synaptosomes. The present study used in vivo microdialysis to determine the relationship between these previous measures and the in vivo neurochemical selectivity of these compounds to alter nucleus accumbens (NAc) DA and 5-HT levels. Male Sprague-Dawley rats were implanted with bilateral guide cannulae targeting the NAc. MCAT and five para-substituted analogs (4-F, 4-Cl, 4-Br, 4-CH3, and 4-OCH3) produced dose- and time-dependent increases in NAc DA and/or 5-HT levels. Selectivity was determined as the dose required to increase peak 5-HT levels by 250% divided by the dose required to increase peak DA levels by 250%. This measure of in vivo neurochemical selectivity varied across compounds and correlated with 1) in vivo expression of abuse-related behavioral effects (r = 0.89, P = 0.02); 2) in vitro selectivity to promote monoamine release via DA and 5-HT transporters (r = 0.95, P < 0.01); and 3) molecular volume of the para substituent (r = −0.85, P = 0.03). These results support a relationship between these molecular, neurochemical, and behavioral measures and support a role for molecular structure as a determinant of abuse-related neurochemical and behavioral effects of MCAT analogs. PMID:26645638

The Coxsackievirus and Adenovirus Receptor (CAR) Undergoes Ectodomain Shedding and Regulated Intramembrane Proteolysis (RIP)

PubMed Central

Houri, Nadia; Huang, Kuo-Cheng; Nalbantoglu, Josephine

2013-01-01

The Coxsackievirus and Adenovirus Receptor (CAR) is a cell adhesion molecule originally characterized as a virus receptor but subsequently shown to be involved in physiological processes such as neuronal and heart development, epithelial tight junction integrity, and tumour suppression. Proteolysis of cell adhesion molecules and a wide variety of other cell surface proteins serves as a mechanism for protein turnover and, in some cases, cell signaling. Metalloproteases such as A Disintegrin and Metalloprotease (ADAM) family members cleave cell surface receptors to release their substrates’ ectodomains, while the presenilin/ɣ-secretase complex mediates regulated intramembrane proteolysis (RIP), releasing intracellular domain fragments from the plasma membrane. In the case of some substrates such as Notch and amyloid precursor protein (APP), the released intracellular domains enter the nucleus to modulate gene expression. We report that CAR ectodomain is constitutively shed from glioma cells and developing neurons, and is also shed when cells are treated with the phorbol ester phorbol 12-myristate 13-acetate (PMA) and the calcium ionophore ionomycin. We identified ADAM10 as a sheddase of CAR using assays involving shRNA knockdown and rescue, overexpression of wild-type ADAM10 and inhibition of ADAM10 activity by addition of its prodomain. In vitro peptide cleavage, mass spectrometry and mutagenesis revealed the amino acids M224 to L227 of CAR as the site of ADAM10-mediated ectodomain cleavage. CAR also undergoes RIP by the presenilin/γ-secretase complex, and the intracellular domain of CAR enters the nucleus. Ectodomain shedding is a prerequisite for RIP of CAR. Thus, CAR belongs to the increasing list of cell surface molecules that undergo ectodomain shedding and that are substrates for ɣ-secretase-mediated RIP. PMID:24015300

Increased presynaptic regulation of dopamine neurotransmission in the nucleus accumbens core following chronic ethanol self-administration in female macaques

PubMed Central

Siciliano, Cody A.; Calipari, Erin S.; Yorgason, Jordan T.; Lovinger, David M.; Mateo, Yolanda; Jimenez, Vanessa A.; Helms, Christa M.; Grant, Kathleen A.; Jones, Sara R.

2016-01-01

Rationale Hypofunction of striatal dopamine neurotransmission, or hypodopaminergia, is a consequence of excessive ethanol use, and is hypothesized to be a critical component of alcoholism, driving alcohol intake in an attempt to restore dopamine levels; however, the neurochemical mechanisms involved in these dopaminergic deficiencies are unknown. Objective Here we examined the specific dopaminergic adaptations that produce hypodopaminergia and contribute to alcohol use disorders using direct, sub-second measurements of dopamine signaling in nonhuman primates following chronic ethanol self-administration. Methods Female rhesus macaques completed one year of daily (22 hr/day) ethanol self-administration. Subsequently, fast-scan cyclic voltammetry was used in nucleus accumbens core brain slices to determine alterations in dopamine terminal function, including release and uptake kinetics, and sensitivity to quinpirole (D2/D3 dopamine receptor agonist) and U50,488 (kappa-opioid receptor agonist) induced inhibition of dopamine release. Results Ethanol drinking greatly increased uptake rates, which were positively correlated with lifetime ethanol intake. Furthermore, the sensitivity of dopamine D2/D3 autoreceptors and kappa-opioid receptors, which both act as negative regulators of presynaptic dopamine release, were moderately and robustly enhanced in ethanol drinkers. Conclusions Greater uptake rates and sensitivity to D2-type autoreceptor and kappa-opioid receptor agonists could converge to drive a hypodopaminergic state, characterized by reduced basal dopamine and an inability to mount appropriate dopaminergic responses to salient stimuli. Together, we outline the specific alterations to dopamine signaling that may drive ethanol-induced hypofunction of the dopamine system, and suggest that the dopamine and dynorphin/kappa-opioid receptor systems may be efficacious pharmcotherapeutic targets in the treatment of alcohol use disorders. PMID:26892380

Reduced dopamine and glutamate neurotransmission in the nucleus accumbens of quinpirole-sensitized rats hints at inhibitory D2 autoreceptor function.

PubMed

Escobar, Angélica P; Cornejo, Francisca A; Olivares-Costa, Montserrat; González, Marcela; Fuentealba, José A; Gysling, Katia; España, Rodrigo A; Andrés, María E

2015-09-01

Dopamine from the ventral tegmental area and glutamate from several brain nuclei converge in the nucleus accumbens (NAc) to drive motivated behaviors. Repeated activation of D2 receptors with quinpirole (QNP) induces locomotor sensitization and compulsive behaviors, but the mechanisms are unknown. In this study, in vivo microdialysis and fast scan cyclic voltammetry in adult anesthetized rats were used to investigate the effect of repeated QNP on dopamine and glutamate neurotransmission within the NAc. Following eight injections of QNP, a significant decrease in phasic and tonic dopamine release was observed in rats that displayed locomotor sensitization. Either a systemic injection or the infusion of QNP into the NAc decreased dopamine release, and the extent of this effect was similar in QNP-sensitized and control rats, indicating that inhibitory D2 autoreceptor function is maintained despite repeated activation of D2 receptors and decreased dopamine extracellular levels. Basal extracellular levels of glutamate in the NAc were also significantly lower in QNP-treated rats than in controls. Moreover, the increase in NAc glutamate release induced by direct stimulation of medial prefrontal cortex was significantly lower in QNP-sensitized rats. Together, these results indicate that repeated activation of D2 receptors disconnects NAc from medial prefrontal cortex and ventral tegmental area. Repeated administration of the dopamine D2 receptor agonist quinpirole (QNP) induces locomotor sensitization. We found that the NAc of QNP-sensitized rats has reduced glutamate levels coming from prefrontal cortex together with a decreased phasic and tonic dopamine neurotransmission but a conserved presynaptic D2 receptor function. We suggest that locomotor sensitization is because of increased affinity state of D2 post-synaptic receptors. © 2015 International Society for Neurochemistry.

Neuromedin B and gastrin-releasing peptide excite arcuate nucleus neuropeptide Y neurons in a novel transgenic mouse expressing strong Renilla green fluorescent protein in NPY neurons.

PubMed

van den Pol, Anthony N; Yao, Yang; Fu, Li-Ying; Foo, Kylie; Huang, Hao; Coppari, Roberto; Lowell, Bradford B; Broberger, Christian

2009-04-08

Neuropeptide Y (NPY) is one of the most widespread neuropeptides in the brain. Transgenic mice were generated that expressed bright Renilla green fluorescent protein (GFP) in most or all of the known NPY cells in the brain, which otherwise were not identifiable. GFP expression in NPY cells was confirmed with immunocytochemistry and single-cell reverse transcription-PCR. NPY neurons in the hypothalamic arcuate nucleus play an important role in energy homeostasis and endocrine control. Whole-cell patch clamp recording was used to study identified arcuate NPY cells. Primary agents that regulate energy balance include melanocortin receptor agonists, AgRP, and cannabinoids; none of these substances substantially influenced electrical properties of NPY neurons. In striking contrast, neuropeptides of the bombesin family, including gastrin-releasing peptide and neuromedin B, which are found in axons in the mediobasal hypothalamus and may also be released from the gut to signal the brain, showed strong direct excitatory actions at nanomolar levels on the NPY neurons, stronger than the actions of ghrelin and hypocretin/orexin. Bombesin-related peptides reduced input resistance and depolarized the membrane potential. The depolarization was attenuated by several factors: substitution of choline for sodium, extracellular Ni(2+), inclusion of BAPTA in the pipette, KB-R7943, and SKF96365. Reduced extracellular calcium enhanced the current, which reversed around -20 mV. Together, these data suggest two mechanisms, activation of nonselective cation channels and the sodium/calcium exchanger. Since both NPY and POMC neurons, which we also studied, are similarly directly excited by bombesin-like peptides, the peptides may function to initiate broad activation, rather than the cell-type selective activation or inhibition reported for many other compounds that modulate energy homeostasis.

Neonatal finasteride administration decreases dopamine release in nucleus accumbens after alcohol and food presentation in adult male rats.

PubMed

Llidó, Anna; Bartolomé, Iris; Darbra, Sònia; Pallarès, Marc

2016-08-01

Endogenous levels of the neurosteroid (NS) allopregnanolone (AlloP) during neonatal stages are crucial for the correct development of the central nervous system (CNS). In a recent work we reported that the neonatal administration of AlloP or finasteride (Finas), an inhibitor of the enzyme 5α-reductase needed for AlloP synthesis, altered the voluntary consumption of ethanol and the ventrostriatal dopamine (DA) levels in adulthood, suggesting that neonatal NS manipulations can increase alcohol abuse vulnerability in adulthood. Moreover, other authors have associated neonatal NS alterations with diverse dopaminergic (DAergic) alterations. Thus, the aim of the present work is to analyse if manipulations of neonatal AlloP alter the DAergic response in the nucleus accumbens (NAcc) during alcohol intake in rats. We administered AlloP or Finas from postnatal day (PND) 5 to PND9. At PND98, we measured alcohol consumption using a two-bottle free-choice model (ethanol 10% (v/v)+glucose 3% (w/v), and glucose 3% (w/v)) for 12 days. On the last day of consumption, we measured the DA and 3,4-dihydroxyphenylacetic acid (DOPAC) release in NAcc in response to ethanol intake. The samples were obtained by means of in vivo microdialysis in freely moving rats, and DA and DOPAC levels were determined by means of high-performance liquid chromatography analysis (HPLC). The results revealed that neonatal Finas increased ethanol consumption in some days of the consumption phase, and decreased the DA release in the NAcc in response to solutions (ethanol+glucose) and food presentation. Taken together, these results suggest that neonatal NS alterations can affect alcohol rewarding properties. Copyright © 2016 Elsevier B.V. All rights reserved.

St. John’s Wort enhances the synaptic activity of the nucleus of the solitary tract

PubMed Central

Vance, Katie M.; Ribnicky, David M.; Hermann, Gerlinda E.; Rogers, Richard C.

2014-01-01

Objective St. John’s Wort extract, which is commonly used to treat depression, inhibits the reuptake of several neurotransmitters, including glutamate, serotonin, norepinephrine, and dopamine. Glutamatergic visceral vagal afferents synapse upon neurons of the solitary tract (NST); thus, we evaluated whether St. John’s Wort extract modulates glutamatergic neurotransmission within the NST. Materials and Methods We used live cell calcium imaging to evaluate whether St. John’s Wort and its isolated components hypericin and hyperforin increase the excitability of pre-labeled vagal afferent terminals synapsing upon the NST. We used voltage-clamp recordings of spontaneous miniature excitatory postsynaptic currents (mEPSCs) to evaluate whether St. John’s Wort alters glutamate release from vagal afferents onto NST neurons. Results Our imaging data show that St. John’s Wort (50 μg/mL) increased the intracellular calcium levels of stimulated vagal afferent terminals compared to the bath control. This increase in presynaptic vagal afferent calcium by the extract coincides with an increase in neurotransmitter release within the nucleus of the solitary tract, as the frequency of mEPSCs is significantly higher in the presence of the extract compared to the control. Finally, our imaging data show that hyperforin, a known component of St. John’s Wort extract, also significantly increases terminal calcium levels. Conclusion These data suggest that St. John’s Wort extract can significantly increase the probability of glutamate release from vagal afferents onto the NST by increasing presynaptic calcium. The in vitro vagal afferent synapse with NST neurons is an ideal model system to examine the mechanism of action of botanical agents on glutamatergic neurotransmission. PMID:24985104

Effects of corticotropin-releasing factor receptor-1 antagonists on the brain stress system responses to morphine withdrawal.

