The same enhancer regulates the earliest Emx2 expression in caudal forebrain primordium, subsequent expression in dorsal telencephalon and later expression in the cortical ventricular zone.

PubMed

Suda, Yoko; Kokura, Kenji; Kimura, Jun; Kajikawa, Eriko; Inoue, Fumitaka; Aizawa, Shinichi

2010-09-01

We have analyzed Emx2 enhancers to determine how Emx2 functions during forebrain development are regulated. The FB (forebrain) enhancer we identified immediately 3' downstream of the last coding exon is well conserved among tetrapods and unexpectedly directed all the Emx2 expression in forebrain: caudal forebrain primordium at E8.5, dorsal telencephalon at E9.5-E10.5 and the cortical ventricular zone after E12.5. Otx, Tcf, Smad and two unknown transcription factor binding sites were essential to all these activities. The mutant that lacked this enhancer demonstrated that Emx2 expression under the enhancer is solely responsible for diencephalon development. However, in telencephalon, the FB enhancer did not have activities in cortical hem or Cajal-Retzius cells, nor was its activity in the cortex graded. Emx2 expression was greatly reduced, but persisted in the telencephalon of the enhancer mutant, indicating that there exists another enhancer for Emx2 expression unique to mammalian telencephalon.

Muscle architecture of the elongated nose in the Asian elephant (Elephas maximus).

PubMed

Endo, H; Hayashi, Y; Komiya, T; Narushima, E; Sasaki, M

2001-05-01

The architecture of the M. caninus in the elongated nose was examined in the Asian elephant (Elephas maximus). The following complicated musculature of the M. caninus was observed in the proximal and distal regions of the nose: (1) Proximal region: In the superficial layer, the longitudinal bundles are confirmed in the dorsal part, and the obliquely-oriented ones in the ventral part. In the middle layer, some bundles run ventro-distally, while other ones represent longitudinally-oriented running. The deep layer consists of complicated architecture of many bundles. Some muscle bundles run medio-laterally, while the others extend proximo-distally in this space. (2) Distal region: In the dorsal part of the M. caninus, the bundles run at deep-superficial direction, while in the ventral part the bundles are longitudinally arranged. The bundles run at lateral direction near the septum of the nasal conduits. The N. facialis and N. infraorbitalis send many branches in the lateral area of the M. caninus in the trunk. This muscle architecture of multi-oriented bundles and well-developed innervation to them suggest that they enable the elongated nose to act as a refined manipulator in the Asian elephant.

The relationship of lateral anatomic structures to exiting guide pins during femoral tunnel preparation utilizing an accessory medial portal.

PubMed

Farrow, Lutul D; Parker, Richard D

2010-06-01

Anatomic reconstruction of the anterior cruciate ligament through an accessory medial portal has become increasingly popular. The purpose of this study is to describe the relationship of guide pin exit points to the lateral anatomic structures when preparing the anterior cruciate ligament femoral tunnel through an accessory medial portal. We utilized seven fresh frozen cadaveric knees. Utilizing an anteromedial approach, a guide wire was placed into the center of each bundle's footprint. Each guide wire was advanced through the lateral femoral cortex. The guide pins were passed at 90, 110, and 130 degrees of knee flexion. The distances from each guide pin to the closest relevant structures on the lateral side of the knee were measured. At 90 degrees the posterolateral bundle guide pin was closest to the lateral condyle articular cartilage (mean 5.4 +/- 2.2 mm) and gastrocnemius tendon (mean 5.7 +/- 2.1 mm). At 110 degrees the posterolateral bundle pin was closest to the gastrocnemius tendon (mean 4.5 +/- 3.4 mm). At 130 degrees the posterolateral bundle pin was closest to the gastrocnemius tendon (mean 7.2 +/- 5.5 mm) and lateral collateral ligament (mean 6.8 +/- 2.1 mm). At 90 degrees the anteromedial bundle guide pin was closest to the articular cartilage (mean 2.0 +/- 2.0 mm). At 110 degrees the anteromedial bundle pin was closest to the articular cartilage (mean 7.4 +/- 3.5 mm) and gastrocnemius tendon (mean 12.3 +/- 3.1 mm). At 130 degrees the AM bundle pin was closest to the gastrocnemius tendon (mean 8.2 +/- 3.2 mm) and LCL (mean 15.1 +/- 2.9 mm). Neither guide pin (anteromedial or posterolateral bundle) put the peroneal nerve at risk at any knee flexion angle. At low knee flexion angles the anteromedial and posterolateral bundle guide pins closely approximated multiple lateral structures when using an accessory medial arthroscopic portal. Utilizing higher flexion angles increases the margin of error when preparing both femoral tunnels. During preparation of the anterior cruciate ligament femoral tunnel through an accessory anteromedial portal the tunnels should be drilled in at least 110 degrees of knee flexion in order to move guide pin exit points away from important lateral knee structures.

Possible structural abnormality of the brainstem in unipolar depressive illness: a transcranial ultrasound and diffusion tensor magnetic resonance imaging study.

PubMed

Steele, J D; Bastin, M E; Wardlaw, J M; Ebmeier, K P

2005-11-01

Most empirically derived antidepressants increase monoamine levels. The nuclei of cells synthesising these monoamines are located in the brainstem, and projection tracts such as the medial forebrain bundle reach virtually all other brain areas. Two studies of unipolar depressive illness using transcranial ultrasound have reported reduced echogenicity of the brainstem midline in unipolar depressed patients. This may be consistent with disruption of white matter tracts, including the medial forebrain bundle, and it has been suggested that the effect of such disruption could be reversed by antidepressants. To replicate these findings in a group of unipolar depressed patients and controls. Fifteen unipolar depressed patients and 15 controls were studied using transcranial ultrasound imaging and diffusion tensor magnetic resonance imaging (DT-MRI). No difference in echogenicity of the brainstem midline of unipolar depressed patients was found. A possible trend (Cohen's d = 0.39) in the direction of previous studies was found. Although the echogenicity of the brainstem midline of the control group was found to be similar to previous reports, there was no reduction in the patient group. Additionally, no structural abnormality of the brainstem was identified using DT-MRI. While these data do not replicate the findings of previous studies reporting a significant reduction in the echogenicity of the brainstem midline in unipolar depressed patients, the ultrasound investigation indicated that there may be a trend in this direction. Given the importance of identifying the causes of depressive illness, it is important that other groups attempt similar studies.

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

PubMed Central

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

2011-01-01

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

A longitudinal study on deep brain stimulation of the medial forebrain bundle for treatment-resistant depression.

PubMed

Fenoy, Albert J; Schulz, Paul E; Selvaraj, Sudhakar; Burrows, Christina L; Zunta-Soares, Giovanna; Durkin, Kathryn; Zanotti-Fregonara, Paolo; Quevedo, Joao; Soares, Jair C

2018-06-04

Deep brain stimulation (DBS) to the superolateral branch of the medial forebrain bundle (MFB) has been reported to lead to rapid antidepressant effects. In this longitudinal study, we expand upon the initial results we reported at 26 weeks (Fenoy et al., 2016), showing sustained antidepressant effects of MFB DBS on six patients with treatment-resistant depression (TRD) over 1 year. The Montgomery-Åsberg Depression Rating Scale (MADRS) was used as the primary assessment tool. Deterministic fiber tracking was used to individually map the target area; analysis was performed to compare modulated fiber tracts between patients. Intraoperatively, upon stimulation at target, responders reported immediate increases in energy and motivation. An insertional effect was seen during the 4-week sham stimulation phase from baseline (28% mean MADRS reduction, p = 0.02). However, after 1 week of initiating stimulation, three of six patients had a > 50% decrease in MADRS scores relative to baseline (43% mean MADRS reduction, p = 0.005). One patient withdrew from study participation. At 52 weeks, four of remaining five patients have > 70% decrease in MADRS scores relative to baseline (73% mean MADRS reduction, p = 0.007). Evaluation of modulated fiber tracts reveals significant common orbitofrontal connectivity to the target region in all responders. Neuropsychological testing and 18 F-fluoro-deoxyglucose-positron emission tomography cerebral metabolism evaluations performed at baseline and at 52 weeks showed minimal changes and verified safety. This longitudinal evaluation of MFB DBS demonstrated rapid antidepressant effects, as initially reported by Schlaepfer et al. (2013), and supports the use of DBS for TRD.

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.

Different subcellular localization of neurotensin-receptor and neurotensin-acceptor sites in the rat brain dopaminergic system.

PubMed

Schotte, A; Rostène, W; Laduron, P M

1988-04-01

The subcellular localization of neurotensin-receptor sites (NT2 sites) and neurotensin-acceptor sites (NT1 sites) was studied in rat caudate-putamen by isopycnic centrifugation in sucrose density gradients. [3H]Neurotensin binding to NT2 sites occurred as a major peak at higher sucrose densities, colocalized with [3H]dopamine uptake, and as a small peak at a lower density; whereas binding to NT1 sites occurred as a single large peak at an intermediate density. 6-Hydroxydopamine lesions of the median forebrain bundle resulted in a total loss of NT2 sites in the caudate-putamen but did not affect NT2 sites in the nucleus accumbens and the olfactory tubercle. NT1 sites were not affected. Kainic acid injections into the rat caudate-putamen led to a partial decrease of NT1 sites in this region 5 days later. After a few weeks they returned to normal. Therefore NT2 sites are probably associated with presynaptic nigrostriatal dopaminergic terminals in the caudate-putamen but not in the nucleus accumbens and the olfactory tubercle. A possible association of NT1 sites with glial cells is suggested.

Femoral tunnel placement in single-bundle anterior cruciate ligament reconstruction: a cadaveric study relating transtibial lateralized femoral tunnel position to the anteromedial and posterolateral bundle femoral origins of the anterior cruciate ligament.

PubMed

Rue, John-Paul H; Ghodadra, Neil; Bach, Bernard R

2008-01-01

There is controversy regarding the necessity of reconstructing both the posterolateral and anteromedial bundles of the anterior cruciate ligament. A laterally oriented transtibial drilled femoral tunnel replaces portions of the femoral footprints of the anteromedial and posterolateral bundles of the anterior cruciate ligament. Descriptive laboratory study. Footprints of the anteromedial and posterolateral bundles of the anterior cruciate ligament were preserved on 7 matched pairs (5 female, 2 male) of fresh-frozen human cadaveric femurs (14 femurs total). Each femur was anatomically oriented and secured in a custom size-appropriate, side-matched replica tibia model to simulate transtibial retrograde drilling of a 10-mm femoral tunnel in each specimen. The relationship of the tunnel relative to footprints of both bundles of the anterior cruciate ligament was recorded using a Microscribe MX digitizer. The angle of the femoral tunnel relative to the vertical 12-o'clock position was recorded for all 14 specimens; only 10 specimens were used for footprint measurements. On average, the 10-mm femoral tunnel overlapped 50% of the anteromedial bundle (range, 2%-83%) and 51% of the posterolateral bundle (range, 16%-97%). The footprint of the anteromedial bundle occupied 32% (range, 3%-49%) of the area of the tunnel; the footprint of the posterolateral bundle contributed 26% (range, 7%-41%). The remainder of the area of the 10-mm tunnel did not overlap with the anterior cruciate ligament footprint. The mean absolute angle of the femoral tunnel as measured directly on the specimen was 48 degrees (range, 42 degrees-53 degrees) from vertical, corresponding to approximately a 10:30 clock face position on a right knee. Anterior cruciate ligament reconstruction using a laterally oriented transtibial drilled femoral tunnel incorporates portions of the anteromedial and posterolateral bundle origins of the native anterior cruciate ligament. A laterally oriented transtibial drilled femoral tunnel placed at the 10:30 position (1:30 for left knees) reconstructs portions of the anteromedial and posterolateral bundles of the anterior cruciate ligament.

Arrangement of the orbicularis oris muscle in different types of cleft lips.

PubMed

Wijayaweera, C J; Amaratunga, N A; Angunawela, P

2000-05-01

A thorough knowledge of the anatomy of the labial region, especially the arrangement of the muscle fibers, is essential for the success of primary repair of the cleft lip. Pared lateral and medial edges from 20 unilateral incomplete cleft lips and 25 unilateral complete cleft lips were obtained during primary surgery. Three specimens of normal lips were taken from unclaimed infant cadavers as the controls. They were prepared for routine histological studies and were examined to study the direction of muscle fibers. Intrinsic and extrinsic bundles were identified in both lateral and medial sides of specimens of both cleft types. The intrinsic bundle was not displaced but was interrupted by the cleft. The extrinsic bundle in the lateral side of both cleft types ran upward along the lateral cleft margin, whereas in the medial side it ran horizontally to terminate close to the medial cleft margin. The extrinsic bundle is the retractor, which is associated with facial expression, whereas the intrinsic bundle is the constrictor of the mouth. Because there are two functional components in the orbicularis oris muscle, identifying and repairing them separately will enable each of them to accomplish their distinctive functions.

Molecular dynamics simulations of polyelectrolyte brushes under poor solvent conditions: origins of bundle formation.

PubMed

He, Gui-Li; Merlitz, Holger; Sommer, Jens-Uwe

2014-03-14

Molecular dynamics simulations are applied to investigate salt-free planar polyelectrolyte brushes under poor solvent conditions. Starting above the Θ-point with a homogeneous brush and then gradually reducing the temperature, the polymers initially display a lateral structure formation, forming vertical bundles of chains. A further reduction of the temperature (or solvent quality) leads to a vertical collapse of the brush. By varying the size and selectivity of the counterions, we show that lateral structure formation persists and therefore demonstrate that the entropy of counterions being the dominant factor for the formation of the bundle phase. By applying an external compression force on the brush we calculate the minimal work done on the polymer phase only and prove that the entropy gain of counterions in the bundle state, as compared to the homogeneously collapsed state at the same temperature, is responsible for the lateral microphase segregation. As a consequence, the observed lateral structure formation has to be regarded universal for osmotic polymer brushes below the Θ-point.

The ontogenesis of the forebrain commissures and the determination of brain asymmetries.

PubMed

Lent, R; Schmidt, S L

1993-02-01

We have reviewed the organization and development of the interhemispheric projections through the forebrain commissures, especially those of the CC, in connection with the development of brain asymmetries. Analyzing the available data, we conclude that the developing CC plays an important role in the ontogenesis of brain asymmetries. We have extended a previous hypothesis that the rodent CC may exert a stabilizing effect over the unstable populational asymmetries of cortical size and shape, and that it participates in the developmental stabilization of lateralized motor behaviors.

Clonal and molecular analysis of the prospective anterior neural boundary in the mouse embryo

PubMed Central

Cajal, Marieke; Lawson, Kirstie A.; Hill, Bill; Moreau, Anne; Rao, Jianguo; Ross, Allyson; Collignon, Jérôme; Camus, Anne

2012-01-01

In the mouse embryo the anterior ectoderm undergoes extensive growth and morphogenesis to form the forebrain and cephalic non-neural ectoderm. We traced descendants of single ectoderm cells to study cell fate choice and cell behaviour at late gastrulation. In addition, we provide a comprehensive spatiotemporal atlas of anterior gene expression at stages crucial for anterior ectoderm regionalisation and neural plate formation. Our results show that, at late gastrulation stage, expression patterns of anterior ectoderm genes overlap significantly and correlate with areas of distinct prospective fates but do not define lineages. The fate map delineates a rostral limit to forebrain contribution. However, no early subdivision of the presumptive forebrain territory can be detected. Lineage analysis at single-cell resolution revealed that precursors of the anterior neural ridge (ANR), a signalling centre involved in forebrain development and patterning, are clonally related to neural ectoderm. The prospective ANR and the forebrain neuroectoderm arise from cells scattered within the same broad area of anterior ectoderm. This study establishes that although the segregation between non-neural and neural precursors in the anterior midline ectoderm is not complete at late gastrulation stage, this tissue already harbours elements of regionalisation that prefigure the later organisation of the head. PMID:22186731

Saturation of subjective reward magnitude as a function of current and pulse frequency.

PubMed

Simmons, J M; Gallistel, C R

1994-02-01

In rats with electrodes in the medial forebrain bundle, the upper portion of the function relating the experienced magnitude of the reward to pulse frequency was determined at currents ranging from 100 to 1,000 microA. The pulse frequency required to produce an asymptotic level of reward was inversely proportional to current except at the lowest currents and highest pulse frequencies. At a given current, the subjective reward magnitude functions decelerated to an asymptote over an interval in which the pulse frequency doubled or tripled. The asymptotic level of reward was approximately constant for currents between 200 and 1,000 microA but declined substantially at currents at or below 100 microA and pulse frequencies at or above 250 to 400 pulses per second. The results are consistent with the hypothesis that the magnitude of the experienced reward depends only on the number of action potentials generated by the train of pulses in the bundle of reward-relevant axons.

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

PubMed

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

2017-08-01

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

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

PubMed Central

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

2010-01-01

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

C-fos induction in forebrain areas of two different visual pathways during consolidation of sexual imprinting in the zebra finch (Taeniopygia guttata).

PubMed

Sadananda, Monika; Bischof, Hans-Joachim

2006-10-16

Two forebrain areas in the hyperpallium apicale and in the lateral nidopallium of isolated male zebra finches are highly active (2-deoxyglucose technique) on exposure to females for the first time, that is first courtship. These areas also demonstrate enhanced neuronal plasticity when screened with c-fos immunocytochemistry. Both are areas involved in the processing of visual information conveyed by the two major visual pathways in birds, strengthening our hypothesis that courtship in the zebra finch is a visually guided behaviour. First courtship and chased birds show enhanced c-fos induction in the hyperpallial area, which could represent neuronal activity reflecting changes in the immediate environment. The enhanced expression of fos in first courtship birds in lateral nidopallial neurons indicates imminent long-lasting changes at the synaptic level that form the substrate for imprinting, a stable form of learning in birds.

Development of the hypothalamus and pituitary in platypus (Ornithorhynchus anatinus) and short-beaked echidna (Tachyglossus aculeatus)

PubMed Central

Ashwell, Ken W S

2012-01-01

The living monotremes (platypus and echidnas) are distinguished by the development of their young in a leathery-shelled egg, a low and variable body temperature and a primitive teat-less mammary gland. Their young are hatched in an immature state and must deal with the external environment, with all its challenges of hypothermia and stress, as well as sourcing nutrients from the maternal mammary gland. The Hill and Hubrecht embryological collections have been used to follow the structural development of the monotreme hypothalamus and its connections with the pituitary gland both in the period leading up to hatching and during the lactational phase of development, and to relate this structural maturation to behavioural development. In the incubation phase, development of the hypothalamus proceeds from closure of the anterior neuropore to formation of the lateral hypothalamic zone and putative medial forebrain bundle. Some medial zone hypothalamic nuclei are emerging at the time of hatching, but these are poorly differentiated and periventricular zone nuclei do not appear until the first week of post-hatching life. Differentiation of the pituitary is also incomplete at hatching, epithelial cords do not develop in the pars anterior until the first week, and the hypothalamo-neurohypophyseal tract does not appear until the second week of post-hatching life. In many respects, the structure of the hypothalamus and pituitary of the newly hatched monotreme is similar to that seen in newborn marsupials, suggesting that both groups rely solely on lateral hypothalamic zone nuclei for whatever homeostatic mechanisms they are capable of at birth/hatching. PMID:22512474

Modeling Early Cortical Serotonergic Deficits in Autism

PubMed Central

Boylan, Carolyn B.; Blue, Mary E.; Hohmann, Christine F.

2007-01-01

Autism is a developmental brain disorder characterized by deficits in social interaction, language and behavior. Brain imaging studies demonstrate increased cerebral cortical volumes and micro- and macroscopic neuroanatomic changes in children with this disorder. Alterations in forebrain serotonergic function may underlie the neuroanatomic and behavioral features of autism. Serotonin is involved in neuronal growth and plasticity and these actions are likely mediated via serotonergic and glutamatergic receptors. Few animal models of autism have been described that replicate both etiology and pathophysiology. We report here on a selective serotonin (5-HT) depletion model of this disorder in neonatal mice that mimics neurochemical and structural changes in cortex and, in addition, displays a behavioral phenotype consistent with autism. Newborn male and female mice were depleted of forebrain 5-HT with injections of the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), into the bilateral medial forebrain bundle (mfb). Behavioral testing of these animals as adults revealed alterations in social, sensory and stereotypic behaviors. Lesioned mice showed significantly increased cortical width. Serotonin immunocytochemistry showed a dramatic long-lasting depletion of 5-HT containing fibers in cerebral cortex until postnatal day (PND) 60. Autoradiographic binding to high affinity 5-HT transporters was significantly but transiently reduced in cerebral cortex of 5,7-DHT-depleted mice. AMPA glutamate receptor binding was decreased at PND 15. We hypothesize that increased cerebral cortical volume and sensorimotor, cognitive and social deficits observed in both 5-HT-depleted animals and in individuals with autism, may be the result of deficiencies in timely axonal pruning to key cerebral cortical areas. PMID:17034875

Modeling early cortical serotonergic deficits in autism.

PubMed

Boylan, Carolyn B; Blue, Mary E; Hohmann, Christine F

2007-01-10

Autism is a developmental brain disorder characterized by deficits in social interaction, language and behavior. Brain imaging studies demonstrate increased cerebral cortical volumes and micro- and macro-scopic neuroanatomic changes in children with this disorder. Alterations in forebrain serotonergic function may underlie the neuroanatomic and behavioral features of autism. Serotonin is involved in neuronal growth and plasticity and these actions are likely mediated via serotonergic and glutamatergic receptors. Few animal models of autism have been described that replicate both etiology and pathophysiology. We report here on a selective serotonin (5-HT) depletion model of this disorder in neonatal mice that mimics neurochemical and structural changes in cortex and, in addition, displays a behavioral phenotype consistent with autism. Newborn male and female mice were depleted of forebrain 5-HT with injections of the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), into the bilateral medial forebrain bundle (mfb). Behavioral testing of these animals as adults revealed alterations in social, sensory and stereotypic behaviors. Lesioned mice showed significantly increased cortical width. Serotonin immunocytochemistry showed a dramatic long-lasting depletion of 5-HT containing fibers in cerebral cortex until postnatal day (PND) 60. Autoradiographic binding to high affinity 5-HT transporters was significantly but transiently reduced in cerebral cortex of 5,7-DHT-depleted mice. AMPA glutamate receptor binding was decreased at PND 15. We hypothesize that increased cerebral cortical volume and sensorimotor, cognitive and social deficits observed in both 5-HT-depleted animals and in individuals with autism, may be the result of deficiencies in timely axonal pruning to key cerebral cortical areas.

Cations Modulate Actin Bundle Mechanics, Assembly Dynamics, and Structure.

PubMed

Castaneda, Nicholas; Zheng, Tianyu; Rivera-Jacquez, Hector J; Lee, Hyun-Ju; Hyun, Jaekyung; Balaeff, Alexander; Huo, Qun; Kang, Hyeran

2018-04-12

Actin bundles are key factors in the mechanical support and dynamic reorganization of the cytoskeleton. High concentrations of multivalent counterions promote bundle formation through electrostatic attraction between actin filaments that are negatively charged polyelectrolytes. In this study, we evaluate how physiologically relevant divalent cations affect the mechanical, dynamic, and structural properties of actin bundles. Using a combination of total internal reflection fluorescence microscopy, transmission electron microscopy, and dynamic light scattering, we demonstrate that divalent cations modulate bundle stiffness, length distribution, and lateral growth. Molecular dynamics simulations of an all-atom model of the actin bundle reveal specific actin residues coordinate cation-binding sites that promote the bundle formation. Our work suggests that specific cation interactions may play a fundamental role in the assembly, structure, and mechanical properties of actin bundles.

[Approach to the relationship between the changes of the content of free zinc in hippocampus and ischemic neuronal damage].

PubMed

Zhou, Zhu-Juan; Zheng, Jian; He, Ying

2002-08-01

To make approach to the relationship between the changes of free zinc and ischemic neuronal damage in hippocampus after forebrain ischemia/reperfusion. The models of forebrain ischemia/reperfusion were established in rats. The contents of free Zn2+ were measured by TSQ fluorescence method. The Zn2+ chelator (CaEDTA) was injected into lateral ventricles in order to evaluate the effect of free Zn2+ on ischemic neuronal damage. (1) Zn2+ fluorescence in the hilus of dentate gyrus, CA3 region and the stratum radiatum and stratum oriens of CA1 decreased slightly at forty-eight hours after reperfusion. From seventy-two hours to ninety-six hour after reperfusion, the decreased fluorescence gradually returned to the normal level, but some fluorescence dots were found in pyramidal neurons of CA1 and the hilus of dentate gyrus. Seven days after reperfusion, all the changes of the fluorescence almost recovered. (2) The cell membrane-impermeable Zn2+ chelator CaEDTA could reduce the intracellular concentration of free Zn2+ and reduced neuronal damage after forebrain ischemia/reperfusion. (1) The synaptic vesicle Zn2+ released and then translocated into postsynaptic neurons after forebrain ischemia/reperfusion and played a role in ischemic neuronal damage. (2) The cell membrane-impermeable chelator CaEDTA could provide neuroprotection.

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

PubMed

Frankel, Paul S; Cunningham, Kathryn A

2002-12-27

The hallucinogen d-lysergic acid diethylamide (d-LSD) evokes dramatic somatic and psychological effects. In order to analyze the neural activation induced by this unique psychoactive drug, we tested the hypothesis that expression of the immediate-early gene product c-Fos is induced in specific regions of the rat forebrain by a relatively low, behaviorally active, dose of d-LSD (0.16 mg/kg, i.p.); c-Fos protein expression was assessed at 30 min, and 1, 2 and 4 h following d-LSD injection. A time- and region-dependent expression of c-Fos was observed with a significant increase (P<0.05) in the number of c-Fos-positive cells detected in the anterior cingulate cortex at 1 h, the shell of the nucleus accumbens at 1 and 2 h, the bed nucleus of stria terminalis lateral at 2 h and the paraventricular hypothalamic nucleus at 1, 2 and 4 h following systemic d-LSD administration. These data demonstrate a unique pattern of c-Fos expression in the rat forebrain following a relatively low dose of d-LSD and suggest that activation of these forebrain regions contributes to the unique behavioral effects of d-LSD. Copyright 2002 Elsevier Science B.V.

Multi-tensor investigation of orbitofrontal cortex tracts affected in subcaudate tractotomy.

PubMed

Yang, Jimmy C; Papadimitriou, George; Eckbo, Ryan; Yeterian, Edward H; Liang, Lichen; Dougherty, Darin D; Bouix, Sylvain; Rathi, Yogesh; Shenton, Martha; Kubicki, Marek; Eskandar, Emad N; Makris, Nikos

2015-06-01

Subcaudate tractotomy (SCT) is a neurosurgical lesioning procedure that can reduce symptoms in medically intractable obsessive compulsive disorder (OCD). Due to the putative importance of the orbitofrontal cortex (OFC) in symptomatology, fibers that connect the OFC, SCT lesion, and either the thalamus or brainstem were investigated with two-tensor tractography using an unscented Kalman filter approach. From this dataset, fibers were warped to Montreal Neurological Institute space, and probability maps with center-of-mass analysis were subsequently generated. In comparing fibers from the same OFC region, including medial OFC (mOFC), central OFC (cOFC), and lateral OFC (lOFC), the area of divergence for fibers connected with the thalamus versus the brainstem is posterior to the anterior commissure. At the anterior commissure, fibers connected with the thalamus run dorsal to those connected with the brainstem. As OFC fibers travel through the ventral aspect of the internal capsule, lOFC fibers are dorsal to cOFC and mOFC fibers. Using neuroanatomical comparison, tracts coursing between the OFC and thalamus are likely part of the anterior thalamic radiations, while those between the OFC and brainstem likely belong to the medial forebrain bundle. These data support the involvement of the OFC in OCD and may be relevant to creating differential lesional procedures of specific tracts or to developing deep brain stimulation programming paradigms.

The role of the dopaminergic projections in MFB self-stimulation.

PubMed

Gallistel, C R

1986-11-01

Psychophysical experiments indicate that the first stage of the reward pathway in medial forebrain bundle self-stimulation consists of small myelinated descending axons. Pharmacological experiments show that neuroleptics attenuate or abolish the rewarding effect. This had led to the hypothesis that the descending myelinated axons synapse on an ascending dopaminergic second stage projection. 2-Deoxy-[14C]glucose autoradiography in self-stimulating animals or animals receiving automatically administered rewarding stimulation after treatment with reward-blocking doses of pimozide reveals activation of a descending myelinated system but no stimulation-produced activation of an ascending dopaminergic projection system, even though the autoradiographic method reveals the mild elevations and depressions of activity in dopaminergic terminal fields consequent upon injections of neuroleptics and amphetamine, respectively, and the strong activation of the nigrostriatal projection produced by stimulating directly in the substantia nigra. When the effects of neuroleptics and clonidine are measured by the psychophysical method (that is, by lateral shifts in the rate-frequency function), it is found that both drugs produce only gradual and rather small attenuations of rewarding efficacy up to doses at which it is no longer possible to measure their effects. It is suggested that, for neuroleptics at least, the rewarding effect abruptly fails at these doses. It is further suggested that these drugs do not act on the rewarding pathway itself, but on the process by which the rewarding signal is converted to an enduring rewarding effect.

The role of the dopaminergic projections in MFB self-stimulation.

PubMed

Gallistel, C R

1986-06-01

Psychophysical experiments indicate that the first stage of the reward pathway in medial forebrain bundle self-stimulation consists of small myelinated descending axons. Pharmacological experiments show that neuroleptics attenuate or abolish the rewarding effect. This had led to the hypothesis that the descending myelinated axons synapse on an ascending dopaminergic second stage projection. 2-Deoxy-[14C]glucose autoradiography in self-stimulating animals or animals receiving automatically administered rewarding stimulation after treatment with reward-blocking doses of pimozide reveals activation of a descending myelinated system but no stimulation-produced activation of an ascending dopaminergic projection system, even though the autoradiographic method reveals the mild elevations and depressions of activity in dopaminergic terminal fields consequent upon injections of neuroleptics and amphetamine, respectively, and the strong activation of the nigrostriatal projection produced by stimulating directly in the substantia nigra. When the effects of neuroleptics and clonidine are measured by the psychophysical method (that is, by lateral shifts in the rate-frequency function), it is found that both drugs produce only gradual and rather small attenuations of rewarding efficacy up to doses at which it is no longer possible to measure their effects. It is suggested that, for neuroleptics at least, the rewarding effect abruptly fails at these doses. It is further suggested that these drugs do not act on the rewarding pathway itself, but on the process by which the rewarding signal is converted to an enduring rewarding effect.

Development of the hypothalamus and pituitary in platypus (Ornithorhynchus anatinus) and short-beaked echidna (Tachyglossus aculeatus).

PubMed

Ashwell, Ken W S

2012-07-01

The living monotremes (platypus and echidnas) are distinguished by the development of their young in a leathery-shelled egg, a low and variable body temperature and a primitive teat-less mammary gland. Their young are hatched in an immature state and must deal with the external environment, with all its challenges of hypothermia and stress, as well as sourcing nutrients from the maternal mammary gland. The Hill and Hubrecht embryological collections have been used to follow the structural development of the monotreme hypothalamus and its connections with the pituitary gland both in the period leading up to hatching and during the lactational phase of development, and to relate this structural maturation to behavioural development. In the incubation phase, development of the hypothalamus proceeds from closure of the anterior neuropore to formation of the lateral hypothalamic zone and putative medial forebrain bundle. Some medial zone hypothalamic nuclei are emerging at the time of hatching, but these are poorly differentiated and periventricular zone nuclei do not appear until the first week of post-hatching life. Differentiation of the pituitary is also incomplete at hatching, epithelial cords do not develop in the pars anterior until the first week, and the hypothalamo-neurohypophyseal tract does not appear until the second week of post-hatching life. In many respects, the structure of the hypothalamus and pituitary of the newly hatched monotreme is similar to that seen in newborn marsupials, suggesting that both groups rely solely on lateral hypothalamic zone nuclei for whatever homeostatic mechanisms they are capable of at birth/hatching. © 2012 The Author. Journal of Anatomy © 2012 Anatomical Society.

Increased serotonin axons (immunoreactive to 5-HT transporter) in postmortem brains from young autism donors.

PubMed

Azmitia, Efrain C; Singh, Jorawer S; Whitaker-Azmitia, Patricia M

2011-06-01

Imaging studies of serotonin transporter binding or tryptophan retention in autistic patients suggest that the brain serotonin system is decreased. However, treatment with drugs which increase serotonin (5-HT) levels, specific serotonin reuptake inhibitors (SSRIs), commonly produce a worsening of the symptoms. In this study we examined 5-HT axons that were immunoreactive to a serotonin transporter (5-HTT) antibody in a number of postmortem brains from autistic patients and controls with no known diagnosis who ranged in age from 2 to 29 years. Fine, highly branched, and thick straight fibers were found in forebrain pathways (e.g. medial forebrain bundle, stria terminalis and ansa lenticularis). Many immunoreactive varicose fine fibers were seen in target areas (e.g. globus pallidus, amygdala and temporal cortex). Morphometric analysis of the stained axons at all ages studied indicated that the number of serotonin axons was increased in both pathways and terminal regions in cortex from autism donors. Our findings provide morphological evidence to warrant caution when using serotonin enhancing drugs (e.g. SSRIs and receptor agonist) to treat autistic children. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'. Copyright © 2011 Elsevier Ltd. All rights reserved.

Central projections of the nervus terminalis and the nervus praeopticus in the lungfish brain revealed by nitric oxide synthase.

PubMed

Schober, A; Meyer, D L; Von Bartheld, C S

1994-11-01

Lungfishes possess two cranial nerves that are associated with the olfactory system: the nervus terminalis enters the telencephalon with the olfactory nerve, and the nervus praeopticus enters the diencephalon at the level of the optic nerve. We investigated the central projections of the nervus terminalis and the nervus praeopticus in the Australian lungfish (Neoceratodus forsteri) and in the African lungfish (Protopterus dolloi) by NADPH-diaphorase histochemistry (nitric oxide synthase; NOS) and compared them with the projections of the nervus terminalis of the frog (Xenopus laevis). In Neoceratodus, NOS-positive fascicles of the nervus terminalis divide and project with a ventral component through the septum and with a dorsal component through the pallium; fibers of both trajectories extend caudally beyond the anterior commissure and join the lateral forebrain bundle. In the nervus praeopticus, about 300 fibers contain NOS; they innervate the preoptic nucleus and continue their course through the diencephalon; many fibers cross in the commissure of the posterior tuberculum. In Protopterus, ganglion cells of the nervus terminalis and of the nervus praeopticus contain NOS. NOS-positive fibers of the nervus terminalis project through the septal region but not through the pallium. Several major fascicles cross in the rostral part of the anterior commissure, where they are joined by a small number of NOS-containing fibers of the nervus praeopticus. Both nerves innervate the preoptic nucleus. The number and pathways of the fascicles of the nervus terminalis are not always symmetric between the two sides. The nervus terminalis fascicles remain in a ventral position, whereas the nervus praeopticus gives rise to the more dorsal fascicles. Many fibers of the two nerves extend throughout the diencephalon and cross in the commissure of the posterior tuberculum. These findings demonstrate many similarities but also significant differences between the contributions of the nervus terminalis and the nervus praeopticus to forebrain projections in the two lungfishes. They support the view that the nervus praeopticus is part of a nervus terminalis system comparable to that in frogs and other nonmammalian vertebrates.

The effect of high mesencephalic transection (cerveau isolé) and pentobarbital on basal forebrain mechanisms of EEG synchronization.

PubMed

Obál, F; Benedek, G; Szikszay, M; Obál, F

1979-01-01

A study was made of the effects of high mesencephalic transection (cerveau isolé) and low doses of pentobarbital on the cortical synchronizations elicited in acute immobilized cats by (a) low frequency stimulation of the lateral hypothalamus (HL) and nucleus ventralis anterior thalami (VA) and (b) by low and high frequency stimulation of the laterobasal preoptic region (RPO) and olfactory tubercle (TbOf). The results obtained were as follows: (1) The synchronizations induced by basal forebrain stimulations were found to survive in acute cerveau isolé cats, moreover, even a facilitation of the synchronizing effect were observed. (2) A gradual facilitation was observed upon TbOf and RPO stimulation, while in the case of VA and HL stimulations, the facilitation appeared immediately after the transection. (3) Low doses of pentobarbital depressed the cortical effects of TbOf stimulation, while an increase of the synchronizing effect of low frequency VA and HL stimulation was found. The observations suggested that (i) the synchronizing mechanism in the ventral part of the basal forebrain (RPO and TbOf) differs from that of the thalamus and HL; (ii) the basal forebrain synchronizing mechanism is effective without the contribution of the brain stem; (iii) the mechanism responsible for the synchronizing effect of low frequency HL stimulation is similar as that described for the thalamus.

Positional relationships between the masticatory muscles and their innervating nerves with special reference to the lateral pterygoid and the midmedial and discotemporal muscle bundles of temporalis

PubMed Central

AKITA, KEIICHI; SHIMOKAWA, TAKASHI; SATO, TATSUO

2000-01-01

For an accurate assessment of jaw movement, it is crucial to understand the comprehensive formation of the masticatory muscles with special reference to the relationship to the disc of the temporomandibular joint. Detailed dissection was performed on 26 head halves of 14 Japanese cadavers in order to obtain precise anatomical information of the positional relationships between the masticatory muscles and the branches of the mandibular nerve. After complete removal of the bony elements, the midmedial muscle bundle in all specimens and the discotemporal muscle bundle in 6 specimens, derivatives of the temporalis, which insert into the disc were observed. On the anterior area of the articular capsule and the disc of the temporomandibular joint, the upper head of the lateral pterygoid, the midmedial muscle bundle of temporalis and the discotemporal bundle of temporalis were attached mediolaterally, and in 3 specimens the posterosuperior margin of the zygomaticomandibularis was attached to the anterolateral area of the disc. It is suggested that these muscles and muscle bundles contribute to various mandibular movements. Although various patterns of the positional relationships between the muscles and muscle bundles and the their innervating nerves are observed in the present study, relative positional relationships of the muscles and muscle bundles and of nerves of the mandibular nerve are consistent. A possible scheme of the developmental formation of the masticatory muscles based on the findings of the positional relationships between the muscles and the nerves is presented. PMID:11005720

Control of Vocal and Respiratory Patterns in Birdsong: Dissection of Forebrain and Brainstem Mechanisms Using Temperature

PubMed Central

Fee, Michale S.

2011-01-01

Learned motor behaviors require descending forebrain control to be coordinated with midbrain and brainstem motor systems. In songbirds, such as the zebra finch, regular breathing is controlled by brainstem centers, but when the adult songbird begins to sing, its breathing becomes tightly coordinated with forebrain-controlled vocalizations. The periods of silence (gaps) between song syllables are typically filled with brief breaths, allowing the bird to sing uninterrupted for many seconds. While substantial progress has been made in identifying the brain areas and pathways involved in vocal and respiratory control, it is not understood how respiratory and vocal control is coordinated by forebrain motor circuits. Here we combine a recently developed technique for localized brain cooling, together with recordings of thoracic air sac pressure, to examine the role of cortical premotor nucleus HVC (proper name) in respiratory-vocal coordination. We found that HVC cooling, in addition to slowing all song timescales as previously reported, also increased the duration of expiratory pulses (EPs) and inspiratory pulses (IPs). Expiratory pulses, like song syllables, were stretched uniformly by HVC cooling, but most inspiratory pulses exhibited non-uniform stretch of pressure waveform such that the majority of stretch occurred late in the IP. Indeed, some IPs appeared to change duration by the earlier or later truncation of an underlying inspiratory event. These findings are consistent with the idea that during singing the temporal structure of EPs is under the direct control of forebrain circuits, whereas that of IPs can be strongly influenced by circuits downstream of HVC, likely in the brainstem. An analysis of the temporal jitter of respiratory and vocal structure suggests that IPs may be initiated by HVC at the end of each syllable and terminated by HVC immediately before the onset of the next syllable. PMID:21980466

Radiotherapy as a cause of complete atrioventricular block in Hodgkin's disease. An electrophysiological-pathological correlation

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

Cohen, S.I.; Bharati, S.; Glass, J.

1981-04-01

A 20-year-old man contracted Hodgkin's disease and was treated with mantle radiotherapy. Heart block developed 11 years later. Electrocardiograms revealed predominant atrioventricular (AV) block and occasional AV conduction. Intracardiac electrograms demonstrated that the site of AV block was above the level of the His bundle. A permanent transvenous pacemaker was implanted. Seven months later the patient died of complications from cryptococcal meningitis. Pathological study of the heart revealed marked arteriosclerosis with fibrosis of the epicardium, myocardium, and endocardium. Examination of the conduction system revealed extensive arteriolosclerosis of the sinoatrial node and its approaches. In addition, there was marked fibrosis ofmore » the approaches to the AV node, the AV bundle, and both bundle branches. There was no evidence of Hodgkin's disease. This case documents the rare occurrence of AV block due to tissue destruction by radiotherapy. There was a good correlation between block proximal to the His bundle recording site and fibrosis of the approaches to the AV node.« less

Radiotherapy as a cause of complete atrioventricular block in Hodgkin's disease: an electrophysiological-pathological correlation

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

Cohen, S.I.; Bharati, S.; Glass, J.