PubMed

Navarro-Zaragoza, Javier; Núñez, Cristina; Laorden, M Luisa; Milanés, M Victoria

2010-05-01

The role of stress in drug addiction is well established. The negative affective states of withdrawal most probably involve recruitment of brain stress neurocircuitry [e.g., induction of hypothalamo-pituitary-adrenocortical (HPA) axis, noradrenergic activity, and corticotropin-releasing factor (CRF) activity]. The present study investigated t$he role of CRF receptor-1 subtype (CRF1R) on the response of brain stress system to morphine withdrawal. The effects of naloxone-precipitated morphine withdrawal on noradrenaline (NA) turnover in the paraventricular nucleus (PVN), HPA axis activity, signs of withdrawal, and c-Fos expression were measured in rats pretreated with vehicle, CP-154526 [N-butyl-N-ethyl-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidin-4-amine], or antalarmin (selective CRF1R antagonists). Tyrosine hydroxylase-positive neurons expressing CRF1R were seen at the level of the nucleus tractus solitarius-A(2) cell group in both control and morphine-withdrawn rats. CP-154526 and antalarmin attenuated the increases in body weight loss and irritability that were seen during naloxone-induced morphine withdrawal. Pretreatment with CRF1R antagonists resulted in no significant modification of the increased NA turnover at PVN, plasma corticosterone levels, or c-Fos expression that was seen during naloxone-induced morphine withdrawal. However, blockade of CRF1R significantly reduced morphine withdrawal-induced increases in plasma adrenocorticotropin levels. These results suggest that the CRF1R subtype may be involved in the behavioral and somatic signs and in adrenocorticotropin release (partially) during morphine withdrawal. However, CRF1R activation may not contribute to the functional interaction between NA and CRF systems in mediating morphine withdrawal-activation of brain stress neurocircuitry.

Cocaine- and Amphetamine-Regulated Transcript (CART) Expression is Differentially Regulated in the Hypothalamic Para ventricular Nucleus of Lactating Rats Exposed to Suckling or Cold Stimulation

PubMed Central

Sánchez, Edith; Fekete, Csaba; Lechan, Ronald M.; Joseph-Bravo, Patricia

2007-01-01

Neural stimuli, such as suckling or cold exposure, increase TRH mRNA in the paraventricular nucleus (PVN) of the rat hypothalamus, yet only suckling induces prolactin secretion. As TRH co-localizes with cocaine-and amphetamine-regulated transcript (CART) in hypophysiotropic neurons of the PVN, and CART inhibits TRH-induced prolactin release but not TRH-induced TSH release in adenohypophyseal cell cultures, we raised the possibility that differential regulation of CART gene expression in the PVN may explain the differences in prolactin secretion following each of the two stimuli. Primiparous female rats were mated and handled daily during the pre- and postpartum periods. After delivery, the litter was adjusted to 8 pups and at mid-lactation, dams were separated from their pups for 8 hours and exposed to either 1h of cold or 30 min of suckling. Long term effects of suckling were studied by separating pups from their mothers for 24h, followed by a 12h period of continuous suckling. Serum TSH levels increased in response to cold exposure, while prolactin levels were increased by suckling and diminished by cold exposure. CART mRNA levels increased in rostral and mid parts of the medial parvocellular PVN following cold exposure but not after suckling stimulation. These data demonstrate a differential regulation of CART gene expression in hypophysiotropic neurons in response to stimuli that increase TRH mRNA levels, and suggest that CART activation in the PVN may contribute to the decrease in PRL release when the thyroid axis is activated by cold exposure. Section: Regulatory systems PMID:17174283

Increased presynaptic regulation of dopamine neurotransmission in the nucleus accumbens core following chronic ethanol self-administration in female macaques.

PubMed

Siciliano, Cody A; Calipari, Erin S; Yorgason, Jordan T; Lovinger, David M; Mateo, Yolanda; Jimenez, Vanessa A; Helms, Christa M; Grant, Kathleen A; Jones, Sara R

2016-04-01

Hypofunction of striatal dopamine neurotransmission, or hypodopaminergia, is a consequence of excessive ethanol use and is hypothesized to be a critical component of alcoholism, driving alcohol intake in an attempt to restore dopamine levels; however, the neurochemical mechanisms involved in these dopaminergic deficiencies are not fully understood. Here we examined the specific dopaminergic adaptations that produce hypodopaminergia and contribute to alcohol use disorders using direct, sub-second measurements of dopamine signaling in nonhuman primates following chronic ethanol self-administration. Female rhesus macaques completed 1 year of daily (22 h/day) ethanol self-administration. Subsequently, fast-scan cyclic voltammetry was used in nucleus accumbens core brain slices to determine alterations in dopamine terminal function, including release and uptake kinetics, and sensitivity to quinpirole (D2/D3 dopamine receptor agonist) and U50,488 (kappa opioid receptor agonist) induced inhibition of dopamine release. Ethanol drinking greatly increased uptake rates, which were positively correlated with lifetime ethanol intake. Furthermore, the sensitivity of dopamine D2/D3 autoreceptors and kappa opioid receptors, which both act as negative regulators of presynaptic dopamine release, was moderately and robustly enhanced in ethanol drinkers. Greater uptake rates and sensitivity to D2-type autoreceptor and kappa opioid receptor agonists could converge to drive a hypodopaminergic state, characterized by reduced basal dopamine and an inability to mount appropriate dopaminergic responses to salient stimuli. Together, we outline the specific alterations to dopamine signaling that may drive ethanol-induced hypofunction of the dopamine system and suggest that the dopamine and dynorphin/kappa opioid receptor systems may be efficacious pharmacotherapeutic targets in the treatment of alcohol use disorders.

Substance P immunoreactivity exhibits frequent colocalization with kisspeptin and neurokinin B in the human infundibular region.

PubMed

Hrabovszky, Erik; Borsay, Beáta Á; Rácz, Kálmán; Herczeg, László; Ciofi, Philippe; Bloom, Stephen R; Ghatei, Mohammad A; Dhillo, Waljit S; Liposits, Zsolt

2013-01-01

Neurons synthesizing neurokinin B (NKB) and kisspeptin (KP) in the hypothalamic arcuate nucleus represent important upstream regulators of pulsatile gonadotropin-releasing hormone (GnRH) neurosecretion. In search of neuropeptides co-expressed in analogous neurons of the human infundibular nucleus (Inf), we have carried out immunohistochemical studies of the tachykinin peptide Substance P (SP) in autopsy samples from men (21-78 years) and postmenopausal (53-83 years) women. Significantly higher numbers of SP-immunoreactive (IR) neurons and darker labeling were observed in the Inf of postmenopausal women than in age-matched men. Triple-immunofluorescent studies localized SP immunoreactivity to considerable subsets of KP-IR and NKB-IR axons and perikarya in the infundibular region. In postmenopausal women, 25.1% of NKB-IR and 30.6% of KP-IR perikarya contained SP and 16.5% of all immunolabeled cell bodies were triple-labeled. Triple-, double- and single-labeled SP-IR axons innervated densely the portal capillaries of the infundibular stalk. In quadruple-labeled sections, these axons formed occasional contacts with GnRH-IR axons. Presence of SP in NKB and KP neurons increases the functional complexity of the putative pulse generator network. First, it is possible that SP modulates the effects of KP and NKB in axo-somatic and axo-dendritic afferents to GnRH neurons. Intrinsic SP may also affect the activity and/or neuropeptide release of NKB and KP neurons via autocrine/paracrine actions. In the infundibular stalk, SP may influence the KP and NKB secretory output via additional autocrine/paracrine mechanisms or regulate GnRH neurosecretion directly. Finally, possible co-release of SP with KP and NKB into the portal circulation could underlie further actions on adenohypophysial gonadotrophs.

FOOD-INTAKE DYSREGULATION IN TYPE 2 DIABETIC GOTO-KAKIZAKI RATS: HYPOTHESIZED ROLE OF DYSFUNCTIONAL BRAINSTEM THYROTROPIN-RELEASING HORMONE AND IMPAIRED VAGAL OUTPUT

PubMed Central

Zhao, K.; Ao, Y.; Harper, R.M.; Go, V. L.W.; Yang, H.

2013-01-01

Thyrotropin-releasing hormone (TRH), a neuropeptide contained in neural terminals innervating brainstem vagal motor neurons, enhances vagal outflow to modify multisystemic visceral functions and food intake. Type 2 diabetes (T2D) and obesity are accompanied by impaired vagal functioning. We examined the possibility that impaired brainstem TRH action may contribute to the vagal dysregulation of food intake in Goto-Kakizaki (GK) rats, a T2D model with hyperglycemia and impaired central vagal activation by TRH. Food intake induced by intracisternal injection of TRH analog was reduced significantly by 50% in GK rats, compared to Wistar rats. Similarly, natural food intake in the dark phase or food intake after an overnight fast was reduced by 56–81% in GK rats. Fasting (48 h) and refeeding (2 h)-associated changes in serum ghrelin, insulin, peptide YY, pancreatic polypeptide and leptin, and the concomitant changes in orexigenic or anorexigenic peptide expression in the brainstem and hypothalamus, all apparent in Wistar rats, were absent or markedly reduced in GK rats, with hormone release stimulated by vagal activation, such as ghrelin and pancreatic polypeptide, decreased substantially. Fasting-induced Fos expression accompanying endogenous brainstem TRH action decreased by 66% and 91%, respectively, in the nucleus tractus solitarius (NTS) and the dorsal motor nucleus of the vagus (DMV) in GK rats, compared to Wistar rats. Refeeding abolished fasting-induced Fos-expression in the NTS, while that in the DMV remained in Wistar but not GK rats. These findings indicate that dysfunctional brainstem TRH-elicited vagal impairment contributes to the disturbed food intake in T2D GK rats, and may provide a pathophysiological mechanism which prevents further weight gain in T2D and obesity. PMID:23701881

Food-intake dysregulation in type 2 diabetic Goto-Kakizaki rats: hypothesized role of dysfunctional brainstem thyrotropin-releasing hormone and impaired vagal output.

PubMed

Zhao, K; Ao, Y; Harper, R M; Go, V L W; Yang, H

2013-09-05

Thyrotropin-releasing hormone (TRH), a neuropeptide contained in neural terminals innervating brainstem vagal motor neurons, enhances vagal outflow to modify multisystemic visceral functions and food intake. Type 2 diabetes (T2D) and obesity are accompanied by impaired vagal functioning. We examined the possibility that impaired brainstem TRH action may contribute to the vagal dysregulation of food intake in Goto-Kakizaki (GK) rats, a T2D model with hyperglycemia and impaired central vagal activation by TRH. Food intake induced by intracisternal injection of TRH analog was reduced significantly by 50% in GK rats, compared to Wistar rats. Similarly, natural food intake in the dark phase or food intake after an overnight fast was reduced by 56-81% in GK rats. Fasting (48h) and refeeding (2h)-associated changes in serum ghrelin, insulin, peptide YY, pancreatic polypeptide and leptin, and the concomitant changes in orexigenic or anorexigenic peptide expression in the brainstem and hypothalamus, all apparent in Wistar rats, were absent or markedly reduced in GK rats, with hormone release stimulated by vagal activation, such as ghrelin and pancreatic polypeptide, decreased substantially. Fasting-induced Fos expression accompanying endogenous brainstem TRH action decreased by 66% and 91%, respectively, in the nucleus tractus solitarius (NTS) and the dorsal motor nucleus of the vagus (DMV) in GK rats, compared to Wistar rats. Refeeding abolished fasting-induced Fos-expression in the NTS, while that in the DMV remained in Wistar but not GK rats. These findings indicate that dysfunctional brainstem TRH-elicited vagal impairment contributes to the disturbed food intake in T2D GK rats, and may provide a pathophysiological mechanism which prevents further weight gain in T2D and obesity. Published by Elsevier Ltd.

A second corticotropin-releasing hormone gene (CRH2) is conserved across vertebrate classes and expressed in the hindbrain of a basal neopterygian fish, the spotted gar (Lepisosteus oculatus).

PubMed

Grone, Brian P; Maruska, Karen P

2015-05-01

To investigate the origins of the vertebrate stress-response system, we searched sequenced vertebrate genomes for genes resembling corticotropin-releasing hormone (CRH). We found that vertebrate genomes possess, in addition to CRH, another gene that resembles CRH in sequence and syntenic environment. This paralogous gene was previously identified only in the elephant shark (a holocephalan), but we find it also in marsupials, monotremes, lizards, turtles, birds, and fishes. We examined the relationship of this second vertebrate CRH gene, which we name CRH2, to CRH1 (previously known as CRH) and urocortin1/urotensin1 (UCN1/UTS1) in primitive fishes, teleosts, and tetrapods. The paralogs CRH1 and CRH2 likely evolved via duplication of CRH during a whole-genome duplication early in the vertebrate lineage. CRH2 was subsequently lost in both teleost fishes and eutherian mammals but retained in other lineages. To determine where CRH2 is expressed relative to CRH1 and UTS1, we used in situ hybridization on brain tissue from spotted gar (Lepisosteus oculatus), a neopterygian fish closely related to teleosts. In situ hybridization revealed widespread distribution of both crh1 and uts1 in the brain. Expression of crh2 was restricted to the putative secondary gustatory/secondary visceral nucleus, which also expressed calcitonin-related polypeptide alpha (calca), a marker of parabrachial nucleus in mammals. Thus, the evolutionary history of CRH2 includes restricted expression in the brain, sequence changes, and gene loss, likely reflecting release of selective constraints following whole-genome duplication. The discovery of CRH2 opens many new possibilities for understanding the diverse functions of the CRH family of peptides across vertebrates. © 2015 Wiley Periodicals, Inc.