1981-04-01

A 20-year-old man contracted Hodgkin's disease and was treated with mantle radiotherapy. Heart block developed 11 years later. Electrocardiograms revealed predominant atrioventricular (AV) block and occasional AV conduction. Intracardiac electrograms demonstrated that the site of AV block was above the level of the His bundle. A permanent transvenous pacemaker was implanted. Seven months later the patient died of complications from cryptococcal meningitis. Pathological study of the heart revealed marked arteriosclerosis with fibrosis of the epicardium, myocardium, and endocardium. Examination of the conduction system revealed extensive arteriolosclerosis of the sinoatrial node and its approaches. In addition, there was marked fibrosis ofmore » the approaches to the AV node, the AV bundle, and both bundle branches. There was no evidence of Hodgkin's disease. This case documents the rare occurrence of AV block due to tissue destruction by radiotherapy. There was a good correlation between block proximal to the His bundle recording site and fibrosis of the approaches to the AV node.« less

Anatomy of the anterior cruciate ligament with regard to its two bundles.

PubMed

Petersen, Wolf; Zantop, Thore

2007-01-01

The anterior cruciate ligament (ACL) consists of two major fiber bundles, namely the anteromedial and posterolateral bundle. When the knee is extended, the posterolateral bundle (PL) is tight and the anteromedial (AM) bundle is moderately lax. As the knee is flexed, the femoral attachment of the ACL becomes a more horizontal orientation; causing the AM bundle to tighten and the PL bundle to relax. There is some degree of variability for the femoral origin of the anterome-dial and posterolateral bundle. The anteromedial bundle is located proximal and anterior in the femoral ACL origin (high and deep in the notch when the knee is flexed at 90 degrees ); the posterolateral bundle starts in the distal and posterior aspect of the femoral ACL origin (shallow and low when the knee is flexed at 90 degrees ). In the frontal plane the anteromedial bundle origin is in the 10:30 clock position and the postero-lateral bundle origin in the 9:30 clock position. At the tibial insertion the ACL fans out to form the foot region. The anteromedial bundle insertion is in the anterior part of the tibial ACL footprint, the posterolateral bundle in the posterior part. While the anteromedial bundle is the primary restraint against anterior tibial translation, the posterolateral bundle tends to stabilize the knee near full extension, particularly against rotatory loads.

Reduced integrity of the uncinate fasciculus and cingulum in depression: A stem-by-stem analysis.

PubMed

Bhatia, Kartik D; Henderson, Luke A; Hsu, Eugene; Yim, Mark

2018-08-01

The subgenual cingulate gyrus (Brodmann's Area 25: BA25) is hypermetabolic in depression and has been targeted successfully with deep brain stimulation. Two of the white matter tracts that play a role in treatment response are the uncinate fasciculus (UF) and the cingulum bundle. The UF has three prefrontal stems, the most medial of which extends from BA25 (which deals with mood regulation) and the most lateral of which extends from the dorso-lateral prefrontal cortex (concerned with executive function). The cingulum bundle has numerous fibers connecting the lobes of the cerebrum, with the longest fibers extending from BA25 to the amygdala. We hypothesize that there is reduced integrity in the UF, specific to the medial prefrontal stems, as well as in the subgenual and amygdaloid fibers of the cingulum bundle. Our secondary hypothesis is that these changes are present from the early stages of depression. Compare the white matter integrity of stems of the UF and components of the cingulum bundle in first-onset depressed, recurrent/chronic depressed, and non-depressed control subjects. Depressed patients (n = 103, first-onset = 57, chronic = 46) and non-depressed control subjects (n = 74) underwent MRI with 32-directional DTI sequences. The uncinate fasciculi and cingulum bundles were seeded, and the fractional anisotropy (FA) measured in each of the three prefrontal stems and the body of the UF, as well as the subgenual, body, and amygdaloid fiber components of the cingulum bundle. FA measurements were compared between groups using ANOVA testing with post-hoc Tukey analysis. There were significant reductions in FA in the subgenual and polar stems of the UF bilaterally, as well as the subgenual and amygdaloid fibers of the cingulum bundle, in depressed patients compared with controls (p < 0.001). There was no significant difference seen in the lateral UF stem or the main body of the cingulum. No significant difference was demonstrated in any of the tracts between first-onset and chronic depression patients. Depressed patients have reduced white matter integrity in the subgenual and polar stems of the uncinate fasciculi but not the lateral stems, as well as in the subgenual and amygdaloid cingulum fibers. These changes are present from the first-onset of the disease. Copyright © 2018 Elsevier B.V. All rights reserved.

Dystrophic Serotonergic Axons in Neurodegenerative Diseases

PubMed Central

Azmitia, Efrain C.; Nixon, Ralph

2012-01-01

Neurodegenerative diseases such as Parkinson's disease (PD), frontal lobe dementia (FLD) and Diffuse Lewy-Body dementia (DLBD) have diverse neuropathologic features. Here we report that serotonin fibers are dystrophic in the brains of individuals with these three diseases. In neuropathologically normal (control) brains (n=3), serotonin axons immunoreactive (IR) with antibodies against the serotonin transporter (5-HTT) protein were widely distributed in cortex (entorhinal and dorsolateral prefrontal), hippocampus and rostral brainstem. 5-HTT-IR fibers of passage appeared thick, smooth, and un-branched in medial forebrain bundle, medial lemniscus and cortex white matter. The terminal branches were fine, highly branched and varicose in substantia nigra, hippocampus and cortical gray matter. In the diseased brains, however, 5-HTT-IR fibers in the forebrain were reduced in number and were frequently bulbous, splayed, tightly clustered and enlarged. Morphometric analysis revealed significant differences in the size distribution of the 5-HTT-IR profiles in dorsolateral prefrontal area between neurodegenerative diseases and controls. Our observations provide direct morphologic evidence for degeneration of human serotonergic axons in the brains of patients with neurodegenerative diseases despite the limited size (n=3 slices for each region (3) from each brain (4), total slices was n=36) and lack of extensive clinical characterization of the analyzed cohort. This is the first report of dystrophic 5-HTT-IR axons in postmortem human tissue PMID:18502405

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

PubMed Central

Chiu, Chuang-Hsin; Siow, Tiing-Yee; Weng, Shao-Ju; Hsu, Yi-Hua; Huang, Yuahn-Sieh; Chang, Kang-Wei; Cheng, Cheng-Yi; Ma, Kuo-Hsing

2015-01-01

3,4-Methylenedioxymethamphetamine (MDMA), also known as “Ecstasy”, is a common recreational drug of abuse. Several previous studies have attributed the central serotonergic neurotoxicity of MDMA to distal axotomy, since only fine serotonergic axons ascending from the raphe nucleus are lost without apparent damage to their cell bodies. However, this axotomy has never been visualized directly in vivo. The present study examined the axonal integrity of the efferent projections from the midbrain raphe nucleus after MDMA exposure using in vivo manganese-enhanced magnetic resonance imaging (MEMRI). Rats were injected subcutaneously six times with MDMA (5 mg/kg) or saline once daily. Eight days after the last injection, manganese ions (Mn2+) were injected stereotactically into the raphe nucleus, and a series of MEMRI images was acquired over a period of 38 h to monitor the evolution of Mn2+-induced signal enhancement across the ventral tegmental area, the medial forebrain bundle (MFB), and the striatum. The MDMA-induced loss of serotonin transporters was clearly evidenced by immunohistological staining consistent with the Mn2+-induced signal enhancement observed across the MFB and striatum. MEMRI successfully revealed the disruption of the serotonergic raphe-striatal projections and the variable effect of MDMA on the kinetics of Mn2+ accumulation in the MFB and striatum. PMID:26378923

Fiber-optic-bundle-based optical coherence tomography.

PubMed

Xie, Tuqiang; Mukai, David; Guo, Shuguang; Brenner, Matthew; Chen, Zhongping

2005-07-15

A fiber-optic-bundle-based optical coherence tomography (OCT) probe method is presented. The experimental results demonstrate this multimode optical fiber-bundle-based OCT system can achieve a lateral resolution of 12 microm and an axial resolution of 10 microm with a superluminescent diode source. This novel OCT imaging approach eliminates any moving parts in the probe and has a primary advantage for use in extremely compact and safe OCT endoscopes for imaging internal organs and great potential to be combined with confocal endoscopic microscopy.

Experience with Delay-Tolerant Networking from Orbit

NASA Technical Reports Server (NTRS)

Ivancic, W.; Eddy, W. M.; Stewart, D.; Wood, L.; Northam, J.; Jackson, C.

2010-01-01

We describe the first use from space of the Bundle Protocol for Delay-Tolerant Networking (DTN) and lessons learned from experiments made and experience gained with this protocol. The Disaster Monitoring Constellation (DMC), constructed by Surrey Satellite Technology Ltd (SSTL), is a multiple-satellite Earth-imaging low-Earth-orbit sensor network in which recorded image swaths are stored onboard each satellite and later downloaded from the satellite payloads to a ground station. Store-and-forward of images with capture and later download gives each satellite the characteristics of a node in a disruption-tolerant network. Originally developed for the Interplanetary Internet, DTNs are now under investigation in an Internet Research Task Force (IRTF) DTN research group (RG), which has developed a bundle architecture and protocol. The DMC is technically advanced in its adoption of the Internet Protocol (IP) for its imaging payloads and for satellite command and control, based around reuse of commercial networking and link protocols. These satellites use of IP has enabled earlier experiments with the Cisco router in Low Earth Orbit (CLEO) onboard the constellation s UK-DMC satellite. Earth images are downloaded from the satellites using a custom IP-based high-speed transfer protocol developed by SSTL, Saratoga, which tolerates unusual link environments. Saratoga has been documented in the Internet Engineering Task Force (IETF) for wider adoption. We experiment with the use of DTNRG bundle concepts onboard the UK-DMC satellite, by examining how Saratoga can be used as a DTN convergence layer to carry the DTNRG Bundle Protocol, so that sensor images can be delivered to ground stations and beyond as bundles. Our practical experience with the first successful use of the DTNRG Bundle Protocol in a space environment gives us insights into the design of the Bundle Protocol and enables us to identify issues that must be addressed before wider deployment of the Bundle Protocol. Published in 2010 by John Wiley & Sons, Ltd. KEY WORDS: Internet; UK-DMC; satellite; Delay-Tolerant Networking (DTN); Bundle Protocol

Additional Amphivasal Bundles in Pedicel Pith Exacerbate Central Fruit Dominance and Induce Self-Thinning of Lateral Fruitlets in Apple1[C][W

PubMed Central

Celton, Jean-Marc; Dheilly, Emmanuelle; Guillou, Marie-Charlotte; Simonneau, Fabienne; Juchaux, Marjorie; Costes, Evelyne; Laurens, François; Renou, Jean-Pierre

2014-01-01

Apple (Malus × domestica) trees naturally produce an excess of fruitlets that negatively affect the commercial value of fruits brought to maturity and impact their capacity to develop flower buds the following season. Therefore, chemical thinning has become an important cultural practice, allowing the selective removal of unwanted fruitlets. As the public pressure to limit the use of chemical agents increases, the control of thinning becomes a major issue. Here, we characterized the self-thinning capacity of an apple hybrid genotype from the tree scale to the molecular level. Additional amphivasal vascular bundles were identified in the pith of pedicels supporting the fruitlets with the lowest abscission potential (central fruitlet), indicating that these bundles might have a role in the acquisition of dominance over lateral fruitlets. Sugar content analysis revealed that central fruitlets were better supplied in sorbitol than lateral fruitlets. Transcriptomic profiles allowed us to identify genes potentially involved in the overproduction of vascular tissues in central pedicels. In addition, histological and transcriptomic data permitted a detailed characterization of abscission zone development and the identification of key genes involved in this process. Our data confirm the major role of ethylene, auxin, and cell wall-remodeling enzymes in abscission zone formation. The shedding process in this hybrid appears to be triggered by a naturally exacerbated dominance of central fruitlets over lateral ones, brought about by an increased supply of sugars, possibly through additional amphivasal vascular bundles. The characterization of this genotype opens new perspectives for the selection of elite apple cultivars. PMID:24550240

Multiscale mechanics of the lateral pressure effect on enhancing the load transfer between polymer coated CNTs.

PubMed

Yazdandoost, Fatemeh; Mirzaeifar, Reza; Qin, Zhao; Buehler, Markus J

2017-05-04

While individual carbon nanotubes (CNTs) are known as one of the strongest fibers ever known, even the strongest fabricated macroscale CNT yarns and fibers are still significantly weaker than individual nanotubes. The loss in mechanical properties is mainly because the deformation mechanism of CNT fibers is highly governed by the weak shear strength corresponding to sliding of nanotubes on each other. Adding polymer coating to the bundles, and twisting the CNT yarns to enhance the intertube interactions are both efficient methods to improve the mechanical properties of macroscale yarns. Here, we perform molecular dynamics (MD) simulations to unravel the unknown deformation mechanism in the intertube polymer chains and also local deformations of the CNTs at the atomistic scale. Our results show that the lateral pressure can have both beneficial and adverse effects on shear strength of polymer coated CNTs, depending on the local deformations at the atomistic scale. In this paper we also introduce a bottom-up bridging strategy between a full atomistic model and a coarse-grained (CG) model. Our trained CG model is capable of incorporating the atomistic scale local deformations of each CNT to the larger scale collect behavior of bundles, which enables the model to accurately predict the effect of lateral pressure on larger CNT bundles and yarns. The developed multiscale CG model is implemented to study the effect of lateral pressure on the shear strength of straight polymer coated CNT yarns, and also the effect of twisting on the pull-out force of bundles in spun CNT yarns.

Anatomical feasibility study of flexor hallucis longus transfer in treatment of Achilles tendon and posteromedial portal of ankle arthroscopy.

PubMed

Mao, Haijiao; Wang, Linger; Dong, Wenwei; Liu, Zhenxin; Yin, Weigang; Xu, Dachuan; Wapner, Keith L

2018-04-16

The aim of this study was to evaluate the occurrence of anatomical variations of the musculotendinous junction of the flexor hallucis longus (FHL) muscle, the relationship between FHL tendon or muscle and the tibial neurovascular bundle at the level of the posterior ankle joint in human cadavers. Seventy embalmed feet from 20 male and 15 female cadavers, the cadavers' mean age was 65.4 (range from 14 to 82) years, were dissected and anatomically classified to observe FHL muscle morphology define the relationship between FHL tendon or muscle and the tibial neurovascular bundle. The distance between the musculotendinous junction and the relationship between FHL tendon or muscle and the tibial neurovascular bundle was determined. Three morphology types of FHL muscle were identified: a long lateral and shorter medial muscle belly, which was observed in 63 specimens (90%); equal length medial and lateral muscle bellies, this variant was only observed in five specimens (7.1%); one lateral and no medial muscle belly, which was observed in two specimens (2.9%). No statistically significant difference was observed according to gender or side (p > 0.05). Two patterns were identified and described between FHL tendon or muscle and the tibial neurovascular bundle. Pattern 1, the distance between the neurovascular bundle and FHL tendon was 3.46 mm (range 2.34-8.84, SD = 2.12) which was observed in 66 specimens (94.3%); Pattern 2, there was no distance which was observed in four specimens (5.7%). Knowing FHL muscle morphology, variations provide new important insights into secure planning and execution of a FHL transfer for Achilles tendon defect as well as for the interpretation of ultrasound and magnetic resonance images. With posterior arthroscopic for the treatment of various ankle pathologies, posteromedial portal may be introduced into the posterior aspect of the ankle without gross injury to the tibial neurovascular structures because of the gap between the neurovascular bundle and FHL tendon.

Selective activation of mesolimbic and mesocortical dopamine metabolism in rat brain by infusion of a stable substance P analogue into the ventral tegmental area.

PubMed

Elliott, P J; Alpert, J E; Bannon, M J; Iversen, S D

1986-01-15

Microinfusion of the metabolically stable substance P (SP) agonist, [pGlu5,MePhe8,Sar9]-SP5-11 (DiMe-C7), into the ventral tegmental area (VTA) of rat brain increased levels of the dopamine (DA) metabolite dihydroxyphenylacetic acid in the prefrontal cortex (+ 120%) and nucleus accumbens (+30%) but not in other regions of forebrain. In contrast, infusions of DiMe-C7 or SP into the lateral ventricles or microinfusions of SP into VTA failed to elicit increases in DOPAC levels in forebrain. DA levels were unaffected by SP or DiMe-C7 regardless of the route of administration. These data and previous studies suggest a role for endogenous SP in the modulation of mesocortical and mesolimbic DA neurones.

Use of the Delay-Tolerant Networking Bundle Protocol from Space

NASA Technical Reports Server (NTRS)

Wood, Lloyd; Ivancic, William D.; Eddy, Wesley M.; Stewart, Dave; Northam, James; Jackson, Chris; daSilvaCuriel, Alex

2009-01-01

The Disaster Monitoring Constellation (DMC), constructed by Survey Satellite Technology Ltd (SSTL), is a multisatellite Earth-imaging low-Earth-orbit sensor network where captured image swaths are stored onboard each satellite and later downloaded from the satellite payloads to a ground station. Store-and-forward of images with capture and later download gives each satellite the characteristics of a node in a Delay/Disruption Tolerant Network (DTN). Originally developed for the Interplanetary Internet, DTNs are now under investigation in an Internet Research Task Force (IRTF) DTN research group (RG), which has developed a bundle architecture and protocol. The DMC is currently unique in its adoption of the Internet Protocol (IP) for its imaging payloads and for satellite command and control, based around reuse of commercial networking and link protocols. These satellites use of IP has enabled earlier experiments with the Cisco router in Low Earth Orbit (CLEO) onboard the constellation's UK-DMC satellite. Earth images are downloaded from the satellites using a custom IPbased high-speed transfer protocol developed by SSTL, Saratoga, which tolerates unusual link environments. Saratoga has been documented in the Internet Engineering Task Force (IETF) for wider adoption. We experiment with use of DTNRG bundle concepts onboard the UKDMC satellite, by examining how Saratoga can be used as a DTN convergence layer to carry the DTNRG Bundle Protocol, so that sensor images can be delivered to ground stations and beyond as bundles. This is the first successful use of the DTNRG Bundle Protocol in a space environment. We use our practical experience to examine the strengths and weaknesses of the Bundle Protocol for DTN use, paying attention to fragmentation, custody transfer, and reliability issues.

Effect of current on the maximum possible reward.

PubMed

Gallistel, C R; Leon, M; Waraczynski, M; Hanau, M S

1991-12-01

Using a 2-lever choice paradigm with concurrent variable interval schedules of reward, it was found that when pulse frequency is increased, the preference-determining rewarding effect of 0.5-s trains of brief cathodal pulses delivered to the medial forebrain bundle of the rat saturates (stops increasing) at values ranging from 200 to 631 pulses/s (pps). Raising the current lowered the saturation frequency, which confirms earlier, more extensive findings showing that the rewarding effect of short trains saturates at pulse frequencies that vary from less than 100 pps to more than 800 pps, depending on the current. It was also found that the maximum possible reward--the magnitude of the reward at or beyond the saturation pulse frequency--increases with increasing current. Thus, increasing the current reduces the saturation frequency but increases the subjective magnitude of the maximum possible reward.

Bundle-branch reentry ventricular tachycardia after transcatheter aortic valve replacement

PubMed Central

de la Rosa Riestra, Adriana; Rubio Caballero, José Amador; Freites Estévez, Alfonso; Alonso Belló, Javier; Botas Rodríguez, Javier

2016-01-01

An 83-year-old male suffering from severe symptomatic aortic valve stenosis received an implant of a biological aortic prosthesis through the femoral artery without complications. Seven days after dischargement he experienced a syncope. The patient was wearing an ECG holter monitor that day, which showed a wide QRS complex tachycardia of 300 beats per minute. The electrophysiological study revealed a bundle-branch reentry ventricular tachycardia as the cause of the syncope. Radio-frequency was applied on the right-bundle branch. Twelve months later, the patient has remained asymptomatic. PMID:27134443

Diffusion tensor imaging demonstrates brainstem and cerebellar abnormalities in congenital central hypoventilation syndrome.

PubMed

Kumar, Rajesh; Macey, Paul M; Woo, Mary A; Alger, Jeffry R; Harper, Ronald M

2008-09-01

Congenital central hypoventilation syndrome (CCHS) patients show reduced breathing drive during sleep, decreased hypoxic and hypercapnic ventilatory responses, and autonomic and affective deficits, suggesting both brainstem and forebrain injuries. Forebrain damage was previously described in CCHS, but methodological limitations precluded detection of brainstem injury, a concern because genetic mutations in CCHS target brainstem autonomic nuclei. To assess brainstem and cerebellar areas, we used diffusion tensor imaging-based measures, namely axial diffusivity, reflecting water diffusion parallel to fibers, and sensitive to axonal injury, and radial diffusivity, measuring diffusion perpendicular to fibers, and indicative of myelin injury. Diffusion tensor imaging was performed in 12 CCHS and 26 controls, and axial and radial diffusivity maps were compared between groups using analysis of covariance (covariates; age and gender). Increased axial diffusivity in CCHS appeared within the lateral medulla and clusters with injury extended from the dorsal midbrain through the periaqueductal gray, raphé, and superior cerebellar decussation, ventrally to the basal-pons. Cerebellar cortex and deep nuclei, and the superior and inferior cerebellar peduncles showed increased radial diffusivity. Midbrain, pontine, and lateral medullary structures, and the cerebellum and its fiber systems are injured in CCHS, likely contributing to the characteristics found in the syndrome.

Integrity of the midbrain region is required to maintain the diencephalic-mesencephalic boundary in zebrafish no isthmus/pax2.1 mutants.

PubMed

Scholpp, Steffen; Brand, Michael

2003-11-01

Initial anterior-posterior patterning of the neural tube into forebrain, midbrain, and hindbrain primordia occurs already during gastrulation, in response to signals patterning the gastrula embryo. After the initial establishment, further development within each brain part is thought to proceed largely independently of the others. However, mechanisms should exist that ensure proper delineation of brain subdivisions also at later stages; such mechanisms are, however, poorly understood. In zebrafish no isthmus mutant embryos, inactivation of the pax2.1 gene leads to a failure of the midbrain and isthmus primordium to develop normally from the gastrula stage onward (Lun and Brand [1998] Development 125:3049-3062). Here, we report that, after the initially correct establishment during gastrulation stages, the neighbouring forebrain primordium and, partially, the hindbrain primordium expand into the misspecified midbrain territory in no isthmus mutant embryos. The expansion is particularly evident for the posterior part of the diencephalon and less so for the first rhombomeric segment, the territories immediately abutting the midbrain/isthmus primordium. The nucleus of the posterior commissure is expanded in size, and marker genes of the forebrain and rhombomere 1 expand progressively into the misspecified midbrain primordium, eventually resulting in respecification of the midbrain primordium. We therefore suggest that the genetic program controlled by Pax2.1 is not only involved in initiating but also in maintaining the identity of midbrain and isthmus cells to prevent them from assuming a forebrain or hindbrain fate. Copyright 2003 Wiley-Liss, Inc.

Immunocytochemical localization of luteinizing hormone-releasing hormone (LHRH) in the nervus terminalis and brain of the big brown bat, Eptesicus fuscus.

PubMed

Oelschläger, H A; Northcutt, R G

1992-01-15

Little is known about the immunohistochemistry of the nervous system in bats. This is particularly true of the nervus terminalis, which exerts strong influence on the reproductive system during ontogeny and in the adult. Luteinizing hormone-releasing hormone (LHRH) was visualized immunocytochemically in the nervus terminalis and brain of juvenile and adult big brown bats (Eptesicus fuscus). The peripheral LHRH-immunoreactive (ir) cells and fibers (nervus terminalis) are dispersed along the basal surface of the forebrain from the olfactory bulbs to the prepiriform cortex and the interpeduncular fossa. A concentration of peripheral LHRH-ir perikarya and fibers was found at the caudalmost part of the olfactory bulbs, near the medioventral forebrain sulcus; obviously these cells mediate between the bulbs and the remaining forebrain. Within the central nervous system (CNS), LHRH-ir perikarya and fibers were distributed throughout the olfactory tubercle, diagonal band, preoptic area, suprachiasmatic and supraoptic nuclei, the bed nuclei of stria terminalis and stria medullaris, the anterior lateral and posterior hypothalamus, and the tuber cinereum. The highest concentration of cells was found within the arcuate nucleus. Fibers were most concentrated within the median eminence, infundibular stalk, and the medial habenula. The data obtained suggest that this distribution of LHRH immunoreactivity may be characteristic for microchiropteran (insectivorous) bats. The strong projections of LHRH-containing nuclei in the basal forebrain (including the arcuate nucleus) to the habenula, may indicate close functional contact between these brain areas via feedback loops, which could be important for the processing of thermal and other environmental stimuli correlated with hibernation.

Dynamic circuitry for updating spatial representations. II. Physiological evidence for interhemispheric transfer in area LIP of the split-brain macaque.

PubMed

Heiser, Laura M; Berman, Rebecca A; Saunders, Richard C; Colby, Carol L

2005-11-01

With each eye movement, a new image impinges on the retina, yet we do not notice any shift in visual perception. This perceptual stability indicates that the brain must be able to update visual representations to take our eye movements into account. Neurons in the lateral intraparietal area (LIP) update visual representations when the eyes move. The circuitry that supports these updated representations remains unknown, however. In this experiment, we asked whether the forebrain commissures are necessary for updating in area LIP when stimulus representations must be updated from one visual hemifield to the other. We addressed this question by recording from LIP neurons in split-brain monkeys during two conditions: stimulus traces were updated either across or within hemifields. Our expectation was that across-hemifield updating activity in LIP would be reduced or abolished after transection of the forebrain commissures. Our principal finding is that LIP neurons can update stimulus traces from one hemifield to the other even in the absence of the forebrain commissures. This finding provides the first evidence that representations in parietal cortex can be updated without the use of direct cortico-cortical links. The second main finding is that updating activity in LIP is modified in the split-brain monkey: across-hemifield signals are reduced in magnitude and delayed in onset compared with within-hemifield signals, which indicates that the pathways for across-hemifield updating are less effective in the absence of the forebrain commissures. Together these findings reveal a dynamic circuit that contributes to updating spatial representations.

49 CFR 393.118 - What are the rules for securing dressed lumber or similar building products?

Code of Federal Regulations, 2010 CFR

2010-10-01

... Shifting and Falling Cargo Specific Securement Requirements by Commodity Type § 393.118 What are the rules... transported using no more than one tier. Bundles carried on one tier must be secured in accordance with the... one tier. Bundles carried in more than one tier must be either: (1) Blocked against lateral movement...

Post-natal molecular adaptations in anteromedial and posterolateral bundles of the ovine anterior cruciate ligament: one structure with two parts or two distinct ligaments?

PubMed

Huebner, Kyla D; O'Brien, Etienne J O; Heard, Bryan J; Chung, May; Achari, Yamini; Shrive, Nigel G; Frank, Cyril B

2012-01-01

The human anterior cruciate ligament (ACL) is a composite structure of two anatomically distinct bundles: an anteromedial (AM) and posterolateral (PL) bundles. Tendons are often used as autografts for surgical reconstruction of ACL following severe injury. However, despite successful surgical reconstruction, some people experience re-rupture and later development of osteoarthritis. Understanding the structure and molecular makeup of normal ACL is essential for its optimal replacement. Reportedly the two bundles display different tensions throughout joint motion and may be fundamentally different. This study assessed the similarities and differences in ultrastructure and molecular composition of the AM and PL bundles to test the hypothesis that the two bundles of the ACL develop unique characteristics with maturation. ACLs from nine mature and six immature sheep were compared. The bundles were examined for mRNA and protein levels of collagen types I, III, V, and VI, and two proteoglycans. The fibril diameter composition of the two bundles was examined with transmission electron microscopy. Maturation does alter the molecular and structural composition of the two bundles of ACL. Although the PL band appears to mature slower than the AM band, no significant differences were detected between the bundles in the mature animals. We thus reject our hypothesis that the two ACL bundles are distinct. The two anatomically distinct bundles of the sheep ACL can be considered as two parts of one structure at maturity and material that would result in a structure of similar functionality can be used to replace each ACL bundle in the sheep.

The difference in centre position in the ACL femoral footprint inclusive and exclusive of the fan-like extension fibres.

PubMed

Iriuchishima, Takanori; Ryu, Keinosuke; Aizawa, Shin; Fu, Freddie H

2016-01-01

The purpose of this study was to compare the centre position of each anterior cruciate ligament bundle in its femoral footprint in measurements including and excluding the fan-like extension fibres. Fourteen non-paired human cadaver knees were used. All soft tissues around the knee were resected except the ligaments. The ACL was divided into antero-medial (AM) and postero-lateral (PL) bundles according to the difference in tension patterns. The ACL was carefully dissected, and two outlines were made of the periphery of each bundle insertion site: those which included and those which excluded the fan-like extension fibres. An accurate lateral view of the femoral condyle was photographed with a digital camera, and the images were downloaded to a personal computer. The centre position of each bundle, including and excluding the fan-like extension fibres, was measured with ImageJ software (National Institution of Health). Evaluation of the centre position was performed using the modified quadrant method. The centre of the femoral AM bundle including the fan-like extension was located at 28.8% in a shallow-deep direction and 37.2% in a high-low direction. When the AM bundle was evaluated without the fan-like extension, the centre was significantly different at 34.6% in a shallow-deep direction (p = 0.000) and 36% in a high-low direction. The centre of the PL bundle including the fan-like extension was found at 37.1% in a shallow-deep direction and 73.4% in a high-low direction. When the PL bundle was evaluated without the fan-like extension, the centre was significantly different at 42.7% in a shallow-deep direction (p = 0.000) and 69.3% in a high-low direction (p = 0.000). The centre position of the AM and PL bundles in the femoral ACL footprint was significantly different depending on the inclusion or exclusion of the fan-like extension fibres. For the clinical relevance, to reproduce the direct femoral insertion in the anatomical ACL reconstruction, tunnels should be placed relatively shallow and high in the femoral ACL footprint.

Selective impairment of song learning following lesions of a forebrain nucleus in the juvenile zebra finch.

PubMed

Sohrabji, F; Nordeen, E J; Nordeen, K W

1990-01-01

Area X, a large sexually dimorphic nucleus in the avian ventral forebrain, is part of a highly discrete system of interconnected nuclei that have been implicated in either song learning or adult song production. Previously, this nucleus has been included in the song system because of its substantial connections with other vocal control nuclei, and because its volume is positively correlated with the capacity for song. In order to directly assess the role of Area X in song behavior, this nucleus was bilaterally lesioned in both juvenile and adult zebra finches, using ibotenic acid. We report here that lesioning Area X disrupts normal song development in juvenile birds, but does not affect the production of stereotyped song by adult birds. Although juvenile-lesioned birds were consistently judged as being in earlier stages of vocal development than age-matched controls, they continued to produce normal song-like vocalizations. Thus, unlike the lateral magnocellular nucleus of the anterior neostriatum, another avian forebrain nucleus implicated in song learning, Area X does not seem to be necessary for sustaining production of juvenile song. Rather, the behavioral results suggest Area X is important for either the acquisition of a song model or the improvement of song through vocal practice.

Efferent projection from the preoptic area for the control of non-shivering thermogenesis in rats

PubMed Central

Chen, Xiao-Ming; Hosono, Takayoshi; Yoda, Tamae; Fukuda, Yutaka; Kanosue, Kazuyuki

1998-01-01

To investigate the characteristics of efferent projections from the preoptic area for the control of non-shivering thermogenesis, we tested the effects of thermal or chemical stimulation, and transections of the preoptic area on the activity of interscapular brown adipose tissue in cold-acclimated and non-acclimated anaesthetized rats.Electrical stimulation of the ventromedial hypothalamic nucleus (VMH) elicited non-shivering thermogenesis in the brown adipose tissue (BAT); warming the preoptic area to 41.5 °C completely suppressed the thermogenic response.Injections of d,l-homocysteic acid (DLH; 0.5 mm, 0.3 μl) into the preoptic area also significantly attenuated BAT thermogenesis, whereas injections of control vehicle had no effect.Transections of the whole hypothalamus in the coronal plane at the level of the paraventricular nucleus induced rapid and large rises in BAT and rectal temperatures. This response was not blocked by pretreatment with indomethacin. The high rectal and BAT temperatures were sustained more than 1 h, till the end of the experiment. Bilateral knife cuts that included the medial forebrain bundle but not the paraventricular nuclei elicited similar rises in BAT and rectal temperatures. Medial knife cuts had no effect.These results suggest that warm-sensitive neurones in the preoptic area contribute a larger efferent signal for non-shivering thermogenesis than do cold-sensitive neurones, and that the preoptic area contributes a tonic inhibitory input to loci involved with non-shivering thermogenesis. This efferent inhibitory signal passes via lateral, but not medial, hypothalamic pathways. PMID:9769429

Electro-acupuncture stimulation acts on the basal ganglia output pathway to ameliorate motor impairment in Parkinsonian model rats.

PubMed

Jia, Jun; Li, Bo; Sun, Zuo-Li; Yu, Fen; Wang, Xuan; Wang, Xiao-Min

2010-04-01

The role of electro-acupuncture (EA) stimulation on motor symptoms in Parkinson's disease (PD) has not been well studied. In a rat hemiparkinsonian model induced by unilateral transection of the medial forebrain bundle (MFB), EA stimulation improved motor impairment in a frequency-dependent manner. Whereas EA stimulation at a low frequency (2 Hz) had no effect, EA stimulation at a high frequency (100 Hz) significantly improved motor coordination. However, neither low nor high EA stimulation could significantly enhance dopamine levels in the striatum. EA stimulation at 100 Hz normalized the MFB lesion-induced increase in midbrain GABA content, but it had no effect on GABA content in the globus pallidus. These results suggest that high-frequency EA stimulation improves motor impairment in MFB-lesioned rats by increasing GABAergic inhibition in the output structure of the basal ganglia.

Addictive drugs and brain stimulation reward.

PubMed

Wise, R A

1996-01-01

Direct electrical or chemical stimulation of specific brain regions can establish response habits similar to those established by natural rewards such as food or sexual contact. Cocaine, mu and delta opiates, nicotine, phencyclidine, and cannabis each have actions that summate with rewarding electrical stimulation of the medial forebrain bundle (MFB). The reward-potentiating effects of amphetamine and opiates are associated with central sites of action where these drugs also have their direct rewarding effects, suggesting common mechanisms for drug reward per se and for drug potentiation of brain stimulation reward. The central sites at which these and perhaps other drugs of abuse potentiate brain stimulation reward and are rewarding in their own right are consistent with the hypothesis that the laboratory reward of brain stimulation and the pharmacological rewards of addictive drugs are habit forming because they act in the brain circuits that subserve more natural and biologically significant rewards.

Effects of lateral fluid percussion injury on cholinergic markers in the newborn piglet brain.

PubMed

Donat, Cornelius K; Walter, Bernd; Kayser, Tanja; Deuther-Conrad, Winnie; Schliebs, Reinhard; Nieber, Karen; Bauer, Reinhard; Härtig, Wolfgang; Brust, Peter

2010-02-01

Traumatic brain injury is a leading cause of death and disability in children. Studies using adult animal models showed alterations of the central cholinergic neurotransmission as a result of trauma. However, there is a lack of knowledge about consequences of brain trauma on cholinergic function in the immature brain. It is hypothesized that trauma affects the relative acetylcholine esterase activity and causes a loss of cholinergic neurons in the immature brain. Severe fluid percussion trauma (FP-TBI, 3.8+/-0.3atm) was induced in 15 female newborn piglets, monitored for 6h and compared with 12 control animals. The hemispheres ipsilateral to FP-TBI obtained from seven piglets were used for acetylcholine esterase histochemistry on frozen sagittal slices, while regional cerebral blood flow and oxygen availability was determined in the remaining eight FP-TBI animals. Post-fixed slices were immunohistochemically labelled for choline acetyltransferase as well as for low-affinity neurotrophin receptor in order to characterize cholinergic neurons in the basal forebrain. Regional cerebral blood flow and brain oxygen availability were reduced during the first 2h after FP-TBI (P<0.05). In addition, acetylcholine esterase activity was significantly increased in the neocortex, basal forebrain, hypothalamus and medulla after trauma (P<0.05), whereas the number of choline acetyltransferase and low-affinity neurotrophin receptor positive cells in the basal forebrain were unaffected by the injury. Thus, traumatic brain injury evoked an increased relative activity of the acetylcholine esterase in the immature brain early after injury, without loss of cholinergic neurons in the basal forebrain. These changes may contribute to developmental impairments after immature traumatic brain injury. Copyright 2009 ISDN. Published by Elsevier Ltd. All rights reserved.

Lateral distribution of high energy hadrons and gamma ray in air shower cores observed with emulsion chambers

NASA Technical Reports Server (NTRS)

Matano, T.; Machida, M.; Kawasumi, N.; Tsushima, I.; Honda, K.; Hashimoto, K.; Navia, C. E.; Matinic, N.; Aquirre, C.

1985-01-01

A high energy event of a bundle of electrons, gamma rays and hadronic gamma rays in an air shower core were observed. The bundles were detected with an emulsion chamber with thickness of 15 cm lead. This air shower is estimated to be initiated with a proton with energy around 10 to the 17th power to 10 to the 18th power eV at an altitude of around 100 gmc/2. Lateral distributions of the electromagnetic component with energy above 2 TeV and also the hadronic component of energy above 6 TeV of this air shower core were determined. Particles in the bundle are produced with process of the development of the nuclear cascade, the primary energy of each interaction in the cascade which produces these particles is unknown. To know the primary energy dependence of transverse momentum, the average products of energy and distance for various average energies of secondary particles are studied.

Steady-state stiffness of utricular hair cells depends on macular location and hair bundle structure.

PubMed

Spoon, Corrie; Moravec, W J; Rowe, M H; Grant, J W; Peterson, E H

2011-12-01

Spatial and temporal properties of head movement are encoded by vestibular hair cells in the inner ear. One of the most striking features of these receptors is the orderly structural variation in their mechanoreceptive hair bundles, but the functional significance of this diversity is poorly understood. We tested the hypothesis that hair bundle structure is a significant contributor to hair bundle mechanics by comparing structure and steady-state stiffness of 73 hair bundles at varying locations on the utricular macula. Our first major finding is that stiffness of utricular hair bundles varies systematically with macular locus. Stiffness values are highest in the striola, near the line of hair bundle polarity reversal, and decline exponentially toward the medial extrastriola. Striolar bundles are significantly more stiff than those in medial (median: 8.9 μN/m) and lateral (2.0 μN/m) extrastriolae. Within the striola, bundle stiffness is greatest in zone 2 (106.4 μN/m), a band of type II hair cells, and significantly less in zone 3 (30.6 μN/m), which contains the only type I hair cells in the macula. Bathing bundles in media that break interciliary links produced changes in bundle stiffness with predictable time course and magnitude, suggesting that links were intact in our standard media and contributed normally to bundle stiffness during measurements. Our second major finding is that bundle structure is a significant predictor of steady-state stiffness: the heights of kinocilia and the tallest stereocilia are the most important determinants of bundle stiffness. Our results suggest 1) a functional interpretation of bundle height variability in vertebrate vestibular organs, 2) a role for the striola in detecting onset of head movement, and 3) the hypothesis that differences in bundle stiffness contribute to diversity in afferent response dynamics.

Steady-state stiffness of utricular hair cells depends on macular location and hair bundle structure

PubMed Central

Spoon, Corrie; Moravec, W. J.; Rowe, M. H.; Grant, J. W.