DISSECTING PHOTOMETRIC REDSHIFT FOR ACTIVE GALACTIC NUCLEUS USING XMM- AND CHANDRA-COSMOS SAMPLES

DOE Office of Scientific and Technical Information (OSTI.GOV)

Salvato, M.; Hasinger, G.; Ilbert, O.

2011-12-01

In this paper, we release accurate photometric redshifts for 1692 counterparts to Chandra sources in the central square degree of the Cosmic Evolution Survey (COSMOS) field. The availability of a large training set of spectroscopic redshifts that extends to faint magnitudes enabled photometric redshifts comparable to the highest quality results presently available for normal galaxies. We demonstrate that morphologically extended, faint X-ray sources without optical variability are more accurately described by a library of normal galaxies (corrected for emission lines) than by active galactic nucleus (AGN) dominated templates, even if these sources have AGN-like X-ray luminosities. Preselecting the library onmore » the bases of the source properties allowed us to reach an accuracy {sigma}{sub {Delta}z/(1+z{sub s{sub p{sub e{sub c)}}}}}{approx}0.015 with a fraction of outliers of 5.8% for the entire Chandra-COSMOS sample. In addition, we release revised photometric redshifts for the 1735 optical counterparts of the XMM-detected sources over the entire 2 deg{sup 2} of COSMOS. For 248 sources, our updated photometric redshift differs from the previous release by {Delta}z > 0.2. These changes are predominantly due to the inclusion of newly available deep H-band photometry (H{sub AB} = 24 mag). We illustrate once again the importance of a spectroscopic training sample and how an assumption about the nature of a source together, with the number and the depth of the available bands, influences the accuracy of the photometric redshifts determined for AGN. These considerations should be kept in mind when defining the observational strategies of upcoming large surveys targeting AGNs, such as eROSITA at X-ray energies and the Australian Square Kilometre Array Pathfinder Evolutionary Map of the Universe in the radio band.« less

Effect of cochlear nerve electrocautery on the adult cochlear nucleus.

PubMed

Iseli, Claire E; Merwin, William H; Klatt-Cromwell, Cristine; Hutson, Kendall A; Ewend, Matthew G; Adunka, Oliver F; Fitzpatrick, Douglas C; Buchman, Craig A

2015-04-01

Electrocauterization and subsequent transection of the cochlear nerve induce greater injury to the cochlear nucleus than sharp transection alone. Some studies show that neurofibromatosis Type 2 (NF2) patients fit with auditory brainstem implants (ABIs) fail to achieve speech perception abilities similar to ABI recipients without NF2. Reasons for these differences remain speculative. One hypothesis posits poorer performance to surgically induced trauma to the cochlear nucleus from electrocautery. Sustained electrosurgical depolarization of the cochlear nerve may cause excitotoxic-induced postsynaptic nuclear injury. Equally plausible is that cautery in the vicinity of the cochlear nucleus induces necrosis. The cochlear nerve was transected in anesthetized adult gerbils sharply with or without bipolar electrocautery at varying intensities. Gerbils were perfused at 1, 3, 5, and 7 days postoperatively; their brainstem and cochleas were embedded in paraffin and sectioned at 10 μm. Alternate sections were stained with flourescent markers for neuronal injury or Nissl substance. In additional experiments, anterograde tracers were applied directly to a sectioned eighth nerve to verify that fluorescent-labeled profiles seen were terminating auditory nerve fibers. Cochlear nerve injury was observed from 72 hours postoperatively and was identical across cases regardless of surgical technique. Postsynaptic cochlear nucleus injury was not seen after distal transection of the nerve. By contrast, proximal transection was associated with trauma to the cochlear nucleus. Distal application of bipolar electrocautery seems safe for the cochlear nucleus. Application near the root entry zone must be used cautiously because this may compromise nuclear viability needed to support ABI stimulation.

Electrical properties of the first meters of 67P/Churyumov-Gerasimenko's nucleus as constrained by PP-SESAME/Philae/Rosetta

NASA Astrophysics Data System (ADS)

Le Gall, Alice; Lethuillier, Anthony; Hamelin, Michel; Schimdt, Walter; Grard, Rejean; Ciarletti, Valérie; Seidensticker, Klaus; Caujolle-Bert, Sylvain; Fischer, Hans-Herbert

2016-04-01

On November 12, 2014, the Philae module landed on the surface of the nucleus of 67P/Churyumov-Gerasimenko. Among the instruments on-board Philae, the Permittivity Probe experiment (hereafter PP-SESAME), which is part of the SESAME (Surface Electric Sounding and Acoustic Monitoring Experiment) package, operated both during descent and on the surface. The primary scientific objective of this experiment is to measure the low frequency (10 Hz-10 kHz) complex permittivity i.e., the dielectric constant and electrical conductivity, of the first meters of the cometary nucleus. Doing so, it aims at providing insights into the composition of the mantle and in particular into the water content and porosity of the first meters below the surface. In this paper, we will present the data acquired at the final landing site of Philae known as Abydos and the approach we have developed to analyze them. We emphasize that, because the configuration of operation of PP-SESAME was far from nominal, we had to adapt our analysis method in order to account for all available constraints on Philae attitude and environment at Abydos. We also had to do without the in-flight calibration performed during the descent phase but unfortunately perturbed by the concurrent operations of the bistatic radar CONSERT. We find that the first meters of the nucleus at Abydos are made of a likely pure dielectric material (i.e., with a null conductivity) which dielectric constant is larger than 2.3. This lower bound of the dielectric constant is significantly higher than the value of 1.27 inferred from the propagation time of the CONSERT signals that propagated through the smaller lobe of the comet in the vicinity of Abydos reaching depths of a few hundreds of meters. Thus, while PP-SESAME measurements put no constraint on the dust-to-ice ratio, they strongly suggest that the first meters of the nucleus are significantly more compacted (with a porosity below 50%) than its interior as sensed by CONSERT (found to have a porosity in of 75 to 85%, consistent with the low density of the nucleus). In light of other Philae and Rosetta observations, we will discuss the implications of these findings in terms of formation and evolution of cometary mantles.

Calpain mediates AIF-regulated caspase-independent pathway in cisplatin-induced apoptosis

NASA Astrophysics Data System (ADS)

Liu, Lei; Xing, Da; Chen, Wei R.

2007-11-01

Mitochondrial apoptosis inducing factor (AIF) on activation can translocate to the nucleus and induce cell death via caspase-independent pathway in cisplatin-induced apoptosis. Yet the precise signal transduction pathway(s) which regulates AIF-induced apoptotic pathway still remains poorly understood. In this study, we investigated the molecular mechanism of AIF release and redistribution in cisplatin-induced apoptosis in living ASTC-a-1 cells, as assessed by real-time anlysis. Herein, We report that during cisplatin-induced apoptosis, calpain activation, as measured in intact cells by a fluorescent substrates, is an early event, taking place well before AIF release and caspase-3 activation. Confocal imaging of the cells transfected with AIF-GFP demonstrated that AIF release occurred about 9 h after cisplatin treatment. The event proceeded progressively over time, coinciding with a nuclear translocation and lasting for more than 2 hours. AIF release and redistribution were effectively inhibited in samples co-treated with calpeptin and PD150606, two selective calpain inhibitors. Therefore, our results clearly show the kinetics of AIF release and redistribution in cisplatin-induced apoptosis in living ASTC-a-1 cells, and calpain played a crucial role in these events.

Enhanced synthesis and release of dopamine in transgenic mice with gain-of-function α6* nAChRs.

PubMed

Wang, Yuexiang; Lee, Jang-Won; Oh, Gyeon; Grady, Sharon R; McIntosh, J Michael; Brunzell, Darlene H; Cannon, Jason R; Drenan, Ryan M

2014-04-01

α6β2* nicotinic acetylcholine receptors (nAChRs)s in the ventral tegmental area to nucleus accumbens (NAc) pathway are implicated in the response to nicotine, and recent work suggests these receptors play a role in the rewarding action of ethanol. Here, we studied mice expressing gain-of-function α6β2* nAChRs (α6L9'S mice) that are hypersensitive to nicotine and endogenous acetylcholine. Evoked extracellular dopamine (DA) levels were enhanced in α6L9'S NAc slices compared to control, non-transgenic (non-Tg) slices. Extracellular DA levels in both non-Tg and α6L9'S slices were further enhanced in the presence of GBR12909, suggesting intact DA transporter function in both mouse strains. Ongoing α6β2* nAChR activation by acetylcholine plays a role in enhancing DA levels, as α-conotoxin MII completely abolished evoked DA release in α6L9'S slices and decreased spontaneous DA release from striatal synaptosomes. In HPLC experiments, α6L9'S NAc tissue contained significantly more DA, 3,4-dihydroxyphenylacetic acid, and homovanillic acid compared to non-Tg NAc tissue. Serotonin (5-HT), 5-hydroxyindoleacetic acid, and norepinephrine (NE) were unchanged in α6L9'S compared to non-Tg tissue. Western blot analysis revealed increased tyrosine hydroxylase expression in α6L9'S NAc. Overall, these results show that enhanced α6β2* nAChR activity in NAc can stimulate DA production and lead to increased extracellular DA levels. © 2013 International Society for Neurochemistry.

Ventricular fibrillation cardiac arrest produces a chronic striatal hyperdopaminergic state that is worsened by methylphenidate treatment.

PubMed

Nora, Gerald J; Harun, Rashed; Fine, David F; Hutchison, Daniel; Grobart, Adam C; Stezoski, Jason P; Munoz, Miranda J; Kochanek, Patrick M; Leak, Rehana K; Drabek, Tomas; Wagner, Amy K

2017-07-01

Cardiac arrest survival rates have improved with modern resuscitation techniques, but many survivors experience impairments associated with hypoxic-ischemic brain injury (HIBI). Currently, little is understood about chronic changes in striatal dopamine (DA) systems after HIBI. Given the common empiric clinical use of DA enhancing agents in neurorehabilitation, investigation evaluating dopaminergic alterations after cardiac arrest (CA) is necessary to optimize rehabilitation approaches. We hypothesized that striatal DA neurotransmission would be altered chronically after ventricular fibrillation cardiac arrest (VF-CA). Fast-scan cyclic voltammetry was used with median forebrain bundle (MFB) maximal electrical stimulations (60Hz, 10s) in rats to characterize presynaptic components of DA neurotransmission in the dorsal striatum (D-Str) and nucleus accumbens 14 days after a 5-min VF-CA when compared to Sham or Naïve. VF-CA increased D-Str-evoked overflow [DA], total [DA] released, and initial DA release rate versus controls, despite also increasing maximal velocity of DA reuptake (V max ). Methylphenidate (10 mg/kg), a DA transporter inhibitor, was administered to VF-CA and Shams after establishing a baseline, pre-drug 60 Hz, 5 s stimulation response. Methylphenidate increased initial evoked overflow [DA] more-so in VF-CA versus Sham and reduced D-Str V max in VF-CA but not Shams; these findings are consistent with upregulated striatal DA transporter in VF-CA versus Sham. Our work demonstrates that 5-min VF-CA increases electrically stimulated DA release with concomitant upregulation of DA reuptake 2 weeks after brief VF-CA insult. Future work should elucidate how CA insult duration, time after insult, and insult type influence striatal DA neurotransmission and related cognitive and motor functions. © 2017 International Society for Neurochemistry.

Nucleus accumbens corticotropin-releasing factor increases cue-triggered motivation for sucrose reward: paradoxical positive incentive effects in stress?