2011-01-01

Spatial and temporal properties of head movement are encoded by vestibular hair cells in the inner ear. One of the most striking features of these receptors is the orderly structural variation in their mechanoreceptive hair bundles, but the functional significance of this diversity is poorly understood. We tested the hypothesis that hair bundle structure is a significant contributor to hair bundle mechanics by comparing structure and steady-state stiffness of 73 hair bundles at varying locations on the utricular macula. Our first major finding is that stiffness of utricular hair bundles varies systematically with macular locus. Stiffness values are highest in the striola, near the line of hair bundle polarity reversal, and decline exponentially toward the medial extrastriola. Striolar bundles are significantly more stiff than those in medial (median: 8.9 μN/m) and lateral (2.0 μN/m) extrastriolae. Within the striola, bundle stiffness is greatest in zone 2 (106.4 μN/m), a band of type II hair cells, and significantly less in zone 3 (30.6 μN/m), which contains the only type I hair cells in the macula. Bathing bundles in media that break interciliary links produced changes in bundle stiffness with predictable time course and magnitude, suggesting that links were intact in our standard media and contributed normally to bundle stiffness during measurements. Our second major finding is that bundle structure is a significant predictor of steady-state stiffness: the heights of kinocilia and the tallest stereocilia are the most important determinants of bundle stiffness. Our results suggest 1) a functional interpretation of bundle height variability in vertebrate vestibular organs, 2) a role for the striola in detecting onset of head movement, and 3) the hypothesis that differences in bundle stiffness contribute to diversity in afferent response dynamics. PMID:21918003

Volume of the human septal forebrain region is a predictor of source memory accuracy.

PubMed

Butler, Tracy; Blackmon, Karen; Zaborszky, Laszlo; Wang, Xiuyuan; DuBois, Jonathan; Carlson, Chad; Barr, William B; French, Jacqueline; Devinsky, Orrin; Kuzniecky, Ruben; Halgren, Eric; Thesen, Thomas

2012-01-01

Septal nuclei, components of basal forebrain, are strongly and reciprocally connected with hippocampus, and have been shown in animals to play a critical role in memory. In humans, the septal forebrain has received little attention. To examine the role of human septal forebrain in memory, we acquired high-resolution magnetic resonance imaging scans from 25 healthy subjects and calculated septal forebrain volume using recently developed probabilistic cytoarchitectonic maps. We indexed memory with the California Verbal Learning Test-II. Linear regression showed that bilateral septal forebrain volume was a significant positive predictor of recognition memory accuracy. More specifically, larger septal forebrain volume was associated with the ability to recall item source/context accuracy. Results indicate specific involvement of septal forebrain in human source memory, and recall the need for additional research into the role of septal nuclei in memory and other impairments associated with human diseases.

A nodal signaling pathway regulates the laterality of neuroanatomical asymmetries in the zebrafish forebrain.

PubMed

Concha, M L; Burdine, R D; Russell, C; Schier, A F; Wilson, S W

2000-11-01

Animals show behavioral asymmetries that are mediated by differences between the left and right sides of the brain. We report that the laterality of asymmetric development of the diencephalic habenular nuclei and the photoreceptive pineal complex is regulated by the Nodal signaling pathway and by midline tissue. Analysis of zebrafish embryos with compromised Nodal signaling reveals an early role for this pathway in the repression of asymmetrically expressed genes in the diencephalon. Later signaling mediated by the EGF-CFC protein One-eyed pinhead and the forkhead transcription factor Schmalspur is required to overcome this repression. When expression of Nodal pathway genes is either absent or symmetrical, neuroanatomical asymmetries are still established but are randomized. This indicates that Nodal signaling is not required for asymmetric development per se but is essential to determine the laterality of the asymmetry.

Development of the Mayo Investigational Neuromodulation Control System: toward a closed-loop electrochemical feedback system for deep brain stimulation

PubMed Central

Chang, Su-Youne; Kimble, Christopher J.; Kim, Inyong; Paek, Seungleal B.; Kressin, Kenneth R.; Boesche, Joshua B.; Whitlock, Sidney V.; Eaker, Diane R.; Kasasbeh, Aimen; Horne, April E.; Blaha, Charles D.; Bennet, Kevin E.; Lee, Kendall H.

2014-01-01

Object Conventional deep brain stimulation (DBS) devices continue to rely on an open-loop system in which stimulation is independent of functional neural feedback. The authors previously proposed that as the foundation of a DBS “smart” device, a closed-loop system based on neurochemical feedback, may have the potential to improve therapeutic outcomes. Alterations in neurochemical release are thought to be linked to the clinical benefit of DBS, and fast-scan cyclic voltammetry (FSCV) has been shown to be effective for recording these evoked neurochemical changes. However, the combination of FSCV with conventional DBS devices interferes with the recording and identification of the evoked analytes. To integrate neurochemical recording with neurostimulation, the authors developed the Mayo Investigational Neuromodulation Control System (MINCS), a novel, wirelessly controlled stimulation device designed to interface with FSCV performed by their previously described Wireless Instantaneous Neurochemical Concentration Sensing System (WINCS). Methods To test the functionality of these integrated devices, various frequencies of electrical stimulation were applied by MINCS to the medial forebrain bundle of the anesthetized rat, and striatal dopamine release was recorded by WINCS. The parameters for FSCV in the present study consisted of a pyramidal voltage waveform applied to the carbon-fiber microelectrode every 100 msec, ramping between −0.4 V and +1.5 V with respect to an Ag/AgCl reference electrode at a scan rate of either 400 V/sec or 1000 V/sec. The carbon-fiber microelectrode was held at the baseline potential of −0.4 V between scans. Results By using MINCS in conjunction with WINCS coordinated through an optic fiber, the authors interleaved intervals of electrical stimulation with FSCV scans and thus obtained artifact-free wireless FSCV recordings. Electrical stimulation of the medial forebrain bundle in the anesthetized rat by MINCS elicited striatal dopamine release that was time-locked to stimulation and increased progressively with stimulation frequency. Conclusions Here, the authors report a series of proof-of-principle tests in the rat brain demonstrating MINCS to be a reliable and flexible stimulation device that, when used in conjunction with WINCS, performs wirelessly controlled stimulation concurrent with artifact-free neurochemical recording. These findings suggest that the integration of neurochemical recording with neurostimulation may be a useful first step toward the development of a closed-loop DBS system for human application. PMID:24116724

Morphological size evaluation of the mid-substance insertion areas and the fan-like extension fibers in the femoral ACL footprint.

PubMed

Suruga, Makoto; Horaguchi, Takashi; Iriuchishima, Takanori; Yahagi, Yoshiyuki; Iwama, Genki; Tokuhashi, Yasuaki; Aizawa, Shin

2017-08-01

The purpose of this study was to evaluate the detailed anatomy of the femoral anterior cruciate ligament (ACL) insertion site, with special attention given to the morphology of the mid-substance insertion areas and the fan-like extension fibers. Twenty-three non-paired human cadaver knees were used (7 Males, 16 Females, median age 83, range 69-96). All soft tissues around the knee were resected except the ligaments. The ACL was divided into antero-medial (AM) and postero-lateral (PL) bundles according to the difference in macroscopic tension patterns. The ACL was carefully dissected and two outlines were made of the periphery of each bundle insertion site: those which included and those which excluded the fan-like extension fibers. An accurate lateral view of the femoral condyle was photographed with a digital camera, and the images were downloaded to a personal computer. The area of each bundle, including and excluding the fan-like extension fibers, was measured with Image J software (National Institution of Health). The width and length of the mid-substance insertion sites were also evaluated using same image. The femoral ACL footprint was divided into four regions (mid-substance insertion sites of the AM and PL bundles, and fan-like extensions of the AM and PL bundles). The measured areas of the mid-substance insertion sites of the AM and PL bundles were 35.5 ± 12.5, and 32.4 ± 13.8 mm 2 , respectively. Whole width and length of the mid-substance insertion sites were 5.3 ± 1.4, and 15.5 ± 2.9 mm, respectively. The measured areas of the fan-like extensions of the AM and PL bundles were 27 ± 11.5, and 29.5 ± 12.4 mm 2 , respectively. The femoral ACL footprint was divided into quarters of approximately equal size (mid-substance insertion sites of the AM and PL bundles, and fan-like extensions of the AM and PL bundles). For clinical relevance, to perform highly reproducible anatomical ACL reconstruction, the presence of the fan-like extension fibers should be taken into consideration.

Acoustic imprinting leads to differential 2-deoxy-D-glucose uptake in the chick forebrain.

PubMed Central

Maier, V; Scheich, H

1983-01-01

This report describes experiments in which successful acoustic imprinting correlates with differential uptake of D-2-deoxy[14C]glucose in particular forebrain areas that are not considered primarily auditory. Newly hatched guinea chicks (Numida meleagris meleagris) were imprinted by playing 1.8-kHz or 2.5-kHz tone bursts for prolonged periods. Those chicks were considered to be imprinted who approached the imprinting stimulus (emitted from a loudspeaker) and preferred it over a new stimulus in a simultaneous discrimination test. In the 2-deoxy-D-glucose experiment all chicks, imprinted and naive, were exposed to 1.8-kHz tone bursts for 1 hr. As shown by the autoradiographic analysis of the brains, neurons in the 1.8-kHz isofrequency plane of the auditory "cortex" (field L) were activated in all chicks, whether imprinted or not. However, in the most rostral forebrain striking differences were found. Imprinted chicks showed an increased 2-deoxy-D-glucose uptake in three areas, as compared to naive chicks: (i) the lateral neostriatum and hyperstriatum ventrale, (ii) a medial magnocellular field (medial neostriatum/hyperstriatum ventrale), and (iii) the most dorsal layers of the hyperstriatum. Based on these findings we conclude that these areas are involved in the processing of auditory stimuli once they have become meaningful by experience. Images PMID:6574519

Foxp2 regulates neuronal differentiation and neuronal subtype specification.

PubMed

Chiu, Yi-Chi; Li, Ming-Yang; Liu, Yuan-Hsuan; Ding, Jing-Ya; Yu, Jenn-Yah; Wang, Tsu-Wei

2014-07-01

Mutations of the transcription factor FOXP2 in humans cause a severe speech and language disorder. Disruption of Foxp2 in songbirds or mice also leads to deficits in song learning or ultrasonic vocalization, respectively. These data suggest that Foxp2 plays important roles in the developing nervous system. However, the mechanism of Foxp2 in regulating neural development remains elusive. In the current study, we found that Foxp2 increased neuronal differentiation without affecting cell proliferation and cell survival in primary neural progenitors from embryonic forebrains. Foxp2 induced the expression of platelet-derived growth factor receptor α, which mediated the neurognic effect of Foxp2. In addition, Foxp2 positively regulated the differentiation of medium spiny neurons derived from the lateral ganglionic eminence and negatively regulated the formation of interneurons derived from dorsal medial ganglionic eminence by interacting with the Sonic hedgehog pathway. Taken together, our results suggest that Foxp2 regulates multiple aspects of neuronal development in the embryonic forebrain. © 2014 Wiley Periodicals, Inc.

Intracranial Self-Stimulation to Evaluate Abuse Potential of Drugs

PubMed Central

Miller, Laurence L.

2014-01-01

Intracranial self-stimulation (ICSS) is a behavioral procedure in which operant responding is maintained by pulses of electrical brain stimulation. In research to study abuse-related drug effects, ICSS relies on electrode placements that target the medial forebrain bundle at the level of the lateral hypothalamus, and experimental sessions manipulate frequency or amplitude of stimulation to engender a wide range of baseline response rates or response probabilities. Under these conditions, drug-induced increases in low rates/probabilities of responding maintained by low frequencies/amplitudes of stimulation are interpreted as an abuse-related effect. Conversely, drug-induced decreases in high rates/probabilities of responding maintained by high frequencies/amplitudes of stimulation can be interpreted as an abuse-limiting effect. Overall abuse potential can be inferred from the relative expression of abuse-related and abuse-limiting effects. The sensitivity and selectivity of ICSS to detect abuse potential of many classes of abused drugs is similar to the sensitivity and selectivity of drug self-administration procedures. Moreover, similar to progressive-ratio drug self-administration procedures, ICSS data can be used to rank the relative abuse potential of different drugs. Strengths of ICSS in comparison with drug self-administration include 1) potential for simultaneous evaluation of both abuse-related and abuse-limiting effects, 2) flexibility for use with various routes of drug administration or drug vehicles, 3) utility for studies in drug-naive subjects as well as in subjects with controlled levels of prior drug exposure, and 4) utility for studies of drug time course. Taken together, these considerations suggest that ICSS can make significant contributions to the practice of abuse potential testing. PMID:24973197

Amyloid-β expression in retrosplenial cortex of 3xTg-AD mice: relationship to cholinergic axonal afferents from medial septum

PubMed Central

Robertson, Richard T.; Baratta, Janie; Yu, Jen; LaFerla, Frank M.

2009-01-01

Triple transgenic (3xTg-AD) mice harboring the presenilin 1, amyloid precursor protein, and tau transgenes (Oddo et al., 2003) display prominent levels of amyloid-beta (Aβ) immunoreactivity in forebrain regions. The Aβ immunoreactivity is first seen intracellularly in neurons and later as extracellular plaque deposits. The present study examined Aβ immunoreactivity that occurs in layer III of the granular division of retrosplenial cortex (RSg). This pattern of Aβ immunoreactivity in layer III of RSg develops relatively late, and is seen in animals older than 14 mo. The appearance of the Aβ immunoreactivity is similar to an axonal terminal field and thus may offer a unique opportunity to study the relationship between afferent projections and the formation of Aβ deposits. Axonal tract tracing techniques demonstrated that the pattern of axon terminal labeling in layer III of RSg, following placement of DiI in medial septum, is remarkably similar to the pattern of cholinergic axons in RSg, as detected by acetylcholinesterase histochemical staining, choline acetyltransferase immunoreactivity, or p75 receptor immunoreactivity; this pattern also is strikingly similar to the band of Aβ immunoreactivity. In animals sustaining early damage to the medial septal nucleus (prior to the advent of Aβ immunoreactivity), the band of Aβ in layer III of RSg does not develop; the corresponding band of cholinergic markers also is eliminated. In older animals (after the appearance of the Aβ immunoreactivity) damage to cholinergic afferents by electrolytic lesions, immunotoxin lesions, or cutting the cingulate bundle, result in a rapid loss of the cholinergic markers and a slower reduction of Aβ immunoreactivity. These results suggest that the septal cholinergic axonal projections transport Aβ or APP to layer III of RSg. PMID:19772895

Sperm bundle and reproductive organs of carabid beetles tribe Pterostichini (Coleoptera: Carabidae)

NASA Astrophysics Data System (ADS)

Sasakawa, Kôji

2007-05-01

The morphological characteristics of sperm and reproductive organs may offer clues as to how reproductive systems have evolved. In this paper, the morphologies of the sperm and male reproductive organs of carabid beetles in the tribe Pterostichini (Coleoptera: Carabidae) are described, and the morphological associations among characters are examined. All species form sperm bundles in which the head of the sperm was embedded in a rod-shaped structure, i.e., spermatodesm. The spermatodesm shape (left-handed spiral, right-handed spiral, or without conspicuous spiral structure) and the condition of the sperm on the spermatodesm surface (with the tail free-moving or forming a thin, sheetlike structure) vary among species. In all species, the spiral directions of the convoluted seminal vesicles and vasa deferentia are the same on both sides of the body; that is, they show an asymmetric structure. The species in which the sperm bundle and the seminal vesicles both have a spiral structure could be classified into two types, with significant differences in sperm-bundle length between the two types. The species with a sperm-bundle spiral and seminal-vesicle spiral of almost the same diameter have longer sperm bundles than the species with a sperm-bundle spiral and seminal-vesicle tube of almost the same diameter. In the former type, the spiral directions of the sperm bundles and seminal vesicles are inevitably the same, whereas they differ in some species with the later type. Therefore, increased sperm bundle length appears to have been facilitated by the concordance of the sperm bundle’s coiling direction with the coiling direction of the seminal vesicle.

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

PubMed Central

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

2015-01-01

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

Anterior Cruciate Ligament Injury, Reconstruction, and the Optimization of Outcome

PubMed Central

Bliss, James Philip

2017-01-01

Anterior cruciate ligament reconstruction (ACLR) provides an established surgical intervention to control pathological tibiofemoral translational and rotational movement. ACLR is a safe and reproducible intervention, but there remains an underlying rate of failure to return to preinjury sporting activity levels. Postoperative pathological laxity and graft reinjury remain concerns. Previously, unrecognized meniscal lesions, disruption of the lateral capsule, and extracapsular structures offer potential avenues to treat and to therefore improve kinematic outcome and functional results, following reconstruction. Addressing laterally based injuries may also improve the durability of intraarticular ACLR. Improving the anterior cruciate ligament (ACL) graft replication of the normal ACL attachment points on the femur and the tibia, using either double bundle or anatomical single bundle techniques, improves kinematics, which may benefit outcome and functionality, following reconstruction. PMID:28966384

An evaluation of the impact of the ventilator care bundle.

PubMed

Crunden, Eddie; Boyce, Carolyn; Woodman, Helen; Bray, Barbara

2005-01-01

A number of interventions have been shown to improve the outcomes of patients who are invasively ventilated in intensive care units (ICUs). However, significant problems still exist in implementing research findings into clinical practice. The aim of this study was to assess whether the systematic and methodical implementation of evidence-based interventions encapsulated in a care bundle influenced length of ventilation and ICU length of stay (LOS). A ventilator care bundle was introduced within a general ICU and evaluated 1 year later. The care bundle was composed of four protocols that consisted of prophylaxis against peptic ulceration, prophylaxis against deep vein thrombosis, daily cessation of sedation and elevation of the patient's head and chest to at least 30 degrees to the horizontal. Compliance with the bundle was assessed, as was ICU LOS, ICU mortality and ICU/high-dependency unit patient throughput. Mean ICU LOS was reduced from 13-75 [standard deviation (SD) 19.11] days to 8.36 (SD 10.21) days (p<0.05). Mean ventilator days were reduced from 10.8 (SD 15.58) days to 6.1 (SD 8.88) days. Unit patient throughput increased by 30.1% and the number of invasively ventilated patients increased by 39.5%. Care bundles encourage the consistent and systematic application of evidence-based protocols used in particular treatment regimes. Since the introduction of the ventilator care bundle, length of ventilation and ICU LOS have reduced significantly.

Kinetochore-independent chromosome segregation driven by lateral microtubule bundles

PubMed Central

Muscat, Christina C; Torre-Santiago, Keila M; Tran, Michael V; Powers, James A; Wignall, Sarah M

2015-01-01

During cell division, chromosomes attach to spindle microtubules at sites called kinetochores, and force generated at the kinetochore-microtubule interface is the main driver of chromosome movement. Surprisingly, kinetochores are not required for chromosome segregation on acentrosomal spindles in Caenorhabditis elegans oocytes, but the mechanism driving chromosomes apart in their absence is not understood. In this study, we show that lateral microtubule–chromosome associations established during prometaphase remain intact during anaphase to facilitate separation, defining a novel form of kinetochore-independent segregation. Chromosome dynamics during congression and segregation are controlled by opposing forces; plus-end directed forces are mediated by a protein complex that forms a ring around the chromosome center and dynein on chromosome arms provides a minus-end force. At anaphase onset, ring removal shifts the balance between these forces, triggering poleward movement along lateral microtubule bundles. This represents an elegant strategy for controlling chromosomal movements during cell division distinct from the canonical kinetochore-driven mechanism. DOI: http://dx.doi.org/10.7554/eLife.06462.001 PMID:26026148

The effects of propofol on hippocampal caspase-3 and Bcl-2 expression following forebrain ischemia-reperfusion in rats.

PubMed

Li, Jun; Han, Baoqing; Ma, Xuesong; Qi, Sihua

2010-10-14

Transient cerebral ischemia may result in neuronal apoptosis. During this process, several apoptosis-regulatory genes are induced in apoptotic cells. Among these genes, cysteinyl aspartate-specific protease-3 (caspase-3) and B-cell leukemia-2 (Bcl-2) are the most effective apoptotic regulators because they play a decisive role in the occurrence of apoptosis. Research has shown that propofol, which is an intravenous anesthetic agent, exhibits neuroprotective effects against cerebral ischemia-reperfusion injury, although the neuroprotective mechanism is still unclear. In this study, we examined the effects of propofol in rats after forebrain ischemia-reperfusion. We assessed the expression of hippocampal caspase-3, which acts as an apoptotic activator, and Bcl-2, which acts as an apoptotic suppressor. Forebrain ischemia was induced in hypotensive rats by clamping the bilateral common carotid arteries for 10 min. Propofol was administered via a lateral cerebral ventricle injection using a microsyringe after the induction of ischemia. Neuronal damage was determined by histological examination of brain sections at the level of the dorsal hippocampus. Caspase-3 and Bcl-2 expression in the hippocampus were detected using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. We also used an immunohistochemical method after ischemia-reperfusion. In the hippocampus, caspase-3 and Bcl-2 mRNA were dramatically increased at 24h after forebrain ischemia. Following 6-24h of reperfusion, forebrain ischemia for 10 min induced a gradual increase in the expression of caspase-3 and Bcl-2 protein in the rat hippocampus, which peaked at 24h. In the propofol (1.0mg/kg) intervention group, the hippocampal expression of caspase-3 mRNA decreased significantly in rats 24h after ischemia; Bcl-2 mRNA was increased at the same time point. During the 24-h reperfusion period and after treatment with propofol, the level of caspase-3 protein expression was low, while the level of Bcl-2 was high. Thus, our results suggest that the neuroprotective effects of propofol against neuronal apoptosis may be mediated by the inhibition of caspase-3 expression and an increase in Bcl-2 expression. Copyright © 2010 Elsevier B.V. All rights reserved.