PubMed

Peciña, Susana; Schulkin, Jay; Berridge, Kent C

2006-04-13

Corticotropin-releasing factor (CRF) is typically considered to mediate aversive aspects of stress, fear and anxiety. However, CRF release in the brain is also elicited by natural rewards and incentive cues, raising the possibility that some CRF systems in the brain mediate an independent function of positive incentive motivation, such as amplifying incentive salience. Here we asked whether activation of a limbic CRF subsystem magnifies the increase in positive motivation for reward elicited by incentive cues previously associated with that reward, in a way that might exacerbate cue-triggered binge pursuit of food or other incentives? We assessed the impact of CRF microinjections into the medial shell of nucleus accumbens using a pure incentive version of Pavlovian-Instrumental transfer, a measure specifically sensitive to the incentive salience of reward cues (which it separates from influences of aversive stress, stress reduction, frustration and other traditional explanations for stress-increased behavior). Rats were first trained to press one of two levers to obtain sucrose pellets, and then separately conditioned to associate a Pavlovian cue with free sucrose pellets. On test days, rats received microinjections of vehicle, CRF (250 or 500 ng/0.2 microl) or amphetamine (20 microg/0.2 microl). Lever pressing was assessed in the presence or absence of the Pavlovian cues during a half-hour test. Microinjections of the highest dose of CRF (500 ng) or amphetamine (20 microg) selectively enhanced the ability of Pavlovian reward cues to trigger phasic peaks of increased instrumental performance for a sucrose reward, each peak lasting a minute or so before decaying after the cue. Lever pressing was not enhanced by CRF microinjections in the baseline absence of the Pavlovian cue or during the presentation without a cue, showing that the CRF enhancement could not be explained as a result of generalized motor arousal, frustration or stress, or by persistent attempts to ameliorate aversive states. We conclude that CRF in nucleus accumbens shell amplifies positive motivation for cued rewards, in particular by magnifying incentive salience that is attributed to Pavlovian cues previously associated with those rewards. CRF-induced magnification of incentive salience provides a novel explanation as to why stress may produce cue-triggered bursts of binge eating, drug addiction relapse, or other excessive pursuits of rewards.

Nucleus accumbens corticotropin-releasing factor increases cue-triggered motivation for sucrose reward: paradoxical positive incentive effects in stress?

PubMed Central

Peciña, Susana; Schulkin, Jay; Berridge, Kent C

2006-01-01

Background Corticotropin-releasing factor (CRF) is typically considered to mediate aversive aspects of stress, fear and anxiety. However, CRF release in the brain is also elicited by natural rewards and incentive cues, raising the possibility that some CRF systems in the brain mediate an independent function of positive incentive motivation, such as amplifying incentive salience. Here we asked whether activation of a limbic CRF subsystem magnifies the increase in positive motivation for reward elicited by incentive cues previously associated with that reward, in a way that might exacerbate cue-triggered binge pursuit of food or other incentives? We assessed the impact of CRF microinjections into the medial shell of nucleus accumbens using a pure incentive version of Pavlovian-Instrumental transfer, a measure specifically sensitive to the incentive salience of reward cues (which it separates from influences of aversive stress, stress reduction, frustration and other traditional explanations for stress-increased behavior). Rats were first trained to press one of two levers to obtain sucrose pellets, and then separately conditioned to associate a Pavlovian cue with free sucrose pellets. On test days, rats received microinjections of vehicle, CRF (250 or 500 ng/0.2 μl) or amphetamine (20 μg/0.2 μl). Lever pressing was assessed in the presence or absence of the Pavlovian cues during a half-hour test. Results Microinjections of the highest dose of CRF (500 ng) or amphetamine (20 μg) selectively enhanced the ability of Pavlovian reward cues to trigger phasic peaks of increased instrumental performance for a sucrose reward, each peak lasting a minute or so before decaying after the cue. Lever pressing was not enhanced by CRF microinjections in the baseline absence of the Pavlovian cue or during the presentation without a cue, showing that the CRF enhancement could not be explained as a result of generalized motor arousal, frustration or stress, or by persistent attempts to ameliorate aversive states. Conclusion We conclude that CRF in nucleus accumbens shell amplifies positive motivation for cued rewards, in particular by magnifying incentive salience that is attributed to Pavlovian cues previously associated with those rewards. CRF-induced magnification of incentive salience provides a novel explanation as to why stress may produce cue-triggered bursts of binge eating, drug addiction relapse, or other excessive pursuits of rewards. PMID:16613600

Design and construction of a spectrometer facility and experiment for intermediate energy proton scattering on helium. [Wave functions, preliminary experimental techniques

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rolfe, R.M.

1976-12-01

The goal of the research was to investigate proton scattering on nuclei at intermediate energies and in particular to investigate proton scattering on helium. A theoretical investigation of the helium nucleus and the nature of the intermediate energy interaction, design and optimization of an energy-loss spectrometer facility for proton-nucleus scattering, and the unique superfluid helium target and experimental design are discussed.

A Laboratory Experiment on the Statistical Theory of Nuclear Reactions

ERIC Educational Resources Information Center

Loveland, Walter

1971-01-01

Describes an undergraduate laboratory experiment on the statistical theory of nuclear reactions. The experiment involves measuring the relative cross sections for formation of a nucleus in its meta stable excited state and its ground state by applying gamma-ray spectroscopy to an irradiated sample. Involves 3-4 hours of laboratory time plus…

On M31's Double Nucleus

NASA Technical Reports Server (NTRS)

Miller, R. H.; Smith, B. F.; Cuzzi, Jeffrey (Technical Monitor)

1995-01-01

The recent HST discovery of a double nucleus in M31 brings into prominence the question how long, a second core can survive within the nuclear regions of a galaxy. Physical conditions in the nuclear regions of a typical galaxy help a second core survive, so it can orbit for a long time. possibly for thousands of orbits. Given the nearly uniform mass density in a core, tidal forces within a core radius are compressive in all directions and help the core survive the buffeting it takes as it orbits near the center of the galaxy. We use numerical experiments to illustrate these physical principles. Our method allows the full power of the experiments to be concentrated on the nuclear regions. Spatial resolution of about 0.2 pc comfortably resolves detail within the 1.4 parsec core radius of the second, but brighter core (P1) in M31. We use these physical principles to discuss M31's double nucleus, but they apply to other galaxies as well. and in other astronomical situations such as dumbbell galaxies. galaxies orbiting near the center of a galaxy cluster, and subclustering in galaxy clusters. The experiments also illustrate that galaxy encounters and merging are quite sensitive to external tidal forces, such as those produced by the gravitational potential in a group or cluster of galaxies.

Mechanisms of Dopamine Release From Rat Striatum and Nucleus Accumbens Slices:The Role of Transporters, Receptors and Membrane Depolarization

DTIC Science & Technology

1992-07-21

hydroxylase could represent pan of the biochemical basis of cocaine addiction and craving (Beitner-Johnson and Nestler, 1991). Although cocaine...in reinforcement , the mechanisms underlying the stimulant and reinforcing effects of addictive drugs such as D-amphetamine and cocaine remain... baclofen on neurons in the tar substantia nigra slice. Brai n Res. 332:337-340, 1984 Pitts , D.K. and Marwah, J.: Cocaine and central monoaminergic

[Response of vasopressin and tyrosine hydroxylase expressing neurons of the rat supraoptic nucleus to chronic osmotic stimulation].

PubMed

Abramova, M A; Calas, A; Maiily, P; Thibault, J; Ugriumov, M V

1999-06-01

This study has evaluated the dynamic of intracellular vasopressin and tyrosine hydroxylase contents in the neuron cell bodies in the supraoptic nucleus and in the axons of the posterior lobe in rats drinking 2% NaCl for 1, 2, and 3 weeks. The number of vasopressin-immunoreactive neurons increased by the end of the second week of osmotic stimulation that might be explained by the onset of vasopressin synthesis in the neurons which do not synthesize this neurohormone under normal physiological conditions. The concentration of vasopressin fell down continuously during the first two weeks of salt-loading, apparently, due to predominance of the vasopressin release over its synthesis. Over the third week of salt-loading, the intracellular concentration of vasopressin was not changed significantly suggesting the establishment of the dynamic equilibrium between the vasopressin synthesis and release. The number of tyrosine hydroxylase-immunoreactive neurons and the amount of tyrosine hydroxylase in cell bodies and the large axonal swellings, Herring bodies, increased gradually showing that the rate of tyrosine hydroxylase synthesis prevailed over that of its enzymatic degradation. Thus, the chronic stimulation of vasopressin neurons is accompanied by a number of the adaptive reactions; the most important is related to the onset of vasopressin and tyrosine hydroxylase synthesis in the neurons which do not synthetize both of them under normal conditions.

Nucleolin is a nuclear target of heparan sulfate derived from glypican-1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cheng, Fang; Belting, Mattias; Fransson, Lars-Åke

The recycling, S-nitrosylated heparan sulfate (HS) proteoglycan glypican-1 releases anhydromannose (anMan)-containing HS chains by a nitrosothiol-catalyzed cleavage in endosomes that can be constitutive or induced by ascorbate. The HS-anMan chains are then transported to the nucleus. A specific nuclear target for HS-anMan has not been identified. We have monitored endosome-to-nucleus trafficking of HS-anMan by deconvolution and confocal immunofluorescence microscopy using an anMan-specific monoclonal antibody in non-growing, ascorbate-treated, and growing, untreated, wild-type mouse embryonic fibroblasts and hypoxia-exposed Alzheimer mouse Tg2576 fibroblasts and human U87 glioblastoma cells. In all cells, nuclear HS-anMan targeted a limited number of sites of variable size wheremore » it colocalized with DNA and nucleolin, an established marker for nucleoli. HS-anMan also colocalized with ethynyl uridine-tagged nascent RNA and two acetylated forms of histone H3. Acute hypoxia increased the formation of HS-anMan in both Tg2576 and U87 cells. A portion of HS-anMan colocalized with nucleolin at small discrete sites, while most of the nucleolin and nascent RNA was dispersed. In U87 cells, HS-anMan, nucleolin and nascent RNA reassembled after prolonged hypoxia. Nucleolar HS may modulate synthesis and/or release of rRNA.« less

Neutrino-nucleus cross sections for oscillation experiments

NASA Astrophysics Data System (ADS)

Katori, Teppei; Martini, Marco

2018-01-01

Neutrino oscillations physics is entering an era of high precision. In this context, accelerator-based neutrino experiments need a reduction in systematic errors to the level of a few percent. Today, one of the most important sources of systematic errors are neutrino-nucleus cross sections which, in the energy region of hundreds of MeV to a few GeV, are known to a precision not exceeding 20%. In this article we review the present experimental and theoretical knowledge of neutrino-nucleus interaction physics. After introducing neutrino-oscillation physics and accelerator-based neutrino experiments, we give an overview of general aspects of neutrino-nucleus cross sections, from both the theoretical and experimental point of view. Then, we focus on these cross sections in different reaction channels. We start with the quasi-elastic and quasi-elastic-like cross section, placing a special emphasis on the multinucleon emission channel, which has attracted a lot of attention in the last few years. We review the main aspects of the different microscopic models for this channel by discussing analogies and the differences among them. The discussion is always driven by a comparison with the experimental data. We then consider the one-pion production channel where agreement between data and theory remains highly unsatisfactory. We describe how to interpret pion data, and then analyze, in particular, the puzzle related to the difficulty of theoretical models and Monte Carlo to simultaneously describe MiniBooNE and MINERvA experimental results. Inclusive cross sections are also discussed, as well as the comparison between the {ν }μ and {ν }e cross sections, relevant for the charge-conjugation-parity violation experiments. The impact of nuclear effects on the reconstruction of neutrino energy and on the determination of the neutrino-oscillation parameters is also reviewed. Finally, we look to the future by discussing projects and efforts in relation to future detectors, beams, and analysis.

Photo-inducible Crosslinked Nanoassemblies for pH-Controlled Drug Release

PubMed Central

Dickerson, Matthew; Winquist, Nickolas; Bae, Younsoo

2014-01-01

Purpose To control drug release from block copolymer nanoassemblies by variation in the degree of photo-crosslinking and inclusion of acid sensitive linkers. Methods Poly(ethylene glycol)-poly(aspartate-hydrazide-cinnamate) (PEG-CNM) block copolymers were prepared and conjugated with a model drug, doxorubicin (DOX), through acid sensitive hydrazone linkers. The block copolymers formed photo-inducible, self-assembled nanoassemblies (piSNAs), which were used to produce photo-inducible crosslinked nanoassemblies (piCNAs) through UV crosslinking. The nanoassemblies were characterized to determine particle size, surface charge, pH- and crosslinking-dependent DOX release, in vitro cytotoxicity, and intracellular uptake as a function of photo-crosslinking degree. Results Nanoassemblies with varying photo-crosslinking degrees were successfully prepared while retaining particle size and surface charge. Photo-crosslinking caused no noticeable change in DOX release from the nanoassemblies at pH 7.4, but the DOX-loaded nanoassemblies modulated drug release as a function of crosslinking at pH 6.0. The nanoassemblies showed similar cytotoxicity regardless of crosslinking degrees, presumably due to the low cellular uptake and cell nucleus drug accumulation. Conclusion Photo-crosslinking is useful to control drug release from pH-sensitive block copolymer nanoassemblies as a function of crosslinking without altering the particle properties, and thus providing unique tools to investigate the pharmaceutical effects of drug release on cellular response. PMID:24254196

Reduction-Responsive Polymeric Micelles and Vesicles for Triggered Intracellular Drug Release

PubMed Central

Sun, Huanli; Cheng, Ru; Deng, Chao

2014-01-01

Abstract Significance: The therapeutic effects of current micellar and vesicular drug formulations are restricted by slow and inefficient drug release at the pathological site. The development of smart polymeric nanocarriers that release drugs upon arriving at the target site has received a tremendous amount of attention for cancer therapy. Recent Advances: Taking advantage of a high reducing potential in the tumor tissues and in particular inside the tumor cells, various reduction-sensitive polymeric micelles and vesicles have been designed and explored for triggered anticancer drug release. These reduction-responsive nanosystems have demonstrated several unique features, such as good stability under physiological conditions, fast response to intracellular reducing environment, triggering drug release right in the cytosol and cell nucleus, and significantly improved antitumor activity, compared to traditional reduction-insensitive counterparts. Critical Issues: Although reduction-sensitive micelles and polymersomes have accomplished rapid intracellular drug release and enhanced in vitro antitumor effect, their fate inside the cells including the mechanism, site, and rate of reduction reaction remains unclear. Moreover, the systemic fate and performance of reduction-sensitive polymeric drug formulations have to be investigated. Future Directions: Biophysical studies should be carried out to gain insight into the degradation and drug release behaviors of reduction-responsive nanocarriers inside the tumor cells. Furthermore, novel ligand-decorated reduction-sensitive nanoparticulate drug formulations should be designed and explored for targeted cancer therapy in vivo. Antioxid. Redox Signal. 21, 755–767. PMID:24279980

Neuronal somatic ATP release triggers neuron–satellite glial cell communication in dorsal root ganglia

PubMed Central

Zhang, X.; Chen, Y.; Wang, C.; Huang, L.-Y. M.