Glucose-Dependent Insulinotropic Polypeptide Mitigates 6-OHDA-Induced Behavioral Impairments in Parkinsonian Rats

PubMed Central

Yu, Yu-Wen; Hsueh, Shih-Chang; Lai, Jing-Huei; Chen, Yen-Hua; Kang, Shuo-Jhen; Hsieh, Tsung-Hsun; Hoffer, Barry J.; Li, Yazhou; Greig, Nigel H.; Chiang, Yung-Hsiao

2018-01-01

In the present study, the effectiveness of glucose-dependent insulinotropic polypeptide (GIP) was evaluated by behavioral tests in 6-hydroxydopamine (6-OHDA) hemi-parkinsonian (PD) rats. Pharmacokinetic measurements of GIP were carried out at the same dose studied behaviorally, as well as at a lower dose used previously. GIP was delivered by subcutaneous administration (s.c.) using implanted ALZET micro-osmotic pumps. After two days of pre-treatment, male Sprague Dawley rats received a single unilateral injection of 6-OHDA into the medial forebrain bundle (MFB). The neuroprotective effects of GIP were evaluated by apomorphine-induced contralateral rotations, as well as by locomotor and anxiety-like behaviors in open-field tests. Concentrations of human active and total GIP were measured in plasma during a five-day treatment period by ELISA and were found to be within a clinically translatable range. GIP pretreatment reduced behavioral abnormalities induced by the unilateral nigrostriatal dopamine (DA) lesion produced by 6-OHDA, and thus may be a novel target for PD therapeutic development. PMID:29641447

Expression and distribution of TRPV2 in rat brain.

PubMed

Nedungadi, Thekkethil Prashant; Dutta, Mayurika; Bathina, Chandra Sekhar; Caterina, Michael J; Cunningham, J Thomas

2012-09-01

Transient receptor potential (TRP) proteins are non-selective cation channels that mediate sensory transduction. The neuroanatomical localization and the physiological roles of isoform TRPV2 in the rodent brain are largely unknown. We report here the neuroanatomical distribution of TRPV2 in the adult male rat brain focusing on the hypothalamus and hindbrain regions involved in osmoregulation, autonomic function and energy metabolism. For this we utilized immunohistochemistry combined with brightfield microscopy. In the forebrain, the densest immunostaining was seen in both the supraoptic nucleus (SON) and the magnocellular division of the paraventricular nucleus (PVN) of the hypothalamus. TRPV2 immunoreactivity was also seen in the organum vasculosum of the lamina terminalis, the median preoptic nucleus and the subfornical organ, in addition to the arcuate nucleus of the hypothalamus (ARH), the medial forebrain bundle, the cingulate cortex and the globus pallidus to name a few. In the hindbrain, intense staining was seen in the nucleus of the solitary tract, hypoglossal nucleus, nucleus ambiguous, and the rostral division of the ventrolateral medulla (RVLM) and some mild staining in the area prostrema. To ascertain the specificity of the TRPV2 antibody used in this paper, we compared the TRPV2 immunoreactivity of wildtype (WT) and knockout (KO) mouse brain tissue. Double immunostaining with arginine vasopressin (AVP) using confocal microscopy showed a high degree of colocalization of TRPV2 in the magnocellular SON and PVN. Using laser capture microdissection (LCM) we also show that AVP neurons in the SON contain TRPV2 mRNA. TRPV2 was also co-localized with dopamine beta hydroxylase (DBH) in the NTS and the RVLM of the hindbrain. Based on our results, TRPV2 may play an important role in several CNS networks that regulate body fluid homeostasis, autonomic function, and metabolism. Copyright © 2012 Elsevier Inc. All rights reserved.

Expression and Distribution of TRPV2 in Rat Brain

PubMed Central

Nedungadi, Thekkethil Prashant; Dutta, Mayurika; Bathina, Chandra Sekhar; Caterina, Michael J; Cunningham, J. Thomas

2012-01-01

Transient receptor potential (TRP) proteins are non-selective cation channels that mediate sensory transduction. The neuroanatomical localization and the physiological roles of isoform TRPV2 in the rodent brain are largely unknown. We report here the neuroanatomical distribution of TRPV2 in the adult male rat brain focusing on hypothalamus and hindbrain regions involved in osmoregulation, autonomic function and energy metabolism. For this we utilized immunohistochemistry combined with brighfield microscopy. In the forebrain, the densest immunostaining was seen in both the supraoptic nucleus (SON) and the magnocellular division of the paraventricular nucleus (PVN) of the hypothalamus. TRPV2 immunoreactivity was also seen in the organum vasculosum of the lamina terminalis, the median preoptic nucleus and the subfornical organ, in addition to the arcuate nucleus of the hypothalamus (ARH), the medial forebrain bundle, the cingulate cortex and the globus pallidus to name a few. In the hindbrain, intense staining was seen in the nucleus of the solitary tract, hypoglossal nucleus, nucleus ambiguous, and the rostral division of the ventrolateral medulla (RVLM) and some mild staining in the area prostrema. To ascertain the specificity of the TRPV2 antibody used in this paper, we compared the TRPV2 immunoreactivity of wildtype (WT) and knockout (KO) mouse brain tissue. Double immunostaining with arginine vasopressin (AVP) using confocal microscopy showed a high degree of colocalization of TRPV2 in the magnocellular SON and PVN. Using laser capture microdissection (LCM) we also show that AVP neurons in the SON contain TRPV2 mRNA. TRPV2 was also co-localized with dopamine beta hydroxylase (DBH) in the NTS and the RVLM of the hindbrain. Based on our results, TRPV2 may play an important role in several CNS networks that regulate body fluid homeostasis, autonomic function, and metabolism. PMID:22750329

Bmi-1 cooperates with Foxg1 to maintain neural stem cell self-renewal in the forebrain

PubMed Central

Fasano, Christopher A.; Phoenix, Timothy N.; Kokovay, Erzsebet; Lowry, Natalia; Elkabetz, Yechiel; Dimos, John T.; Lemischka, Ihor R.; Studer, Lorenz; Temple, Sally

2009-01-01

Neural stem cells (NSCs) persist throughout life in two forebrain areas: the subventricular zone (SVZ) and the hippocampus. Why forebrain NSCs self-renew more extensively than those from other regions remains unclear. Prior studies have shown that the polycomb factor Bmi-1 is necessary for NSC self-renewal and that it represses the cell cycle inhibitors p16, p19, and p21. Here we show that overexpression of Bmi-1 enhances self-renewal of forebrain NSCs significantly more than those derived from spinal cord, demonstrating a regional difference in responsiveness. We show that forebrain NSCs require the forebrain-specific transcription factor Foxg1 for Bmi-1-dependent self-renewal, and that repression of p21 is a focus of this interaction. Bmi-1 enhancement of NSC self-renewal is significantly greater with increasing age and passage. Importantly, when Bmi-1 is overexpressed in cultured adult forebrain NSCs, they expand dramatically and continue to make neurons even after multiple passages, when control NSCs have become restricted to glial differentiation. Together these findings demonstrate the importance of Bmi-1 and Foxg1 cooperation to maintenance of NSC multipotency and self-renewal, and establish a useful method for generating abundant forebrain neurons ex vivo, outside the neurogenic niche. PMID:19270157

In vivo cholinergic basal forebrain atrophy predicts cognitive decline in de novo Parkinson's disease.

PubMed

Ray, Nicola J; Bradburn, Steven; Murgatroyd, Christopher; Toseeb, Umar; Mir, Pablo; Kountouriotis, George K; Teipel, Stefan J; Grothe, Michel J

2018-01-01

See Gratwicke and Foltynie (doi:10.1093/brain/awx333) for a scientific commentary on this article.Cognitive impairments are a prevalent and disabling non-motor complication of Parkinson's disease, but with variable expression and progression. The onset of serious cognitive decline occurs alongside substantial cholinergic denervation, but imprecision of previously available techniques for in vivo measurement of cholinergic degeneration limit their use as predictive cognitive biomarkers. However, recent developments in stereotactic mapping of the cholinergic basal forebrain have been found useful for predicting cognitive decline in prodromal stages of Alzheimer's disease. These methods have not yet been applied to longitudinal Parkinson's disease data. In a large sample of people with de novo Parkinson's disease (n = 168), retrieved from the Parkinson's Progressive Markers Initiative database, we measured cholinergic basal forebrain volumes, using morphometric analysis of T1-weighted images in combination with a detailed stereotactic atlas of the cholinergic basal forebrain nuclei. Using a binary classification procedure, we defined patients with reduced basal forebrain volumes (relative to age) at baseline, based on volumes measured in a normative sample (n = 76). Additionally, relationships between the basal forebrain volumes at baseline, risk of later cognitive decline, and scores on up to 5 years of annual cognitive assessments were assessed with regression, survival analysis and linear mixed modelling. In patients, smaller volumes in a region corresponding to the nucleus basalis of Meynert were associated with greater change in global cognitive, but not motor scores after 2 years. Using the binary classification procedure, patients classified as having smaller than expected volumes of the nucleus basalis of Meynert had ∼3.5-fold greater risk of being categorized as mildly cognitively impaired over a period of up to 5 years of follow-up (hazard ratio = 3.51). Finally, linear mixed modelling analysis of domain-specific cognitive scores revealed that patients classified as having smaller than expected nucleus basalis volumes showed more severe and rapid decline over up to 5 years on tests of memory and semantic fluency, but not on tests of executive function. Thus, we provide the first evidence that volumetric measurement of the nucleus basalis of Meynert can predict early cognitive decline. Our methods therefore provide the opportunity for multiple-modality biomarker models to include a cholinergic biomarker, which is currently lacking for the prediction of cognitive deterioration in Parkinson's disease. Additionally, finding dissociated relationships between nucleus basalis status and domain-specific cognitive decline has implications for understanding the neural basis of heterogeneity of Parkinson's disease-related cognitive decline. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.

Rare case of left-dominant arrhythmogenic right ventricular cardiomyopathy with dramatic reverse remodeling after cardiac resynchronization as an adjunct to pharmacological therapy.

PubMed

Hsiao, Chih-Chung; Kuo, Jen-Yuan; Yun, Chun-Ho; Hung, Chung-Lieh; Tsai, Cheng-Ho; Yeh, Hung-I

2012-01-01

A 57-year-old man presented with near syncope and hemodynamic compromise after exercise. A sustained ventricular tachycardia (VT) of right bundle-branch block morphology was evident upon examination at our emergency department. Baseline 12-lead electrocardiography revealed a sinus rhythm with a complete left bundle-branch block after successful cardioversion of the VT. Coronary angiography revealed patent coronary arteries, whereas left ventriculography demonstrated impaired systolic function, accompanied by a peculiar basal lateral aneurysm. Both echocardiography and magnetic resonance imaging were consistent with a diagnosis of left-dominant arrhythmogenic right ventricular cardiomyopathy. Four months later, substantial ventricular reverse remodeling and clinical improvements were observed after cardiac resynchronization therapy with a defibrillator, as an adjunct to conventional pharmacological therapy. Copyright © 2012 Elsevier Inc. All rights reserved.

The anteromedial approach to the psoas tendon in patients with cerebral palsy

PubMed Central

Poonnoose, Pradeep M.; Palocaren, Thomas

2007-01-01

Purpose Release of the psoas tendon for flexion deformity of the hip in children with cerebral palsy has traditionally been performed at the pelvic brim, lateral to the neurovascular bundle, or at its insertion into the lesser trochanter. As the psoas tendon is lateral to the pectineus, the traditional exposure of the tendon through an approach medial to the pectineus is limited by the extent to which the pectineus can be retracted proximally. Technical note We describe the use of the anteromedial approach used for the developmentally dislocated hip to expose the psoas tendon between the pectineus and the neurovascular bundle. This provides a much better visualisation of the tendon as it crosses the superior pubic ramus to its insertion. The use of this approach has not been described in cerebral palsy. PMID:19308518

Directional selectivity of afferent neurons in zebrafish neuromasts is regulated by Emx2 in presynaptic hair cells

PubMed Central

Ji, Young Rae; Warrier, Sunita; Jiang, Tao

2018-01-01

The orientation of hair bundles on top of sensory hair cells (HCs) in neuromasts of the lateral line system allows fish to detect direction of water flow. Each neuromast shows hair bundles arranged in two opposing directions and each afferent neuron innervates only HCs of the same orientation. Previously, we showed that this opposition is established by expression of Emx2 in half of the HCs, where it mediates hair bundle reversal (Jiang et al., 2017). Here, we show that Emx2 also regulates neuronal selection: afferent neurons innervate either Emx2-positive or negative HCs. In emx2 knockout and gain-of-function neuromasts, all HCs are unidirectional and the innervation patterns and physiological responses of the afferent neurons are dependent on the presence or absence of Emx2. Our results indicate that Emx2 mediates the directional selectivity of neuromasts by two distinct processes: regulating hair bundle orientation in HCs and selecting afferent neuronal targets. PMID:29671737

Studies on sodium boiling phenomena in out of pile rod bundles for various accidental situations in Liquid Metal Fast Breeder Reactors (LMFBR) experiments and interpretations

NASA Astrophysics Data System (ADS)

Seiler, J. M.; Rameau, B.

Bundle sodium boiling in nominal geometry for different accident conditions is reviewed. Voiding of a subassembly is controlled by not only hydrodynamic effects but mainly by thermal effects. There is a strong influence of the thermal inertia of the bundle material compared to the sodium thermal inertia. Flow instability, during a slow transient, can be analyzed with numerical tools and estimated using simplified approximations. Stable boiling operational conditions under bundle mixed convection (natural convection in the reactor) can be predicted. Voiding during a fast transient can be approximated from single channel calculations. The phenomenology of boiling behavior for a subassembly with inlet completely blocked, submitted to decay heat and lateral cooling; two-phase sodium flow pressure drop in a tube of large hydraulic diameter under adiabatic conditions; critical flow phenomena and voiding rate under high power, slow transient conditions; and onset of dry out under local boiling remains problematical.

Specific compartmental analysis of cartilage status in double-bundle ACL reconstruction patients: a comparative study using pre- and postoperative MR images.

PubMed

Lee, Yong Seuk; Jeong, Yu Mi; Sim, Jae Ang; Kwak, Ji Hoon; Kim, Kwang Hee; Nam, Shin Woo; Lee, Beom Koo

2013-03-01

The purpose of this study was to evaluate the changes in the site-specific cartilage status after a double-bundle ACL reconstruction using preoperative and follow-up MR images. Thirty-six knees that underwent a double-bundle ACL reconstruction from 2001 to 2009 with the available preoperative and follow-up magnetic resonance imaging were included. Patients with a meniscal injury were compared with those without a meniscal injury. The cartilage morphology was classified using a 6-grade scale [from 0 = normal thickness and signal, to 6 = diffuse full-thickness loss (>75 % of the region)]. The changes in cartilage status were evaluated at 14 sites. Cartilage changes were observed in all sites and were classified according to the site and degree of change. The majority of changes were grade 0 and 1, which accounted for 68 and 16.8 % of changes, respectively. The patella medial facet and anterolateral and centromedial femoral regions showed significantly more cartilage loss than the posteromedial, centrolateral, anterolateral, and anteromedial tibial regions. No significance was observed between the knees with or without combined injuries (n.s.). On the other hand, knees with or without combined injuries showed a different pattern of cartilage change, as demonstrated by different levels of grade change at sites. The change in cartilage status was minimal after a double-bundle ACL reconstruction. The patella medial facet, lateral femur anterior region, and medial femur central region showed significantly more cartilage loss than the medial tibia posterior, lateral tibia central, lateral tibia anterior, and medial tibia anterior regions. The presence of a combined injury did not affect the cartilage status changes, even though it was underpowered and too short term to assess the influence of the meniscal injury. Case series, Level IV.

Quantitative autoradiography of muscarinic and benzodiazepine receptors in the forebrain of the turtle, Pseudemys scripta

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

Schlegel, J.R.; Kriegstein, A.R.

1987-11-22

The distribution of muscarinic and benzodiazepine receptors was investigated in the turtle forebrain by the technique of in vitro receptor autoradiography. Muscarinic binding sites were labeled with 1 nM /sup 3/H-quinuclidinyl benzilate (/sup 3/H-QNB), and benzodiazepine sites were demonstrated with the aid of 1 nM /sup 3/H-flunitrazepam (/sup 3/H-FLU). Autoradiograms generated on /sup 3/H-Ultrofilm apposed to tissue slices revealed regionally specific distributions of muscarinic and benzodiazepine binding sites that are comparable with those for mammalian brain. Dense benzodiazepine binding was found in the anterior olfactory nucleus, the lateral and dorsal cortices, and the dorsal ventricular ridge (DVR), a structure withmore » no clear mammalian homologue. Muscarinic binding sites were most dense in the striatum, accumbens, DVR, lateral geniculate, and the anterior olfactory nucleus. Cortical binding sites were studied in greater detail by quantitative analysis of autoradiograms generated by using emulsion-coated coverslips. Laminar gradients of binding were observed that were specific for each radioligand; /sup 3/H-QNB sites were most dense in the inner molecular layer in all cortical regions, whereas /sup 3/H-FLU binding was generally most concentrated in the outer molecular layer and was least dense through all layers in the dorsomedial cortex. Because pyramidal cells are arranged in register in turtle cortex, the laminar patterns of receptor binding may reflect different receptor density gradients along pyramidal cell dendrites.« less

Eye field requires the function of Sfrp1 as a Wnt antagonist.

PubMed

Kim, Hyung-Seok; Shin, Jimann; Kim, Seok-Hyung; Chun, Hang-Suk; Kim, Jun-Dae; Kim, Young-Seop; Kim, Myoung-Jin; Rhee, Myungchull; Yeo, Sang-Yeob; Huh, Tae-Lin

2007-02-27

Wnts have been shown to provide a posteriorizing signal that has to be repressed in the specification of vertebrate forebrain region. Previous studies have shown that Wnt activation by LiCl treatment causes an expansion of optic stalk and mid-hindbrain boundary, whereas eye and ventral diencephalon in the forebrain region were reduced. However, the molecular mechanism, by which inhibits Wnt activity in the forebrain remains poorly defined. To investigate relationship between forebrain specification and Wnt signaling, the zebrafish homologue of secreted frizzled related protein1 (sfrp1) has been characterized. The transcripts of sfrp1 are detected in the presumptive forebrain at gastrula and in the ventral telencephalon, ventral diencephalon, midbrain and optic vesicles at 24h after postfertilization (hpf). Overexpression of sfrp1 causes an anteriorization of embryo, with enlarged head and reduced posterior structure as in the embryo overexpressing dominant-negative form of Frizzled8a or Dkk1. Its overexpression restored the eye defects in the Wnt8b-overexpressing embryos, but not in the LiCl-treated embryos. These results suggest that Sfrp1 expressed in the forebrain and eye field plays a critical role in the extracellular events of antagonizing Wnt activity for the forebrain specification.

Selective Activation of Basal Forebrain Cholinergic Neurons Attenuates Polymicrobial Sepsis-Induced Inflammation via the Cholinergic Anti-Inflammatory Pathway.