2007-01-01

It has been generally assumed that the cell body (soma) of a neuron, which contains the nucleus, is mainly responsible for synthesis of macromolecules and has a limited role in cell-to-cell communication. Using sniffer patch recordings, we show here that electrical stimulation of dorsal root ganglion (DRG) neurons elicits robust vesicular ATP release from their somata. The rate of release events increases with the frequency of nerve stimulation; external Ca2+ entry is required for the release. FM1–43 photoconversion analysis further reveals that small clear vesicles participate in exocytosis. In addition, the released ATP activates P2X7 receptors in satellite cells that enwrap each DRG neuron and triggers the communication between neuronal somata and glial cells. Blocking L-type Ca2+ channels completely eliminates the neuron–glia communication. We further show that activation of P2X7 receptors can lead to the release of tumor necrosis factor-α (TNFα) from satellite cells. TNFα in turn potentiates the P2X3 receptor-mediated responses and increases the excitability of DRG neurons. This study provides strong evidence that somata of DRG neurons actively release transmitters and play a crucial role in bidirectional communication between neurons and surrounding satellite glial cells. These results also suggest that, contrary to the conventional view, neuronal somata have a significant role in cell–cell signaling. PMID:17525149

Halo Nucleic Molecules: Molecules Formed from at Least One Atom with a Halo Nucleus. Emphasis on 11,11Li_2 Along with Other Exotic Isotopologues.

NASA Astrophysics Data System (ADS)

Dattani, Nikesh S.; Welsh, Staszek

2014-06-01

Atoms whose nuclei have an exotic number of nucleons can have a `core nucleus' surrounded by a `halo' formed by a nucleon orbiting the core nucleus. For example, due to the two halo neutrons orbiting the core nucleus of 11Li, its nucleus has a cross section that is roughly the same size as that of 208Pb. Halo nucleic atoms have been studied extensively both in theory and in experiments, however halo nucleic molecules have not been studied in either. We first show, using HeH^+, BeH, and MgH as examples, that with measurements of any two isotopologues of a molecule, we can determine crucial properties of a third isotopologue well within spectroscopic accuracy. We then use the extremely precise empirical information available for the low-lying states of 6,6Li_2, 6,7Li_2 and 7,7Li_2 to predict potentials and various properties of the halo nucleic molecule 11,11Li_2, along with isotopologues containing 3Li, 4Li, 5Li, 8Li, 9Li, 10Li, and 12Li. We believe that our predictions of the ro-vibrational energies are reliable for experiments for the first detection of a halo nucleic molecule. R. J. Le Roy, N. S. Dattani, J. A. Coxon, A. J. Ross, P. Crozet, C. Linton, J. Chem. Phys. 131, 204309 (2009). N. S. Dattani, R. J. Le Roy, J. Mol. Spec. 268, 199-210 (2011). M. Semczuk, X. Li, W. Gunton, M. Haw, N. S. Dattani, J. Witz, A. Mills, D. J. Jones, K. W. Madison, Phys. Rev. A 87, 052505 (2013) W. Gunton, M. Semczuk, N. S. Dattani, K. W. Madison, Phys. Rev. A 88, 062510 (2013)

NA61/SHINE facility at the CERN SPS: beams and detector system

NASA Astrophysics Data System (ADS)

Abgrall, N.; Andreeva, O.; Aduszkiewicz, A.; Ali, Y.; Anticic, T.; Antoniou, N.; Baatar, B.; Bay, F.; Blondel, A.; Blumer, J.; Bogomilov, M.; Bogusz, M.; Bravar, A.; Brzychczyk, J.; Bunyatov, S. A.; Christakoglou, P.; Cirkovic, M.; Czopowicz, T.; Davis, N.; Debieux, S.; Dembinski, H.; Diakonos, F.; Di Luise, S.; Dominik, W.; Drozhzhova, T.; Dumarchez, J.; Dynowski, K.; Engel, R.; Efthymiopoulos, I.; Ereditato, A.; Fabich, A.; Feofilov, G. A.; Fodor, Z.; Fulop, A.; Gaździcki, M.; Golubeva, M.; Grebieszkow, K.; Grzeszczuk, A.; Guber, F.; Haesler, A.; Hasegawa, T.; Hierholzer, M.; Idczak, R.; Igolkin, S.; Ivashkin, A.; Jokovic, D.; Kadija, K.; Kapoyannis, A.; Kaptur, E.; Kielczewska, D.; Kirejczyk, M.; Kisiel, J.; Kiss, T.; Kleinfelder, S.; Kobayashi, T.; Kolesnikov, V. I.; Kolev, D.; Kondratiev, V. P.; Korzenev, A.; Koversarski, P.; Kowalski, S.; Krasnoperov, A.; Kurepin, A.; Larsen, D.; Laszlo, A.; Lyubushkin, V. V.; Maćkowiak-Pawłowska, M.; Majka, Z.; Maksiak, B.; Malakhov, A. I.; Maletic, D.; Manglunki, D.; Manic, D.; Marchionni, A.; Marcinek, A.; Marin, V.; Marton, K.; Mathes, H.-J.; Matulewicz, T.; Matveev, V.; Melkumov, G. L.; Messina, M.; Mrówczyński, St.; Murphy, S.; Nakadaira, T.; Nirkko, M.; Nishikawa, K.; Palczewski, T.; Palla, G.; Panagiotou, A. D.; Paul, T.; Peryt, W.; Petukhov, O.; Pistillo, C.; Płaneta, R.; Pluta, J.; Popov, B. A.; Posiadala, M.; Puławski, S.; Puzovic, J.; Rauch, W.; Ravonel, M.; Redij, A.; Renfordt, R.; Richter-Was, E.; Robert, A.; Röhrich, D.; Rondio, E.; Rossi, B.; Roth, M.; Rubbia, A.; Rustamov, A.; Rybczyński, M.; Sadovsky, A.; Sakashita, K.; Savic, M.; Schmidt, K.; Sekiguchi, T.; Seyboth, P.; Sgalaberna, D.; Shibata, M.; Sipos, R.; Skrzypczak, E.; Słodkowski, M.; Sosin, Z.; Staszel, P.; Stefanek, G.; Stepaniak, J.; Stroebele, H.; Susa, T.; Szuba, M.; Tada, M.; Tereshchenko, V.; Tolyhi, T.; Tsenov, R.; Turko, L.; Ulrich, R.; Unger, M.; Vassiliou, M.; Veberic, D.; Vechernin, V. V.; Vesztergombi, G.; Vinogradov, L.; Wilczek, A.; Włodarczyk, Z.; Wojtaszek-Szwarz, A.; Wyszyński, O.; Zambelli, L.; Zipper, W.

2014-06-01

NA61/SHINE (SPS Heavy Ion and Neutrino Experiment) is a multi-purpose experimental facility to study hadron production in hadron-proton, hadron-nucleus and nucleus-nucleus collisions at the CERN Super Proton Synchrotron. It recorded the first physics data with hadron beams in 2009 and with ion beams (secondary 7Be beams) in 2011. NA61/SHINE has greatly profited from the long development of the CERN proton and ion sources and the accelerator chain as well as the H2 beamline of the CERN North Area. The latter has recently been modified to also serve as a fragment separator as needed to produce the Be beams for NA61/SHINE. Numerous components of the NA61/SHINE set-up were inherited from its predecessors, in particular, the last one, the NA49 experiment. Important new detectors and upgrades of the legacy equipment were introduced by the NA61/SHINE Collaboration. This paper describes the state of the NA61/SHINE facility — the beams and the detector system — before the CERN Long Shutdown I, which started in March 2013.

The Hypothalamic-Pituitary-Adrenal Axis and Serotonin Metabolism in Individual Brain Nuclei of Mice with Genetic Disruption of the NK1 Receptor Exposed to Acute Stress.

PubMed

Culman, Juraj; Mühlenhoff, Stephan; Blume, Annegret; Hedderich, Jürgen; Lützen, Ulf; Hunt, Stephen P; Rupniak, Nadia M J; Zhao, Yi

2018-06-15

Mice lacking the substance P (SP) neurokinin-1 (NK1) receptor (NK1R-/-mice) were used to investigate whether SP affects serotonin (5-HT) function in the brain and to assess the effects of acute immobilisation stress on the hypothalamic-pituitary-adrenocortical (HPA) axis and 5-HT turnover in individual brain nuclei. Basal HPA activity and the expression of hypothalamic corticotropin-releasing hormone (CRH) in wild-type (WT)- and NK1R-/- mice were identical. Stress-induced increases in plasma ACTH concentration were considerably higher in NK1R-/- mice than in WT mice while corticosterone concentrations were equally elevated in both mouse lines. Acute stress did not alter the expression of CRH. In the dorsal raphe nucleus (DRN), basal 5-HT turnover was increased in NK1R-/- mice and a 15 min stress further magnified 5-HT utilisation in this region. In the frontoparietal cortex, medial prefrontal cortex, central nucleus of amygdala, and the hippocampal CA1 region, stress increased 5-HT and/or 5-hydroxyindoleacetic acid (5-HIAA) concentrations to a similar extent in WT and NK1R-/- mice. 5-HT turnover in the hypothalamic paraventricular nucleus was not affected by stress, but stress induced similar increases in 5-HT and 5-HIAA in the ventromedial and dorsomedial hypothalamic nuclei in WT and NK1R-/- mice. Our findings indicate that NK1 receptor activation suppresses ACTH release during acute stress but does not exert sustained inhibition of the HPA axis. Genetic deletion of the NK1 receptor accelerates 5-HT turnover in DRN under basal and stress conditions. No differences between the responses of serotonergic system to acute stress in WT and NK1R-/- mice occur in forebrain nuclei linked to the regulation of anxiety and neuroendocrine stress responses.

Stress-induced suppression of neuropeptide Y-induced hunger in anorexic chicks involves corticotrophin-releasing factor signalling and the paraventricular nucleus of the hypothalamus.

PubMed

Wang, J; Yi, J; Siegel, P B; Cline, M A; Gilbert, E R

2017-12-01

The Virginia lines of chickens have been selected for low (LWS) or high (HWS) juvenile body weight and have different severities of anorexia and obesity, respectively. The LWS that are exposed to stressors at hatch are refractory to neuropeptide Y (NPY)-induced food intake and the objective of the present study was to determine the underlying mechanisms. Chicks were exposed to a stressor (-20°C for 6 minutes and 22°C and delayed access to food for 24 hours) after hatching and the hypothalamic nuclei, including the lateral hypothalamus (LH), paraventricular nucleus (PVN), ventromedial hypothalamus (VMH) and arcuate nucleus (ARC), were collected 5 days later. In LWS but not HWS, stress exposure up-regulated corticotrophin-releasing factor (CRF), CRF receptor subtypes 1 and 2 (CRFR1 and CRFR2, respectively), melanocortin receptor 4 and urocortin 3 in the PVN, as well as CRFR2 mRNA in the VMH and ARC. In LWS, stress exposure was also associated with greater NPY and NPY receptor subtype 5 mRNA in the ARC and PVN, respectively, as well as decreased agouti-related peptide mRNA in the ARC. In HWS, stress exposure was associated with increased CRFR1 and decreased cocaine- and amphetamine-regulated transcript in the ARC and PVN, respectively. Refractoriness of the food intake response to NPY in LWS may thus result from the over-riding anorexigenic tone in the PVN associated with CRF signalling. Indeed, the orexigenic effect of NPY was restored when LWS were injected with a CRF receptor antagonist, astressin, before stress exposure. The results of the present study provide insights into the molecular basis of eating disorders and suggest that CRF signalling in the PVN may exacerbate the anorexic phenotype in the presence of environmental stressors. © 2017 British Society for Neuroendocrinology.

Modeling Subsidence-Like Events on Cometary Nuclei

NASA Astrophysics Data System (ADS)

Rosenberg, Eric; Prialnik, Dina

2017-10-01

There is ample evidence, particularly from the Rosetta mission, that cometary nuclei have very low tensile strength. Consequently, morphological changes are expected to occur, caused by buildup of pressure due to gas release in the interior of the nucleus. Such changes have been observed on the surface of comet 67P/Churyumov-Gerasimenko, as reported for example by Groussin et al.(2015). A mechanism for explaining comet surface depressions has been recently proposed by Prialnik & Sierks (2017). Here we report on a numerical study, elaborating on this mechanism. Essentially, the model considers a cometary nucleus composed of a low-density mixture of ice and dust, assuming that the ice is amorphous and traps volatile gasses, such as CO and CO2. The model assumes that the tensile strength of the subsurface material is low and that the surface is covered by a thin crust of low permeability. As the comet evolves, the amorphous ice crystallizes, and the crystallization front recedes from the surface, releasing the trapped gasses, which accumulate beneath the surface, building up pressure. The gas pressure weakens the material strength, but sustains the gas-filled layer against hydrostatic pressure. Eventually, the gas will break its way through the outer crust in an outburst. The rapid pressure drop may cause the collapse of the gas depleted layer, as seen on the nucleus of 67P/Churyumov-Gerasimenko. This mechanism is similar to subsidence events in gas fields on earth.We have performed quasi-3D numerical simulations in an attempt to determine the extent of the area that would be affected by such a mechanism. The frequency of such subsidence events and the depth of the collapse are investigated as functions of solar angle and spin axis inclination. The necessary conditions for outburst-induced collapse are determined and confronted with observations.References:Groussin, O., Sierks, H., et al. 2015, A&A, 583, A35Prialnik, D. & Sierks, H., 2017, MNRAS, in press

Tyrosine hydroxylase-immunoreactivity and its relations with gonadotropin-releasing hormone and neuropeptide Y in the preoptic area of the guinea pig.

PubMed

Bogus-Nowakowska, Krystyna; Równiak, Maciej; Hermanowicz-Sobieraj, Beata; Wasilewska, Barbara; Najdzion, Janusz; Robak, Anna

2016-12-01

The present study examines the distribution of tyrosine hydroxylase (TH) immunoreactivity and its morphological relationships with neuropeptide Y (NPY)- and gonadoliberin (GnRH)-immunoreactive (IR) structures in the preoptic area (POA) of the male guinea pig. Tyrosine hydroxylase was expressed in relatively small population of perikarya and they were mostly observed in the periventricular preoptic nucleus and medial preoptic area. The tyrosine hydroxylase-immunoreactive (TH-IR) fibers were dispersed troughout the whole POA. The highest density of these fibers was observed in the median preoptic nucleus, however, in the periventricular preoptic nucleus and medial preoptic area they were only slightly less numerous. In the lateral preoptic area, the density of TH-IR fibers was moderate. Two morphological types of TH-IR fibers were distinguished: smooth and varicose. Double immunofluorescence staining showed that TH and GnRH overlapped in the guinea pig POA but they never coexisted in the same structures. TH-IR fibers often intersected with GnRH-IR structures and many of them touched the GnRH-IR perikarya or dendrites. NPY wchich was abundantly present in the POA only in fibers showed topographical proximity with TH-IR structures. Althoug TH-IR perikarya and fibers were often touched by NPY-IR fibers, colocalization of TH and NPY in the same structures was very rare. There was only a small population of fibers which contained both NPY and TH. In conclusion, the morphological evidence of contacts between TH- and GnRH-IR nerve structures may be the basis of catecholaminergic control of GnRH release in the preoptic area of the male guinea pig. Moreover, TH-IR neurons were conatcted by NPY-IR fibers and TH and NPY colocalized in some fibers, thus NPY may regulate catecholaminergic neurons in the POA. Copyright © 2016 Elsevier B.V. All rights reserved.

Effects of gold thioglucose treatment on central corticotrophin-releasing hormone systems in mice.

PubMed

Noguchi, T; Makino, S; Shinahara, M; Nishiyama, M; Hashimoto, K; Terada, Y

2013-04-01

Systemic administration of gold thioglucose (GTG) causes a hypothalamic lesion that extends from the ventral part of the ventromedial hypothalamus (VMH) to the dorsal part of the arcuate nucleus (ARC), resulting in hyperphagia and obesity in mice. In the present study, we used in situ hybridisation histochemistry to explore the effects of GTG on the central corticotrophin-releasing hormone (CRH) system, which regulates feeding and energy homeostasis. Type 2 CRH receptor (CRHR-2) mRNA expression decreased by 40% at 8 weeks in the VMH and by 40-60% at 2 and 8 weeks in the ARC after GTG injection. By contrast, CRHR-2 mRNA expression in the hypothalamic paraventricular nucleus (PVN) and lateral septum was unchanged. Urocortin (Ucn) 3 mRNA expression in the perifornical area and medial amygdala decreased, whereas CRH mRNA expression in the PVN increased at 2 and 8 weeks after GTG injection. Ucn 1 mRNA expression in the Edingher-Westphal nucleus and Ucn 2 mRNA expression in the PVN were unchanged. Because Ucn 3 is an anorexigenic and a possible endogenous ligand for VMH CRHR-2, our results suggest that decreased Ucn 3 expression and decreased VMH CRHR-2 expression contribute, in part, to GTG-induced hyperphagia and obesity. To determine whether VMH CRHR-2 mediates the anorexigenic effects of Ucn 3, Ucn 3 was administered i.c.v. and food intake was measured 8 weeks after GTG treatment. Ucn 3 decreased cumulative food intake on days 4-7 after surgery compared to i.c.v. administration of vehicle in control mice. By contrast, the anorexigenic effects of i.c.v. Ucn 3 were abolished in GTG-treated mice. Taken together, our results indicate that the Ucn 3 pathway, which innervates the VMH, is involved in appetite regulation via CRHR-2. It remains to be determined whether CRHR-2 in the ARC has additional roles in appetite regulation by Ucn 3. © 2012 British Society for Neuroendocrinology.

Design and evaluation of pH-sensitive liposomes constructed by poly(2-ethyl-2-oxazoline)-cholesterol hemisuccinate for doxorubicin delivery.

PubMed

Xu, Huan; Hu, Meina; Yu, Xiu; Li, Yan; Fu, Yuanshan; Zhou, Xiaoxia; Zhang, Di; Li, Jianying

2015-04-01

In this study, a novel material, poly(2-ethyl-2-oxazoline)-cholesterol hemisuccinate (PEtOz-CHEMS), was synthesized to construct pH-sensitive liposomes. The structure of PEtOz-CHEMS was confirmed by thin-layer chromatography, Fourier transform infrared spectroscopy, and (1)H NMR. Anticancer fluorescent drug doxorubicin (DOX) was encapsulated into the liposomes. Compared with conventional liposomes (CL), CHEMS modified liposomes (CH-L) and PEGylated liposomes (PEG-L), the PEtOzylated liposomes (PEtOz-L) showed an acidic pH-induced increase in particle size. At pH 6.4, the heme release of PEtOz-L group was close to that of the positive control group, whereas that of CL, CH-L and PEG-L was close to that of the negative control group. In vitro drug release studies demonstrated that DOX was released from PEtOz-L in a pH-dependent manner, and the release of DOX from conventional DOX liposomes (CL-DOX), DOX loaded CH-L (CH-DOX-L) and PEGylated DOX liposomes (PEG-DOX-L) had no pronounced differences under each pH medium. In vitro cellular uptake assays showed that PEtOz-DOX-L indicated a significant fluorescence intensity at pH 6.4 compared with at pH 7.4. CL-DOX, CH-DOX-L and PEG-DOX-L did not achieve any obvious diversity at different pH conditions. Confocal laser scanning microscopy images showed that PEtOz-DOX-L can fuse with the endosomal membrane under acidic conditions of endosome, release DOX into the cytoplasm, then gather into the nucleus. Therefore, PEtOz can help liposomes achieve "endosomal escape". The in vitro cytotoxicity experiment results on A375 cells showed that PEtOz-DOX-L resulted in lower cell viability than CL-DOX, CH-DOX-L and PEG-DOX-L under low pH conditions. These results confirm that the pH-responsive PEtOz was a promising material for intracellular targeted delivery system and might be used for overcoming the "PEG dilemma". Copyright © 2015 Elsevier B.V. All rights reserved.

Retinohypothalamic connections in the rhesus monkey

NASA Astrophysics Data System (ADS)

Chijuka, John C.

Previous studies of retinohypothalamic projections in macaques were performed with anterograde degeneration or autoradiographic techniques that were not sufficiently sensitive to fully define these projections. Results of studies in non-primates using sensitive tracers have revealed more extensive retinohypothalamic projection than previously seen. We hypothesize that there are more extensive retinohypothalamic projections in the higher primate, macaque monkey. Thus, the primary goal of this investigation was to characterize the retinohypothalamic projections in the macaque monkey using the more sensitive tract tracer, cholera toxin subunit B (CTB) unilaterally injected intravitreally. Secondary goals were to determine: (1) whether there is a retinal projection to the sleep-related ventrolateral preoptic area of the hypothalamus; (2) whether there are direct retinal projections to gonadotropin-releasing hormone neurons in the hypothalamus; and (3) whether any retinally-projecting hypothalamic neurons can be retrogradely labeled by intravitreal CTB injections. Our results confirmed our hypothesis that there are more extensive projections to the central targets. We found that, in addition to the well-described retinal projection to the suprachiasmatic nucleus, a number of other hypothalamic areas were labeled. We observed projections to the medial and lateral preoptic areas, including the sleep-related ventrolateral preoptic area. A number of retinal fibers terminated immediately dorsal to the supraoptic nucleus (SO), with a few fibers penetrating and terminating within the nucleus. A few fibers continued laterally beyond the SO into the substantia innominata immediately ventral to the nucleus basalis of Meynert. In addition, a dense plexus of CTB-labeled, retinal fibers were present in the subventricular nucleus and adjacent subventricular area. Some of these fibers coursed dorsally from this region to penetrate the ependyma lining the third ventricle and apparently contacted the cerebrospinal fluid (CSF). We also observed projections to the anterior hypothalamic area throughout its rostrocaudal extent and to the posterior region of the lateral preoptic area immediately dorsal to the supraoptic nucleus. More posteriorly, fibers projected to the arcuate/infundibular region, and a few fibers could be seen to course towards the paraventricular, parvicellular region and posterior hypothalamic region close to the third ventricle. Finally, some retrogradely-labeled neurons were present in most injected cases. Overall, these results show that retinohypothalamic projections in the macaque are more extensive than once thought, and presumably play more roles than solely entraining the suprachiasmatic nucleus, the central circadian controller. (Abstract shortened by UMI.)

Nucleus-associated actin in Amoeba proteus.

PubMed

Berdieva, Mariia; Bogolyubov, Dmitry; Podlipaeva, Yuliya; Goodkov, Andrew

2016-10-01

The presence, spatial distribution and forms of intranuclear and nucleus-associated cytoplasmic actin were studied in Amoeba proteus with immunocytochemical approaches. Labeling with different anti-actin antibodies and staining with TRITC-phalloidin and fluorescent deoxyribonuclease I were used. We showed that actin is abundant within the nucleus as well as in the cytoplasm of A. proteus cells. According to DNase I experiments, the predominant form of intranuclear actin is G-actin which is associated with chromatin strands. Besides, unpolymerized actin was shown to participate in organization of a prominent actin layer adjacent to the outer surface of nuclear envelope. No significant amount of F-actin was found in the nucleus. At the same time, the amoeba nucleus is enclosed in a basket-like structure formed by circumnuclear actin filaments and bundles connected with global cytoplasmic actin cytoskeleton. A supposed architectural function of actin filaments was studied by treatment with actin-depolymerizing agent latrunculin A. It disassembled the circumnuclear actin system, but did not affect the intranuclear chromatin structure. The results obtained for amoeba cells support the modern concept that actin is involved in fundamental nuclear processes that have evolved in the cells of multicellular organisms. Copyright © 2016 Elsevier GmbH. All rights reserved.

Postsynaptic Depolarization Enhances GABA Drive to Dorsomedial Hypothalamic Neurons through Somatodendritic Cholecystokinin Release.

PubMed

Crosby, Karen M; Baimoukhametova, Dinara V; Bains, Jaideep S; Pittman, Quentin J

2015-09-23

Somatodendritically released peptides alter synaptic function through a variety of mechanisms, including autocrine actions that liberate retrograde transmitters. Cholecystokinin (CCK) is a neuropeptide expressed in neurons in the dorsomedial hypothalamic nucleus (DMH), a region implicated in satiety and stress. There are clear demonstrations that exogenous CCK modulates food intake and neuropeptide expression in the DMH, but there is no information on how endogenous CCK alters synaptic properties. Here, we provide the first report of somatodendritic release of CCK in the brain in male Sprague Dawley rats. CCK is released from DMH neurons in response to repeated postsynaptic depolarizations, and acts in an autocrine fashion on CCK2 receptors to enhance postsynaptic NMDA receptor function and liberate the retrograde transmitter, nitric oxide (NO). NO subsequently acts presynaptically to enhance GABA release through a soluble guanylate cyclase-mediated pathway. These data provide the first demonstration of synaptic actions of somatodendritically released CCK in the hypothalamus and reveal a new form of retrograde plasticity, depolarization-induced potentiation of inhibition. Significance statement: Somatodendritic signaling using endocannabinoids or nitric oxide to alter the efficacy of afferent transmission is well established. Despite early convincing evidence for somatodendritic release of neurohypophysial peptides in the hypothalamus, there is only limited evidence for this mode of release for other peptides. Here, we provide the first evidence for somatodendritic release of the satiety peptide cholecystokinin (CCK) in the brain. We also reveal a new form of synaptic plasticity in which postsynaptic depolarization results in enhancement of inhibition through the somatodendritic release of CCK. Copyright © 2015 the authors 0270-6474/15/3513160-11$15.00/0.