PubMed

Zhai, Qian; Lai, Dengming; Cui, Ping; Zhou, Rui; Chen, Qixing; Hou, Jinchao; Su, Yunting; Pan, Libiao; Ye, Hui; Zhao, Jing-Wei; Fang, Xiangming

2017-10-01

Basal forebrain cholinergic neurons are proposed as a major neuromodulatory system in inflammatory modulation. However, the function of basal forebrain cholinergic neurons in sepsis is unknown, and the neural pathways underlying cholinergic anti-inflammation remain unexplored. Animal research. University research laboratory. Male wild-type C57BL/6 mice and ChAT-ChR2-EYFP (ChAT) transgenic mice. The cholinergic neuronal activity of the basal forebrain was manipulated optogenetically. Cecal ligation and puncture was produced to induce sepsis. Left cervical vagotomy and 6-hydroxydopamine injection to the spleen were used. Photostimulation of basal forebrain cholinergic neurons induced a significant decrease in the levels of tumor necrosis factor-α and interleukin-6 in the serum and spleen. When cecal ligation and puncture was combined with left cervical vagotomy in photostimulated ChAT mice, these reductions in tumor necrosis factor-α and interleukin-6 were partly reversed. Furthermore, photostimulating basal forebrain cholinergic neurons induced a large increase in c-Fos expression in the basal forebrain, the dorsal motor nucleus of the vagus, and the ventral part of the solitary nucleus. Among them, 35.2% were tyrosine hydroxylase positive neurons. Furthermore, chemical denervation showed that dopaminergic neurotransmission to the spleen is indispensable for the anti-inflammation. These results are the first to demonstrate that selectively activating basal forebrain cholinergic neurons is sufficient to attenuate systemic inflammation in sepsis. Specifically, photostimulation of basal forebrain cholinergic neurons activated dopaminergic neurons in dorsal motor nucleus of the vagus/ventral part of the solitary nucleus, and this dopaminergic efferent signal was further transmitted by the vagus nerve to the spleen. This cholinergic-to-dopaminergic neural circuitry, connecting central cholinergic neurons to the peripheral organ, might have mediated the anti-inflammatory effect in sepsis.

Song environment affects singing effort and vasotocin immunoreactivity in the forebrain of male Lincoln’s sparrows

PubMed Central

Sewall, Kendra B.; Dankoski, Elyse C.; Sockman, Keith W.

2010-01-01

Male songbirds often establish territories and attract mates by singing, and some song features can reflect the singer’s condition or quality. The quality of the song environment can change, so male songbirds should benefit from assessing the competitiveness of the song environment and appropriately adjusting their own singing behavior and the neural substrates by which song is controlled. In a wide range of taxa social modulation of behavior is partly mediated by the arginine vasopressin or vasotocin (AVP/AVT) systems. To examine the modulation of singing behavior in response to the quality of the song environment we compared the song output of laboratory-housed male Lincoln’s sparrows (Melospiza lincolnii) exposed to one week of chronic playback of songs categorized as either high or low quality, based on song length, complexity and trill performance. To explore the neural basis of any facultative shifts in behavior, we also quantified the subjects’ AVT immunoreactivity (AVT-IR) in three forebrain regions that regulate socio-sexual behavior: the medial bed nucleus of the stria terminalis (BSTm), the lateral septum (LS) and the preoptic area. We found that high quality songs increased singing effort and reduced AVT-IR in the BSTm and LS, relative to low quality songs. The effect of the quality of the song environment on both singing effort and forebrain AVT-IR raises the hypothesis that AVT within these brain regions plays a role in the modulation of behavior in response to competition that individual males may assess from the prevailing song environment. PMID:20399213

Suppression of third ventricular NPY-elicited feeding following medullary reticular formation infusions of muscimol.

PubMed

Travers, Joseph B; Herman, Kenneth; Travers, Susan P

2010-04-01

The appetitive component of feeding is controlled by forebrain substrates, but the consummatory behaviors of licking, mastication, and swallowing are organized in the brainstem. The target of forebrain appetitive signals is unclear but likely includes regions of the medullary reticular formation (RF). This study was undertaken to determine the necessity of different RF regions for mastication induced by a descending appetitive signal. We measured solid food intake in response to third ventricular (3V) infusions of the orexigenic peptide neuropeptide Y 3-36 in awake, freely moving rats and determined whether focal RF infusions of the GABAA agonist muscimol suppressed eating. RF infusions were centered in either the lateral tegmental field, comprising the intermediate (IRt) and parvocellular (PCRt) RF, or in the nucleus gigantocellularis (Gi). Infusions of NPY 3-36 (5 microg/5 microl) into 3V significantly increased feeding of solid food over a 90-min period compared with the noninfused condition (4.3 g +/- 0.56 vs. 0.57 g +/- 0.57, p < .001). NPY 3-36-induced food intake was suppressed (1.7 g +/- 0.48) by simultaneous infusions of muscimol (0.6 mM/100 nl) into the IRt/PCRt (p < .01). Coincident with the decrease in feeding was a decrease in the amplitude of anterior digastric muscle contractions in response to intraoral sucrose infusions. In contrast, infusions of muscimol into Gi had no discernible effect on food intake or EMG amplitude. These data suggest that the IRt/PCRt is essential for forebrain-initiated mastication, but that the Gi is not a necessary link in this pathway.

Immunocytochemical localization of choline acetyltransferase-like immunoreactivity in the guinea pig cochlea.

PubMed

Altschuler, R A; Kachar, B; Rubio, J A; Parakkal, M H; Fex, J

1985-07-08

The immunocytochemical localization of the enzyme choline acetyltransferase (ChAT) was examined in the guinea pig organ of Corti to determine if both lateral and medial systems of efferents would show immunoreactive labeling for this specific enzyme marker of cholinergic neurons. Cochleae were also examined after lesion of efferents to determine if ChAT-like immunoreactivity is confined to efferents. ChAT-like immunoreactivity was seen in the inner spiral bundle, tunnel spiral bundle and by the bases of inner hair cells corresponding to the lateral system of efferents. ChAT-like immunoreactivity was also seen in crossing fibers and puncta at the bases and by the nuclei of outer hair cells corresponding to the medial system of efferents. With the use of video enhanced contrast microscopy more than 9 ChAT-like immunoreactive puncta at the bases of outer hair cells could be resolved. In cochleae examined 6 weeks after ipsilateral lesion of efferents, no ChAT-like immunoreactivity was observed. These results add strong evidence that acetylcholine is a transmitter of both the medial and lateral systems of efferents.

Hippocampal Sclerosis but Not Normal Aging or Alzheimer Disease Is Associated With TDP-43 Pathology in the Basal Forebrain of Aged Persons.

PubMed

Cykowski, Matthew D; Takei, Hidehiro; Van Eldik, Linda J; Schmitt, Frederick A; Jicha, Gregory A; Powell, Suzanne Z; Nelson, Peter T

2016-05-01

Transactivating responsive sequence (TAR) DNA-binding protein 43-kDa (TDP-43) pathology has been described in various brain diseases, but the full anatomical distribution and clinical and biological implications of that pathology are incompletely characterized. Here, we describe TDP-43 neuropathology in the basal forebrain, hypothalamus, and adjacent nuclei in 98 individuals (mean age, 86 years; median final mini-mental state examination score, 27). On examination blinded to clinical and pathologic diagnoses, we identified TDP-43 pathology that most frequently involved the ventromedial basal forebrain in 19 individuals (19.4%). As expected, many of these brains had comorbid pathologies including those of Alzheimer disease (AD), Lewy body disease (LBD), and/or hippocampal sclerosis of aging (HS-Aging). The basal forebrain TDP-43 pathology was strongly associated with comorbid HS-Aging (odds ratio = 6.8, p = 0.001), whereas there was no significant association between basal forebrain TDP-43 pathology and either AD or LBD neuropathology. In this sample, there were some cases with apparent preclinical TDP-43 pathology in the basal forebrain that may indicate that this is an early affected area in HS-Aging. We conclude that TDP-43 pathology in the basal forebrain is strongly associated with HS-Aging. These results raise questions about a specific pathogenetic relationship between basal forebrain TDP-43 and non-HS-Aging comorbid diseases (AD and LBD). © 2016 American Association of Neuropathologists, Inc. All rights reserved.

Hippocampal Sclerosis but Not Normal Aging or Alzheimer Disease Is Associated With TDP-43 Pathology in the Basal Forebrain of Aged Persons

PubMed Central

Takei, Hidehiro; Van Eldik, Linda J.; Schmitt, Frederick A.; Jicha, Gregory A.; Powell, Suzanne Z.; Nelson, Peter T.

2016-01-01

Transactivating responsive sequence (TAR) DNA-binding protein 43-kDa (TDP-43) pathology has been described in various brain diseases, but the full anatomical distribution and clinical and biological implications of that pathology are incompletely characterized. Here, we describe TDP-43 neuropathology in the basal forebrain, hypothalamus, and adjacent nuclei in 98 individuals (mean age, 86 years; median final mini-mental state examination score, 27). On examination blinded to clinical and pathologic diagnoses, we identified TDP-43 pathology that most frequently involved the ventromedial basal forebrain in 19 individuals (19.4%). As expected, many of these brains had comorbid pathologies including those of Alzheimer disease (AD), Lewy body disease (LBD), and/or hippocampal sclerosis of aging (HS-Aging). The basal forebrain TDP-43 pathology was strongly associated with comorbid HS-Aging (odds ratio = 6.8, p = 0.001), whereas there was no significant association between basal forebrain TDP-43 pathology and either AD or LBD neuropathology. In this sample, there were some cases with apparent preclinical TDP-43 pathology in the basal forebrain that may indicate that this is an early affected area in HS-Aging. We conclude that TDP-43 pathology in the basal forebrain is strongly associated with HS-Aging. These results raise questions about a specific pathogenetic relationship between basal forebrain TDP-43 and non-HS-Aging comorbid diseases (AD and LBD). PMID:26971127

Kinematics of ACL and anterolateral ligament. Part II: anterolateral and anterior cruciate ligament reconstruction.

PubMed

Bonanzinga, T; Signorelli, C; Grassi, A; Lopomo, N; Jain, M; Mosca, M; Iacono, F; Marcacci, M; Zaffagnini, S

2017-04-01

To quantify the influence of Single-Bundle with Lateral Plasty and Double-Bundle reconstruction on static and dynamic laxity in combined ACL- and ALL-deficient knees. The study included 10 fresh-frozen human knees. The joints were analyzed in the following conditions: ACL + ALL resection, Single-Bundle with Lateral Plasty (SBLP) reconstruction, Double-Bundle (DB) reconstruction. Testing parameters were: anterior displacement at 30° and 90° of flexion (AP30, AP90) applying a manual maximum load; internal rotation at 30° and 90° of flexion (INT30, INT90) applying a 5 Nm torque and acceleration and internal rotation Pivot-Shift (PS) test. Kinematics was acquired by a navigation system. Paired Student's t test was conducted to assess statistical difference (P < 0.05). At both 30° and 90° of knee flexion, both SBLP and DB surgical techniques showed a significant reduction (P < 0.01) of anterior-posterior tibial displacement compared to the resection of ACL + ALL. At 30° on knee flexion it is the SBLP that allows the greatest reduction of internal rotational laxity when compared to DB reconstruction. Concerning the PS test, only SBPL procedure had a significant laxity decrease considering the acceleration reached by the joint when compared with the ACL + ALL state (P < 0.01). Clinical relevance of this study is that the internal rotation and PS test were more efficiently controlled by the SBLP technique than by the DB one at both 30° and 90° of flexion in case of ACL + ALL lesions.

Choline acetyltransferase (ChAT) immunoelectron microscopy distinguishes at least three types of efferent synapses in the organ of Corti.

PubMed

Eybalin, M; Pujol, R

1987-01-01

Using anatomical criteria, the olivo-cochlear fibers ending in the organ of Corti (efferent fibers) have recently been separated into two systems: a lateral system innervating principally the inner hair cell (IHC) area and a medial system innervating mainly the outer hair cells (OHCs). Electrophysiological and biochemical experiments suggest that acetylcholine may be a neurotransmitter of these efferent fibers. However, efferent synapses that use acetylcholine as neurotransmitter have not yet been identified at the electron microscopic level. Using a pre-embedding immunoelectron microscopic technique with a monoclonal antibody against choline acetyltransferase (ChAT), we localized ChAT-immunostained fibers below both the IHCs and OHCs. In the inner spiral bundle, one type of ChAT-immunostained fibers was vesiculated and formed axo-dendritic synapses with the afferent auditory dendrites contacting the inner hair cells. A second type of ChAT-immunostained fibers seen in the inner spiral bundle was unvesiculated. Unstained vesiculated varicosities synapsing with the auditory dendrites were also seen in the inner spiral bundle. At the OHC level, ChAT immunostaining was found in nearly all the terminals synapsing with the OHCs. The finding of two types of ChAT-immunostained efferent synapses in the organ of Corti, i.e. axo-dendritic synapses in the inner spiral bundle and axo-somatic synapses with the OHCs, supports the hypothesis that both the lateral and the medial olivo-cochlear systems use acetylcholine as a neurotransmitter. The finding of numerous unstained synapses in the inner spiral bundle, and some below OHCs, together with previous data about putative cochlear neurotransmitters, suggests the possibility of additional non-cholinergic olivo-cochlear systems. It might soon appear useful to reclassify efferents according to the nature of the different neurotransmitters/co-transmitters found in the various efferent synapses of the organ of Corti.

Fourth ventricle injection of ghrelin decreases angiotensin II-induced fluid intake and neuronal activation in the paraventricular nucleus of the hypothalamus.

PubMed

Plyler, Kimberly S; Daniels, Derek

2017-09-01

Ghrelin acts in the CNS to decrease fluid intake under a variety of dipsogenic and natriorexigenic conditions. Previous studies on this topic, however, focused on the forebrain as a site of action for this effect of ghrelin. Because the hindbrain contains neural substrates that are capable of mediating the well-established orexigenic effects of ghrelin, the current study tested the hypothesis that ghrelin applied to the hindbrain also would affect fluid intake. To this end, water and saline intakes were stimulated by central injection of angiotensin II (AngII) in rats that also received injections of ghrelin (0.5μg/μl) into either the lateral or fourth ventricle. Ghrelin injected into either ventricle reduced both water and 1.8% NaCl intake that was stimulated by AngII. The nature of the intake effect revealed some differences between the injection sites. For example, forebrain application of ghrelin reduced saline intake by a reduction in both the number of licking bursts and the size of each licking burst, but hindbrain application of ghrelin had a more selective effect on burst number. In an attempt to elucidate a brain structure in which hindbrain-administered ghrelin and forebrain-administered AngII interact to cause the ingestive response, we used Fos-immunohistochemistry in rats given the treatments used in the behavioral experiments. Although several brain areas were found to respond to either ghrelin or AngII, of the sites examined, only the paraventricular nucleus of the hypothalamus (PVN) emerged as a potential site of interaction. Specifically, AngII treatment caused expression of Fos in the PVN that was attenuated by concomitant treatment with ghrelin. These experiments provide the novel finding that the hindbrain contains elements that can respond to ghrelin and cause decreases in AngII-induced fluid intake, and that direct actions by ghrelin on forebrain structures is not necessary. Moreover, these studies suggest that the PVN is an important site of interaction between these two peptides. Copyright © 2016 Elsevier Inc. All rights reserved.

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

PubMed Central

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

2017-01-01

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

Basal Forebrain Gating by Somatostatin Neurons Drives Prefrontal Cortical Activity.

PubMed

Espinosa, Nelson; Alonso, Alejandra; Morales, Cristian; Espinosa, Pedro; Chávez, Andrés E; Fuentealba, Pablo

2017-11-17

The basal forebrain provides modulatory input to the cortex regulating brain states and cognitive processing. Somatostatin-expressing neurons constitute a heterogeneous GABAergic population known to functionally inhibit basal forebrain cortically projecting cells thus favoring sleep and cortical synchronization. However, it remains unclear if somatostatin cells can regulate population activity patterns in the basal forebrain and modulate cortical dynamics. Here, we demonstrate that somatostatin neurons regulate the corticopetal synaptic output of the basal forebrain impinging on cortical activity and behavior. Optogenetic inactivation of somatostatin neurons in vivo rapidly modified neural activity in the basal forebrain, with the consequent enhancement and desynchronization of activity in the prefrontal cortex, reflected in both neuronal spiking and network oscillations. Cortical activation was partially dependent on cholinergic transmission, suppressing slow waves and potentiating gamma oscillations. In addition, recruitment dynamics was cell type-specific, with interneurons showing similar temporal profiles, but stronger responses than pyramidal cells. Finally, optogenetic stimulation of quiescent animals during resting periods prompted locomotor activity, suggesting generalized cortical activation and increased arousal. Altogether, we provide physiological and behavioral evidence indicating that somatostatin neurons are pivotal in gating the synaptic output of the basal forebrain, thus indirectly controlling cortical operations via both cholinergic and non-cholinergic mechanisms. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Combined use of clips and nylon snare ("tulip-bundle") as a rescue endoscopic bleeding control in a mallory-weiss syndrome.

PubMed

Ivekovic, Hrvoje; Radulovic, Bojana; Jankovic, Suzana; Markos, Pave; Rustemovic, Nadan

2014-01-01

Mallory-Weiss syndrome (MWS) accounts for 6-14% of all cases of upper gastrointestinal bleeding. Prognosis of patients with MWS is generally good, with a benign course and rare recurrence of bleeding. However, no strict recommendations exist in regard to the mode of action after a failure of primary endoscopic hemostasis. We report a case of an 83-year-old male with MWS and rebleeding after the initial endoscopic treatment with epinephrine and clips. The final endoscopic control of bleeding was achieved by a combined application of clips and a nylon snare in a "tulip-bundle" fashion. The patient had an uneventful postprocedural clinical course and was discharged from the hospital five days later. To the best of our knowledge, this is the first case report showing the "tulip-bundle" technique as a rescue endoscopic bleeding control in the esophagus.

Basal forebrain projections to the lateral habenula modulate aggression reward.

PubMed

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

2016-06-30

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

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

PubMed

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

2016-07-15

A large body of literature has shown that the disruption of circadian clock timing has profound effects on mood, memory and complex thinking. Central to this time keeping process is the master circadian pacemaker located within the suprachiasmatic nucleus (SCN). Of note, within the central nervous system, clock timing is not exclusive to the SCN, but rather, ancillary oscillatory capacity has been detected in a wide range of cell types and brain regions, including forebrain circuits that underlie complex cognitive processes. These observations raise questions about the hierarchical and functional relationship between the SCN and forebrain oscillators, and, relatedly, about the underlying clock-gated synaptic circuitry that modulates cognition. Here, we utilized a clock knockout strategy in which the essential circadian timing gene Bmal1 was selectively deleted from excitatory forebrain neurons, whilst the SCN clock remained intact, to test the role of forebrain clock timing in learning, memory, anxiety, and behavioral despair. With this model system, we observed numerous effects on hippocampus-dependent measures of cognition. Mice lacking forebrain Bmal1 exhibited deficits in both acquisition and recall on the Barnes maze. Notably, loss of forebrain Bmal1 abrogated time-of-day dependent novel object location memory. However, the loss of Bmal1 did not alter performance on the elevated plus maze, open field assay, and tail suspension test, indicating that this phenotype specifically impairs cognition but not affect. Together, these data suggest that forebrain clock timing plays a critical role in shaping the efficiency of learning and memory retrieval over the circadian day. Copyright © 2016 Elsevier B.V. All rights reserved.

Umbilical cord mesenchymal stem cells labeled with multimodal iron oxide nanoparticles with fluorescent and magnetic properties: application for in vivo cell tracking

PubMed Central

Sibov, Tatiana T; Pavon, Lorena F; Miyaki, Liza A; Mamani, Javier B; Nucci, Leopoldo P; Alvarim, Larissa T; Silveira, Paulo H; Marti, Luciana C; Gamarra, LF

2014-01-01

Here we describe multimodal iron oxide nanoparticles conjugated to Rhodamine-B (MION-Rh), their stability in culture medium, and subsequent validation of an in vitro protocol to label mesenchymal stem cells from umbilical cord blood (UC-MSC) with MION-Rh. These cells showed robust labeling in vitro without impairment of their functional properties, the viability of which were evaluated by proliferation kinetic and ultrastructural analyzes. Thus, labeled cells were infused into striatum of adult male rats of animal model that mimic late onset of Parkinson’s disease and, after 15 days, it was observed that cells migrated along the medial forebrain bundle to the substantia nigra as hypointense spots in T2 magnetic resonance imaging. These data were supported by short-term magnetic resonance imaging. Studies were performed in vivo, which showed that about 5 × 105 cells could be efficiently detected in the short term following infusion. Our results indicate that these labeled cells can be efficiently tracked in a neurodegenerative disease model. PMID:24531365

Cocaine enhances resistance to extinction of responding for brain-stimulation reward in adult prenatally stressed rats.