Depopulation of the ventromedial hypothalamic nucleus in the diabetic Chinese hamster.

PubMed

Garris, D R; Diani, A R; Smith, C; Gerritsen, G C

1982-01-01

The relationship between diabetes and the size, density and area of the ventromedial hypothalamic nucleus (VMH) was studied in the genetically diabetic Chinese hamster. Matched diabetic and non-diabetic control chinese hamsters were perfused, the hypothalamus collected, sectioned and stained for light microscopy. The mid-point of each VMH nucleus was located, photographed and enlarged for morphometric analysis. Each neuron that possessed a nucleolus and was located within the confines of a VMH was counted, and subsequently the area of each nucleus and the density of neurons per area of VMH were calculated. The results indicated that both the area and absolute number of neurons within the VMH of diabetic hamsters were significantly reduced compared to control values (P less than 0.01) The density of neurons per unit area of VMH was similar in both groups. These data suggest that the VMH experiences a neuronal depopulation in diabetic hamsters which may have a functional influence on the hypothalamic-pancreatic axis in this species.

Localization of the herpes simplex virus type 1 major capsid protein VP5 to the cell nucleus requires the abundant scaffolding protein VP22a.

PubMed

Nicholson, P; Addison, C; Cross, A M; Kennard, J; Preston, V G; Rixon, F J

1994-05-01

The intracellular distributions of three herpes simplex virus type 1 (HSV-1) capsid proteins, VP23, VP5 and VP22a, were examined using vaccinia virus and plasmid expression systems. During infection of cells with HSV-1 wild-type virus, all three proteins were predominantly located in the nucleus, which is the site of capsid assembly. However, when expressed in the absence of any other HSV-1 proteins, although VP22a was found exclusively in the nucleus as expected, VP5 and VP23 were distributed throughout the cell. Thus nuclear localization is not an intrinsic property of these proteins but must be mediated by one or more HSV-1-induced proteins. Co-expression experiments demonstrated that VP5 was efficiently transported to the nucleus in the presence of VP22a, but the distribution of VP23 was unaffected by the presence of either or both of the other two proteins.

Japanese-American Cooperative Emulsion Experiment /JACEE/. [high energy cosmic ray studies

NASA Technical Reports Server (NTRS)

Huggett, R. W.; Hunter, S. D.; Jones, W. V.; Takahashi, Y.; Ogata, T.; Saito, T.; Holynski, R.; Jurak, A.; Wolter, W.; Parnell, T. A.

1981-01-01

The instrumentation and results of long duration balloon flights carried out jointly by U.S. and Japan researchers to examine high energy cosmic rays are reported. Basic detector geometries are 2.5 sq m sr with operation at altitudes with 3-4 g/sq cm pressure, with observations thus far of over 100 hr. Energies from 2-100 TeV are recorded for nucleus-nucleus and hadron-nucleus interactions, and searches are made for new particle or interactions. The detector is an emulsion chamber which comprises doubly-coated nuclear emulsions on 800 micron thick methacryl substrates, X-ray films, etchable detectors, low density spacers, and lead sheets. Segmentation of the instrument into a primary charge module, a target section, a spacer section, and a lead-emulsion calorimeter allows accurate charge measurement for primary nuclei, reliable energy resolution, and a large geometrical factor for collecting high energy events. A primary Ca nucleus of 300 TeV has been observed.

From Cytoskeleton to Gene Expression: Actin in the Nucleus.

PubMed

Viita, Tiina; Vartiainen, Maria K

2017-01-01

Although most people still associate actin mainly with the cytoskeleton, several lines of evidence, with the earliest studies dating back to decades ago, have emphasized the importance of actin also inside the cell nucleus. Actin has been linked to many gene expression processes from gene activation to chromatin remodeling, but also to maintenance of genomic integrity and intranuclear movement of chromosomes and chromosomal loci. Recent advances in visualizing different forms and dynamic properties of nuclear actin have clearly advanced our understanding of the basic concepts by which actin operates in the nucleus. In this chapter we address the different breakthroughs in nuclear actin studies, as well as discuss the regulation nuclear actin and the importance of nuclear actin dynamics in relation to its different nuclear functions. Our aim is to highlight the fact that actin should be considered as an essential component of the cell nucleus, and its nuclear actions should be taken into account also in experiments on cytoplasmic actin networks.

Chemoarchitecture and afferent connections of the "olfactostriatum": a specialized vomeronasal structure within the basal ganglia of snakes.

PubMed

Martinez-Marcos, Alino; Ubeda-Bañon, Isabel; Lanuza, Enrique; Halpern, Mimi

2005-01-01

The olfactostriatum, a portion of the striatal complex of snakes, is the major tertiary vomeronasal structure in the ophidian brain, receiving substantial afferents from the nucleus sphericus, the primary target of accessory olfactory bulb efferents. In the present study, we have characterized the olfactostriatum of garter snakes (Thamnophis sirtalis) on the basis of chemoarchitecture (distribution of serotonin, neuropeptide Y and tyrosine hydroxylase) and hodology (afferent connections). The olfactostriatum is densely immunoreactive for serotonin and neuropeptide Y and shows moderate-to-weak immunoreactivity for tyrosine hydroxylase. In addition to afferents from the nucleus sphericus, the olfactostriatum receives inputs from the dorsal and lateral cortices, nucleus of the accessory olfactory tract, external and dorsolateral amygdalae, dorsomedial thalamic nucleus, ventral tegmental area and raphe nuclei. Double labeling experiments demonstrated that the distribution of serotonin and neuropeptide Y in this area almost completely overlaps the terminal field of projections from the nucleus sphericus. Also, serotonergic and dopaminergic innervation of the olfactostriatum likely arise, respectively, from the raphe nuclei and the ventral tegmental area, whereas local circuit neurons originate the neuropeptide Y immunoreactivity. These results indicate that the olfactostriatum of snakes could be a portion of the nucleus accumbens, with features characteristic of the accumbens shell, devoted to processing vomeronasal information. Comparative data suggest that a similar structure is present in the ventral striatum of amphibians and mammals.

An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger.

PubMed

Krashes, Michael J; Shah, Bhavik P; Madara, Joseph C; Olson, David P; Strochlic, David E; Garfield, Alastair S; Vong, Linh; Pei, Hongjuan; Watabe-Uchida, Mitsuko; Uchida, Naoshige; Liberles, Stephen D; Lowell, Bradford B

2014-03-13

Hunger is a hard-wired motivational state essential for survival. Agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus (ARC) at the base of the hypothalamus are crucial to the control of hunger. They are activated by caloric deficiency and, when naturally or artificially stimulated, they potently induce intense hunger and subsequent food intake. Consistent with their obligatory role in regulating appetite, genetic ablation or chemogenetic inhibition of AgRP neurons decreases feeding. Excitatory input to AgRP neurons is important in caloric-deficiency-induced activation, and is notable for its remarkable degree of caloric-state-dependent synaptic plasticity. Despite the important role of excitatory input, its source(s) has been unknown. Here, through the use of Cre-recombinase-enabled, cell-specific neuron mapping techniques in mice, we have discovered strong excitatory drive that, unexpectedly, emanates from the hypothalamic paraventricular nucleus, specifically from subsets of neurons expressing thyrotropin-releasing hormone (TRH) and pituitary adenylate cyclase-activating polypeptide (PACAP, also known as ADCYAP1). Chemogenetic stimulation of these afferent neurons in sated mice markedly activates AgRP neurons and induces intense feeding. Conversely, acute inhibition in mice with caloric-deficiency-induced hunger decreases feeding. Discovery of these afferent neurons capable of triggering hunger advances understanding of how this intense motivational state is regulated.

Baculovirus infection induces disruption of the nuclear lamina.

PubMed

Zhang, Xiaomei; Xu, Kaiyan; Wei, Denghui; Wu, Wenbi; Yang, Kai; Yuan, Meijin

2017-08-10

Baculovirus nucleocapsids egress from the nucleus primarily via budding at the nuclear membrane. The nuclear lamina underlying the nuclear membrane represents a substantial barrier to nuclear egress. Whether the nuclear lamina undergoes disruption during baculovirus infection remains unknown. In this report, we generated a clonal cell line, Sf9-L, that stably expresses GFP-tagged Drosophila lamin B. GFP autofluorescence colocalized with immunofluorescent anti-lamin B at the nuclear rim of Sf9-L cells, indicating GFP-lamin B was incorporated into the nuclear lamina. Meanwhile, virus was able to replicate normally in Sf9-L cells. Next, we investigated alterations to the nuclear lamina during baculovirus infection in Sf9-L cells. A portion of GFP-lamin B localized diffusely at the nuclear rim, and some GFP-lamin B was redistributed within the nucleus during the late phase of infection, suggesting the nuclear lamina was partially disrupted. Immunoelectron microscopy revealed associations between GFP-lamin B and the edges of the electron-dense stromal mattes of the virogenic stroma, intranuclear microvesicles, and ODV envelopes and nucleocapsids within the nucleus, indicating the release of some GFP-lamin B from the nuclear lamina. Additionally, GFP-lamin B phosphorylation increased upon infection. Based on these data, baculovirus infection induced lamin B phosphorylation and disruption of the nuclear lamina.

Ca2+ channel blockade prevents lysergic acid diethylamide-induced changes in dopamine and serotonin metabolism.

PubMed

Antkiewicz-Michaluk, L; Románska, I; Vetulani, J

1997-07-30

To investigate the effect of a single and multiple administration of lysergic acid diethylamide (LSD) on cerebral metabolism of dopamine and serotonin, male Wistar rats were treated with low and high doses (0.1 and 2.0 mg/kg i.p.) of LSD and the levels of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, 3-methoxytyramine, serotonin and 5-hydroxyindoleacetic acid were assayed by HPLC in the nucleus accumbens, striatum and frontal cortex. Some rats received nifedipine, 5 mg/kg i.p., before each injection of LSD to assess the effect of a Ca2+ channel blockade. High-dose LSD treatment (8 x 2 mg/kg per day) caused a strong stimulation of dopamine metabolism in the nucleus accumbens and striatum, and serotonin metabolism in the nucleus accumbens: the changes were observed 24 (but not 1 h) after the last dose. The changes induced by the low-dose treatment (8 x 0.1 mg/kg per day) had a different pattern, suggesting the release of dopamine from vesicles to cytoplasm. Co-administration of nifedipine completely prevented the LSD-induced biochemical changes. The results suggest that Ca2+ channel blocking agents may prevent development of some behavioral consequences of chronically used LSD.

Confocal observations of late-acting self-incompatibility in Theobroma cacao L.

PubMed

Ford, Caroline S; Wilkinson, Mike J

2012-09-01

Cocoa (Theobroma cacao) has an idiosyncratic form of late-acting self-incompatibility that operates through the non-fusion of incompatible gametes. Here, we used high-resolution confocal microscopy to define fine level changes to the embryo sac of the strongly self-incompatible cocoa genotype SCA 24 in the absence of pollination, and following compatible and incompatible pollination. All sperm nuclei had fused with the female nuclei by 48 h following compatible pollinations. However, following incompatible pollinations, we observed divergence in the behaviour of sperm nuclei following release into the embryo sac. Incomplete sperm nucleus migration occurred in approximately half of the embryo sacs, where the sperm nuclei had so far failed to reach the female gamete nuclei. Sperm nuclei reached but did not fuse with the female gamete nuclei in the residual cases. We argue that the cellular mechanisms governing sperm nucleus migration to the egg nucleus and those controlling subsequent nuclear fusion are likely to differ and should be considered independently. Accordingly, we recommend that future efforts to characterise the genetic basis of LSI in cocoa should take care to differentiate between these two events, both of which contribute to failed karyogamy. Implications of these results for continuing efforts to gain better understanding of the genetic control of LSI in cocoa are discussed.

[Postsynaptic reactions of cerebral cortex neurons, activated by nociceptive afferents during stimulation of the Raphe nuclei].

PubMed

Labakhua, T Sh; Dzhanashiia, T K; Gedevanishvili, G I; Dzhokhadze, L D; Tkemaladze, T T; Abzianidze, I V

2012-01-01

On cats, we studied the influence of stimulation of the Raphe nuclei (RN) on postsynaptic processes evoked in neurons of the somatosensory cortex by stimulation of nociceptive (intensive stimulation of the tooth pulp) and non-nociceptive (moderate stimulation of the ventroposteromedial--VPN--nucleus of the thalamus) afferent inputs. 6 cells, selectively excited by stimulation of nocciceptors and 9 cells, activated by both the above nociceptive and non-nociceptive influences (nociceptive and convergent neurons, respectively) were recorded intracellular. In neurons of both groups, responses to nociceptive stimulation (of sufficient intensity) looked like an EPSP-spike-IPSP (the letter of significant duration, up to 200-300 ms) compleх. Conditioning stimulation of the RN which preceded test stimulus applied to the tooth pulp or VPM nucleus by 100 to 800 ms, induced 40-60 % decrease of the IPSP amplitude only, while maхimal effect of influence, in both cases, was noted within intervals of 300-800 ms between conditioning and test stimulus. During stimulation of the RN, serotonin released via receptor and second messengers, provides postsynaptic modulation of GABAergic system, decreasing the IPSP amplitude which occurs after stimulation of both the tooth pulp and VPM thalamic nucleus. This process may be realized trough either pre- or postsynaptic mechanisms.

On the Dust Environment of Comet C/2012 S1 (ISON) from 12 AU Pre-perihelion to the End of its Activity around Perihelion

NASA Astrophysics Data System (ADS)

Moreno, F.; Pozuelos, F.; Aceituno, F.; Casanova, V.; Duffard, R.; López-Moreno, J. J.; Molina, A.; Ortiz, J. L.; Santos-Sanz, P.; Sota, A.; Diepvens, A.; Segundo, A. S.; Bell, C.; Labordena, C.; Bryssinck, E.; Cortés, E.; Reina, E.; García, F.; Gómez, F.; Limón, F.; Soldán, F.; Tifner, F.; Muler, G.; Almendros, I.; Aledo, J.; Bel, J.; Carrillo, J.; Castellano, J.; Curto, J.; Gaitan, J.; Salto, J. L.; Lopesino, J.; Lozano, J.; Hernández, J. F.; González, J. J.; Martín, J. L.; Aymamí, J. M.; Bosch, J. M.; Fernández, J. M.; Vidal, J. R.; Montoro, L.; Tremosa, L.; Campas, M.; Canales, O.; Dekelver, P. J.; Benavides, R.; Naves, R.; Castillo, R.; Climent, T.; Cupillari, T.; Yanamandra-Fisher, P.

2014-08-01

A Monte Carlo dust tail model has been applied to extract the dust environment parameters of the comet C/2012 S1 (ISON) from both Earth-based and SOHO LASCO C3 observations, performed from about six astronomical units (AU) inbound, to just after perihelion passage, when only a small portion of the original comet nucleus has survived in the form of a cloud of tiny particles. The early Afρ and image data are consistent with particle ejection from an extended active area located at latitudes 35°N to 90°N (for a prograde rotating nucleus), with the spin axis having a large obliquity (I ~ 70°). This configuration nicely fits the early images and Afρ data until 3.9 AU inbound, when the emission should become isotropic in order to fit the data. The analysis of LASCO images reveals that, assuming an original nucleus of RN = 500 m with ρ = 1000 kg m-3, at least half of its mass was vaporized when the comet was at about 17 R ⊙ inbound. We conclude that at that time the nucleus suffered a cataclysmic fragmentation releasing a huge amount of material of 2.3 ×1011 kg, equivalent to a sphere of 380 m in radius with density 1000 kg m-3. The surviving material after perihelion passage consists of very small dust particles of 0.1-50 μm in radius with a total mass of just 6.7×108 kg.

Activation of Pedunculopontine Glutamate Neurons Is Reinforcing

PubMed Central

Yoo, Ji Hoon; Zell, Vivien; Wu, Johnathan; Punta, Cindy; Ramajayam, Nivedita; Shen, Xinyi; Faget, Lauren; Lilascharoen, Varoth; Lim, Byung Kook

2017-01-01

Dopamine transmission from midbrain ventral tegmental area (VTA) neurons underlies behavioral processes related to motivation and drug addiction. The pedunculopontine tegmental nucleus (PPTg) is a brainstem nucleus containing glutamate-, acetylcholine-, and GABA-releasing neurons with connections to basal ganglia and limbic brain regions. Here we investigated the role of PPTg glutamate neurons in reinforcement, with an emphasis on their projections to VTA dopamine neurons. We used cell-type-specific anterograde tracing and optogenetic methods to selectively label and manipulate glutamate projections from PPTg neurons in mice. We used anatomical, electrophysiological, and behavioral assays to determine their patterns of connectivity and ascribe functional roles in reinforcement. We found that photoactivation of PPTg glutamate cell bodies could serve as a direct positive reinforcer on intracranial self-photostimulation assays. Further, PPTg glutamate neurons directly innervate VTA; photostimulation of this pathway preferentially excites VTA dopamine neurons and is sufficient to induce behavioral reinforcement. These results demonstrate that ascending PPTg glutamate projections can drive motivated behavior, and PPTg to VTA synapses may represent an important target relevant to drug addiction and other mental health disorders. SIGNIFICANCE STATEMENT Uncovering brain circuits underlying reward-seeking is an important step toward understanding the circuit bases of drug addiction and other psychiatric disorders. The dopaminergic system emanating from the ventral tegmental area (VTA) plays a key role in regulating reward-seeking behaviors. We used optogenetics to demonstrate that the pedunculopontine tegmental nucleus sends glutamatergic projections to VTA dopamine neurons, and that stimulation of this circuit promotes behavioral reinforcement. The findings support a critical role for pedunculopontine tegmental nucleus glutamate neurotransmission in modulating VTA dopamine neuron activity and behavioral reinforcement. PMID:28053028

GABAergic neurons in nucleus accumbens are correlated to resilience and vulnerability to chronic stress for major depression

PubMed Central

Cui, Shan; Wang, Jin-Hui

2017-01-01

Background Major depression, persistent low mood, is one of common psychiatric diseases. Chronic stressful life is believed to be a major risk factor that leads to dysfunctions of the limbic system. However, a large number of the individuals with experiencing chronic stress do not suffer from major depression, called as resilience. Endogenous mechanisms underlying neuronal invulnerability to chronic stress versus major depression are largely unknown. As GABAergic neurons are vulnerable to chronic stress and their impairments is associated with major depression, we have examined whether the invulnerability of GABAergic neurons in the limbic system is involved in resilience. Results GABAergic neurons in the nucleus accumbens from depression-like mice induced by chronic unpredictable mild stress appear the decreases in their GABA release, spiking capability and excitatory input reception, compared with those in resilience mice. The levels of decarboxylase and vesicular GABA transporters decrease in depression-like mice, but not resilience. Materials and Methods Mice were treated by chronic unpredictable mild stress for three weeks. Depression-like behaviors or resilience was confirmed by seeing whether their behaviors change significantly in sucrose preference, Y-maze and forced swimming tests. Mice from controls as well as depression and resilience in response to chronic unpredictable mild stress were studied in terms of GABAergic neuron activity in the nucleus accumbens by cell electrophysiology and protein chemistry. Conclusions The impairment of GABAergic neurons in the nucleus accumbens is associated with major depression. The invulnerability of GABAergic neurons to chronic stress may be one of cellular mechanisms for the resilience to chronic stress. PMID:28415589

Stimulation of D2 receptors in the prefrontal cortex reduces PCP-induced hyperactivity, acetylcholine release and dopamine metabolism in the nucleus accumbens.

PubMed

Del Arco, A; Mora, F; Mohammed, A H; Fuxe, K

2007-02-01

The aim of the present study was to investigate the effects of stimulation of D2 receptors in the prefrontal cortex (PFC) on spontaneous motor activity and the hyperactivity induced by the psychomimetic phencyclidine (PCP). In addition, the effects of prefrontal D2 stimulation under PCP treatment on dialysate concentrations of acetylcholine, choline, dopamine, DOPAC and HVA in the nucleus accumbens were also investigated. Sprague-Dawley male rats were implanted with guide cannulae to perform bilateral injections into the medial PFC of the D2 agonist quinpirole (1.5 and 5 microg/side). Horizontal and vertical spontaneous motor activity and the motor activity induced by systemic injections of the PCP (5 mg/kg i.p.) were monitored in the open field. PFC injections of quinpirole (1.5 and 5 microg/side) significantly decreased horizontal and vertical spontaneous motor activity in a dose-related manner. These effects were blocked by the D2 antagonist raclopride (5 microg/side). Microinjections of quinpirole (1.5 and 5 microg/side) into the PFC also significantly attenuated the hyperactivity produced by PCP (5 mg/kg i.p.). PCP also increased dialysate concentrations of acetylcholine, and dopamine metabolites in the nucleus accumbens. These increases were also reduced by injections of quinpirole (5 microg/side) into the PFC. These results suggest that the stimulation of prefrontal D2 receptors plays an inhibitory role in regulating spontaneous and PCP-induced motor activity and also in the neurochemical changes produced by PCP in the nucleus accumbens.

Neutrino Flux Prediction for the NuMI Beamline

DOE Office of Scientific and Technical Information (OSTI.GOV)

Soplin, Leonidas Aliaga

2016-01-01

The determination of the neutrino flux in any conventional neutrino beam presents a challenge for the current and future short and long baseline neutrino experiments. The uncertainties associated with the production and attenuation of the hadrons in the beamline materials along with those associated with the beam optics have a big effect in the flux spectrum knowledge. For experiments like MINERvA, understanding the flux is crucial since it enters directly into every neutrino-nucleus cross-sections measurements. The foundation of this work is predicting the neutrino flux at MINERvA using dedicated measurements of hadron production in hadron-nucleus collisions and incorporating in-situ MINERvAmore » data that can provide additional constraints. This work also includes the prospect for predicting the flux at other detectors like the NOvA Near detector. The procedure and conclusions of this thesis will have a big impact on future hadron production experiments and on determining the flux for the upcoming DUNE experiment.« less

Neutrino Flux Prediction for the NuMI Beamline

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aliaga Soplin, Leonidas

2016-01-01

The determination of the neutrino flux in any conventional neutrino beam presents a challenge for the current and future short and long baseline neutrino experiments. The uncertainties associated with the production and attenuation of the hadrons in the beamline materials along with those associated with the beam optics have a big effect in the flux spectrum knowledge. For experiments like MINERvA, understanding the flux is crucial since it enters directly into every neutrino-nucleus cross-sections measurements. The foundation of this work is predicting the neutrino flux at MINERvA using dedicated measurements of hadron production in hadron-nucleus collisions and incorporating in-situ MINERvAmore » data that can provide additional constraints. This work also includes the prospect for predicting the flux at other detectors like the NOvA Near detector. The procedure and conclusions of this thesis will have a big impact on future hadron production experiments and on determining the fl ux for the upcoming DUNE experiment.« less

Simulation of dependence of the cross section of deuterons beam fragmentation into cumulative pions and protons on the mass of the target nucleus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Litvinenko, A. G., E-mail: alitvin@jinr.ru; Litvinenko, E. I.

2015-03-15

We have studied the mechanisms influencing production of cumulative pions and protons in the fragmentation of the incident deuterons into cumulative pions and protons emitted at zero angle. We argue that the peripheral dependence on the atomic mass of the target nucleus, which was obtained in the experiments for medium and heavy nuclei, can be explained by scattering on target nucleons without introducing additional parameters.

Dark sequential Z ' portal: Collider and direct detection experiments

NASA Astrophysics Data System (ADS)

Arcadi, Giorgio; Campos, Miguel D.; Lindner, Manfred; Masiero, Antonio; Queiroz, Farinaldo S.

2018-02-01

We revisit the status of a Majorana fermion as a dark matter candidate when a sequential Z' gauge boson dictates the dark matter phenomenology. Direct dark matter detection signatures rise from dark matter-nucleus scatterings at bubble chamber and liquid xenon detectors, and from the flux of neutrinos from the Sun measured by the IceCube experiment, which is governed by the spin-dependent dark matter-nucleus scattering. On the collider side, LHC searches for dilepton and monojet + missing energy signals play an important role. The relic density and perturbativity requirements are also addressed. By exploiting the dark matter complementarity we outline the region of parameter space where one can successfully have a Majorana dark matter particle in light of current and planned experimental sensitivities.

Implementing the correlated fermi gas nuclear model for quasielastic neutrino-nucleus scattering

NASA Astrophysics Data System (ADS)

Tockstein, Jameson

2017-09-01

When studying neutrino oscillations an understanding of charged current quasielastic (CCQE) neutrino-nucleus scattering is imperative. This interaction depends on a nuclear model as well as knowledge of form factors. Neutrino experiments, such as MiniBooNE, often use the Relativistic Fermi Gas (RFG) nuclear model. Recently, the Correlated Fermi Gas (CFG) nuclear model was suggested in, based on inclusive and exclusive scattering experiments at JLab. We implement the CFG model for CCQE scattering. In particular, we provide analytic expressions for this implementation that can be used to analyze current and future neutrino CCQE data. This project was supported through the Wayne State University REU program under NSF Grant PHY-1460853 and by the DOE Grant DE-SC0007983.