PubMed

Gao, Shuibo; Suenaga, Toshiko; Oki, Yutaka; Yukie, Masao; Nakahara, Daiichiro

2011-10-01

The present experiment assessed whether prenatal stress (PS) can alter the ability of acute and chronic cocaine administration to increase and decrease the rewarding effectiveness of the medial forebrain bundle (MFB) using intracranial self-stimulation (ICSS), and also whether PS can affect the extinction of the MFB stimulation response. Adult male offspring of female rats that received PS or no PS (nPS) were implanted with MFB stimulating electrodes, and were then tested in ICSS paradigms. In both nPS and PS offspring, acute cocaine injection decreased ICSS thresholds dose-dependently. However, the threshold-lowering effects at any dose were not significantly different between groups. There was also no group-difference in the threshold-elevating effects of chronic cocaine administration. Nevertheless, chronically drug-administered PS rats exhibited a resistance to the extinguishing of the response for brain-stimulation reward when acutely treated with cocaine, as compared to extinction without cocaine treatment. The results suggest that PS may weaken the ability for response inhibition under cocaine loading in male adult offspring. Copyright © 2011 Elsevier B.V. All rights reserved.

Enriched environment protects the nigrostriatal dopaminergic system and induces astroglial reaction in the 6-OHDA rat model of Parkinson's disease.

PubMed

Anastasía, Agustín; Torre, Luciana; de Erausquin, Gabriel A; Mascó, Daniel H

2009-05-01

Enriched environment (EE) is neuroprotective in several animal models of neurodegeneration. It stimulates the expression of trophic factors and modifies the astrocyte cell population which has been said to exert neuroprotective effects. We have investigated the effects of EE on 6-hydroxydopamine (6-OHDA)-induced neuronal death after unilateral administration to the medial forebrain bundle, which reaches 85-95% of dopaminergic neurons in the substantia nigra after 3 weeks. Continuous exposure to EE 3 weeks before and after 6-OHDA injection prevents neuronal death (assessed by tyrosine hydroxylase staining), protects the nigrostriatal pathway (assessed by Fluorogold retrograde labeling) and reduces motor impairment. Four days after 6-OHDA injection, EE was associated with a marked increase in glial fibrillary acidic protein staining and prevented neuronal death (assessed by Fluoro Jade-B) but not partial loss of tyrosine hydroxylase staining in the anterior substantia nigra. These results robustly demonstrate that EE preserves the entire nigrostriatal system against 6-OHDA-induced toxicity, and suggests that an early post-lesion astrocytic reaction may participate in the neuroprotective mechanism.

Reward magnitude tracking by neural populations in ventral striatum

PubMed Central

Fiallos, Ana M.; Bricault, Sarah J.; Cai, Lili X.; Worku, Hermoon A.; Colonnese, Matthew T.; Westmeyer, Gil; Jasanoff, Alan

2017-01-01

Evaluation of the magnitudes of intrinsically rewarding stimuli is essential for assigning value and guiding behavior. By combining parametric manipulation of a primary reward, medial forebrain bundle (MFB) microstimulation, with functional magnetic imaging (fMRI) in rodents, we delineated a broad network of structures activated by behaviorally characterized levels of rewarding stimulation. Correlation of psychometric behavioral measurements with fMRI response magnitudes revealed regions whose activity corresponded closely to the subjective magnitude of rewards. The largest and most reliable focus of reward magnitude tracking was observed in the shell region of the nucleus accumbens (NAc). Although the nonlinear nature of neurovascular coupling complicates interpretation of fMRI findings in precise neurophysiological terms, reward magnitude tracking was not observed in vascular compartments and could not be explained by saturation of region-specific hemodynamic responses. In addition, local pharmacological inactivation of NAc changed the profile of animals’ responses to rewards of different magnitudes without altering mean reward response rates, further supporting a hypothesis that neural population activity in this region contributes to assessment of reward magnitudes. PMID:27789262

Effects of Icariside II on Corpus Cavernosum and Major Pelvic Ganglion Neuropathy in Streptozotocin-Induced Diabetic Rats

PubMed Central

Bai, Guang-Yi; Zhou, Feng; Hui, Yu; Xu, Yong-De; Lei, Hong-En; Pu, Jin-Xian; Xin, Zhong-Cheng

2014-01-01

Diabetic erectile dysfunction is associated with penile dorsal nerve bundle neuropathy in the corpus cavernosum and the mechanism is not well understood. We investigated the neuropathy changes in the corpus cavernosum of rats with streptozotocin-induced diabetes and the effects of Icariside II (ICA II) on improving neuropathy. Thirty-six 8-week-old Sprague-Dawley rats were randomly distributed into normal control group, diabetic group and ICA-II treated group. Diabetes was induced by a one-time intraperitoneal injection of streptozotocin (60 mg/kg). Three days later, the diabetic rats were randomly divided into 2 groups including a saline treated placebo group and an ICA II-treated group (5 mg/kg/day, by intragastric administration daily). Twelve weeks later, erectile function was measured by cavernous nerve electrostimulation with real time intracorporal pressure assessment. The penis was harvested for the histological examination (immunofluorescence and immunohistochemical staining) and transmission electron microscopy detecting. Diabetic animals exhibited a decreased density of dorsal nerve bundle in penis. The neurofilament of the dorsal nerve bundle was fragmented in the diabetic rats. There was a decreased expression of nNOS and NGF in the diabetic group. The ICA II group had higher density of dorsal nerve bundle, higher expression of NGF and nNOS in the penis. The pathological change of major pelvic nerve ganglion (including the microstructure by transmission electron microscope and the neurite outgrowth length of major pelvic nerve ganglion tissue cultured in vitro) was greatly attenuated in the ICA II-treated group (p < 0.01). ICA II treatment attenuates the diabetes-related impairment of corpus cavernosum and major pelvic ganglion neuropathy in rats with Streptozotocin-Induced Diabetes. PMID:25517034

Histological analysis of the structural composition of ankle ligaments.

PubMed

Rein, Susanne; Hagert, Elisabet; Schneiders, Wolfgang; Fieguth, Armin; Zwipp, Hans

2015-02-01

Various ankle ligaments have different structural composition. The aim of this study was to analyze the morphological structure of ankle ligaments to further understand their function in ankle stability. One hundred forty ligaments from 10 fresh-frozen cadaver ankle joints were dissected: the calcaneofibular, anterior, and posterior talofibular ligaments; the inferior extensor retinaculum, the talocalcaneal oblique ligament, the canalis tarsi ligament; the deltoid ligament; and the anterior tibiofibular ligament. Hematoxylin-eosin and Elastica van Gieson stains were used for determination of tissue morphology. Three different morphological compositions were identified: dense, mixed, and interlaced compositions. Densely packed ligaments, characterized by parallel bundles of collagen, were primarily seen in the lateral region, the canalis tarsi, and the anterior tibiofibular ligaments. Ligaments with mixed tight and loose parallel bundles of collagenous connective tissue were mainly found in the inferior extensor retinaculum and talocalcaneal oblique ligament. Densely packed and fiber-rich interlacing collagen was primarily seen in the areas of ligament insertion into bone of the deltoid ligament. Ligaments of the lateral region, the canalis tarsi, and the anterior tibiofibular ligaments have tightly packed, parallel collagen bundles and thus can resist high tensile forces. The mixed tight and loose, parallel oriented collagenous connective tissue of the inferior extensor retinaculum and the talocalcaneal oblique ligament support the dynamic positioning of the foot on the ground. The interlacing collagen bundles seen at the insertion of the deltoid ligament suggest that these insertion areas are susceptible to tension in a multitude of directions. The morphology and mechanical properties of ankle ligaments may provide an understanding of their response to the loads to which they are subjected. © The Author(s) 2015.

An extended OpenSim knee model for analysis of strains of connective tissues.

PubMed

Marieswaran, M; Sikidar, Arnab; Goel, Anu; Joshi, Deepak; Kalyanasundaram, Dinesh

2018-04-17

OpenSim musculoskeletal models provide an accurate simulation environment that eases limitations of in vivo and in vitro studies. In this work, a biomechanical knee model was formulated with femoral articular cartilages and menisci along with 25 connective tissue bundles representing ligaments and capsules. The strain patterns of the connective tissues in the presence of femoral articular cartilage and menisci in the OpenSim knee model was probed in a first of its kind study. The effect of knee flexion (0°-120°), knee rotation (- 40° to 30°) and knee adduction (- 15° to 15°) on the anterior cruciate, posterior cruciate, medial collateral, lateral collateral ligaments and other connective tissues were studied by passive simulation. Further, a new parameter for assessment of strain namely, the differential inter-bundle strain of the connective tissues were analyzed to provide new insights for injury kinematics. ACL, PCL, LCL and PL was observed to follow a parabolic strain pattern during flexion while MCL represented linear strain patterns. All connective tissues showed non-symmetric parabolic strain variation during rotation. During adduction, the strain variation was linear for the knee bundles except for FL, PFL and TL. Strains higher than 0.1 were observed in most of the bundles during lateral rotation followed by abduction, medial rotation and adduction. In the case of flexion, highest strains were observed in aACL and aPCL. A combination of strains at a flexion of 0° with medial rotation of 30° or a flexion of 80° with rotation of 30° are evaluated as rupture-prone kinematics.

Axonal abnormalities in vanishing white matter.

PubMed

Klok, Melanie D; Bugiani, Marianna; de Vries, Sharon I; Gerritsen, Wouter; Breur, Marjolein; van der Sluis, Sophie; Heine, Vivi M; Kole, Maarten H P; Baron, Wia; van der Knaap, Marjo S

2018-04-01

We aimed to study the occurrence and development of axonal pathology and the influence of astrocytes in vanishing white matter. Axons and myelin were analyzed using electron microscopy and immunohistochemistry on Eif2b4 and Eif2b5 single- and double-mutant mice and patient brain tissue. In addition, astrocyte-forebrain co-culture studies were performed. In the corpus callosum of Eif2b5- mutant mice, myelin sheath thickness, axonal diameter, and G-ratio developed normally up to 4 months. At 7 months, however, axons had become thinner, while in control mice axonal diameters had increased further. Myelin sheath thickness remained close to normal, resulting in an abnormally low G-ratio in Eif2b5- mutant mice. In more severely affected Eif2b4-Eif2b5 double-mutants, similar abnormalities were already present at 4 months, while in milder affected Eif2b4 mutants, few abnormalities were observed at 7 months. Additionally, from 2 months onward an increased percentage of thin, unmyelinated axons and increased axonal density were present in Eif2b5 -mutant mice. Co-cultures showed that Eif2b5 mutant astrocytes induced increased axonal density, also in control forebrain tissue, and that control astrocytes induced normal axonal density, also in mutant forebrain tissue. In vanishing white matter patient brains, axons and myelin sheaths were thinner than normal in moderately and severely affected white matter. In mutant mice and patients, signs of axonal transport defects and cytoskeletal abnormalities were minimal. In vanishing white matter, axons are initially normal and atrophy later. Astrocytes are central in this process. If therapy becomes available, axonal pathology may be prevented with early intervention.

Brain regional differences in social encounter-induced Fos expression in male and female rats after post-weaning social isolation.

PubMed

Ahern, Megan; Goodell, Dayton J; Adams, Jessica; Bland, Sondra T

2016-01-01

Early life adversity has been related to a number of psychological disorders including mood and other disorders that can manifest as inappropriate or aggressive responses to social challenges. The present study used post-weaning social isolation (PSI) in rats, a model of early life adversity, to examine its effects on Fos protein expression produced by exposure to a novel social encounter. We have previously reported that the social encounter-induced increase in Fos expression in the medial prefrontal cortex observed in group-housed controls (GRP) was attenuated in rats that had experienced PSI. Here we assessed Fos expression in other brain regions thought to be involved in emotion regulation and social behavior. Male and female rats were housed in same-sex groups or in isolation (ISO) for 4 weeks beginning on postnatal day (P) 21 and were exposed to a single 15 min social encounter with a novel same-sex conspecific on P49. Fos positive cells were assessed using immunohistochemistry in 16 regions within the forebrain. Exposure to a novel conspecific increased Fos expression in the forebrain of GRP rats in a region- and sex-specific fashion. This increase was blunted or absent in ISO rats within many regions including cortical regions, thalamus, habenula, dentate gyrus, lateral septum, and basolateral amygdala. In several regions, the increase in Fos was greater in male than in female group housed rats. Negative relationships were observed between social interactions and Fos in some regions. Forebrain hypofunction produced by early-life adversity may be involved in socially inappropriate behavior. Copyright © 2015 Elsevier B.V. All rights reserved.

Multiple forebrain systems converge on motor neurons innervating the thyroarytenoid muscle

PubMed Central

Van Daele, Douglas J.; Cassell, Martin D.

2009-01-01

The present study investigated the central connections of motor neurons innervating the thyroarytenoid laryngeal muscle that is active in swallowing, respiration and vocalization. In both intact and sympathectomized rats, the pseudorabies virus (PRV) was inoculated into the muscle. After initial infection of laryngomotor neurons in the ipsilateral loose division of the nucleus ambiguous (NA) by 3 days post-inoculation., PRV spread to the ipsilateral compact portion of the NA, the central and intermediate divisions of the nucleus tractus solitarii (NTS), the Botzinger complex, and the parvocellular reticular formation by 4 days. Infection was subsequently expanded to include the ipsilateral granular and dysgranular parietal insular cortex, the ipsilateral medial division of the central nucleus of the amygdala, the lateral, paraventricular, ventrolateral and medial preoptic nuclei of the hypothalamus (generally bilaterally), the lateral periaqueductal gray, the A7 and oral and caudal pontine nuclei. At the latest time points sampled post-inoculation (5 days), infected neurons were identified in the ipsilateral agranular insular cortex, the caudal parietal insular cortex, the anterior cingulate cortex, and the contralateral motor cortex. In the amygdala, infection had spread to the lateral central nucleus and the parvocellular portion of the basolateral nucleus. Hypothalamic infection was largely characterized by an increase in the number of infected cells in earlier infected regions though the posterior, dorsomedial, tuberomammillary and mammillary nuclei contained infected cells. Comparison with previous connectional data suggest PRV followed three interconnected systems originating in the forebrain; a bilateral system including the ventral anterior cingulate cortex, periaqueductal gray and ventral respiratory group; an ipsilateral system involving the parietal insular cortex, central nucleus of the amygdala and parvicellular reticular formation, and a minor contralateral system originating in motor cortex. Hypothalamic innervation involved several functionally specific nuclei. Overall, the data imply complex central nervous system control over the multi-functional thyroarytenoid muscle.[297 words] PMID:19426785

Regional acetylcholinesterase activity and its correlation with behavioral performances in 15-month old transgenic mice expressing the human C99 fragment of APP.

PubMed

Dumont, M; Lalonde, R; Ghersi-Egea, J-F; Fukuchi, K; Strazielle, C

2006-09-01

In addition to Abeta plaques and neurofibrillary tangles, Alzheimer's disease (AD) is characterized by increased brain levels of APP C-terminal fragments. In the present investigation, the cholinergic innervation in forebrain regions of transgenic mice (Tg13592) expressing the human betaAPP C99 fragment was compared to that of non-transgenic controls by measuring the activity of the non-specific catabolic enzyme, acetylcholinesterase (AChE). The AchE activity of Tg13592 mice was altered in several regions implicated in the functional loop of regulation between septum and hippocampus, vulnerable in Alzheimer pathology and critically involved in cognitive functions. In particular, AChE activity was upregulated in three basal forebrain regions containing cholinergic cell bodies, prelimbic cortex, anterior subiculum, and paraventricular thalamus, but downregulated in lateral septum and reticular thalamus. The increased activity in medial septum and anterior subiculum was linearly correlated with poor performances in a spatial learning task, possibly due to cell stress mechanisms. Because of some similarities in terms of neurochemistry and behavior, this mouse model may be of use for studying prodromal AD.

A stereotaxic atlas of the forebrain of the bank vole (Clethrionomys glareolus).

PubMed

Vandebroek, I; Bouche, K; D'Herde, K; Caemaert, J; Roels, F; Odberg, F O

1999-04-01

In this article part of the forebrain of the bank vole (Clethrionomys glareolus) is presented in stereotaxic coordinates. The stereotaxic procedure was performed as follows. With the vole's head mounted in a stereotaxic adaptor, internal reference tracks were made with a 0.5-mm diameter microdialysis cannula and India ink, 2 mm in front and 2.6 mm behind the skull landmark bregma. Brains were fixed for 72 h in 4% commercial formaldehyde in sodiumcacodylate buffer containing 1% CaCl2. To determine shrinkage they were weighed before and after fixation. After embedding in paraffin they were sectioned at 25 microm and stained with Nissl. Photomicrographs were taken from the brain of one animal while its frontal (antero-posterior) coordinates of five neural structures were compared with those of 12 other voles. Variability was also checked in lateral and vertical directions at frontal level -1.0 mm (relative to bregma). The results show that the distance between the two skull landmarks bregma and lambda correlates significantly and negatively with the antero-posterior position of each of the brain areas. On the basis of these results an equation is proposed to improve accuracy in locating neural structures that deviate due to biological variability.

Genomic Perspectives of Transcriptional Regulation in Forebrain Development

DOE PAGES

Nord, Alex S.; Pattabiraman, Kartik; Visel, Axel; ...

2015-01-07

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

Posterior root tear fixation of the lateral meniscus combined with arthroscopic ACL double-bundle reconstruction: technical note of a transosseous fixation using the tibial PL tunnel.

PubMed

Forkel, Philipp; Petersen, Wolf

2012-03-01

According to our observation in ACL reconstruction, we find root tears of the posterior horn of the lateral meniscus as a common concomitant injury in ACL-deficient knees. This might be a consequence of initial trauma or of the increased anterior-posterior translation of the tibia and an overload impact on the posterior meniscus root in ACL-deficient knees. A tear of the posterior horn of the medial meniscus causes a 25% increase in peak pressure in the medial compartment compared with that found in the intact condition. The repair restores the peak contact pressure to normal (Allaire et al. in J Bone Joint Surg Am 90(9):1922-1931, [2008]). A tear of the posterior horn of the lateral meniscus might have similar consequences. We hypothesize the surgical anatomical reattachment of the root at the tibia helping to restore knee joint kinematics and helping to advance ACL-graft function. This article presents an arthroscopical technique to reattach the posterior meniscus root in combination with ACL double-bundle reconstruction. The procedure uses the tibial PL tunnel to fix the meniscus suture.

Tibial tunnel aperture location during single-bundle posterior cruciate ligament reconstruction: comparison of tibial guide positions.

PubMed

Shin, Young-Soo; Han, Seung-Beom; Hwang, Yeok-Ku; Suh, Dong-Won; Lee, Dae-Hee

2015-05-01

We aimed to compare posterior cruciate ligament (PCL) tibial tunnel location after tibial guide insertion medial (between the PCL remnant and the medial femoral condyle) and lateral (between the PCL remnant and the anterior cruciate ligament) to the PCL stump as determined by in vivo 3-dimensional computed tomography (3D-CT). Tibial tunnel aperture location was analyzed by immediate postoperative in vivo CT in 66 patients who underwent single-bundle PCL reconstruction, 31 by over-the-PCL and 35 by under-the-PCL tibial guide insertion techniques. Tibial tunnel positions were measured in the medial to lateral and proximal to distal directions of the posterior proximal tibia. The center of the tibial tunnel aperture was located more laterally (by 2.7 mm) in the over-the-PCL group than in the under-the-PCL group (P = .040) and by a relative percentage (absolute value/tibial width) of 3.2% (P = .031). Tibial tunnel positions in the proximal to distal direction, determined by absolute value and relative percentage, were similar in the 2 groups. Tibial tunnel apertures were located more laterally after lateral-to-the-PCL tibial guide insertion than after medial-to-the-PCL tibial guide insertion. There was, however, no significant difference between these techniques in distance from the joint line to the tibial tunnel aperture. Insertion lateral to the PCL stump may result in better placement of the PCL in its anatomic footprint. Level III, retrospective comparative study. Copyright © 2015 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

Photoacoustic endoscopy probe using a coherent fibre-optic bundle and Fabry-Pérot ultrasound sensor (Conference Presentation)

NASA Astrophysics Data System (ADS)

Ansari, Rehman; Beard, Paul C.; Zhang, Edward Z.; Desjardins, Adrien E.

2016-03-01

There is considerable interest in the development of photoacoustic endoscopy (PAE) probes for the clinical assessment of pathologies in the gastrointestinal (GI) tract, guiding minimally invasive laparoscopic surgeries and applications in foetal medicine. However, most previous PAE probes integrate mechanical scanners and piezoelectric transducers at the distal end which can be technically complex, expensive and pose challenges in achieving the necessary level of miniaturisation. We present two novel all-optical forward-viewing endoscopic probes operating in widefield tomography mode that have the potential to overcome these limitations. In one configuration, the probe comprises a transparent 40 MHz Fabry-Pérot ultrasound sensor deposited at the tip of a rigid, 3 mm diameter coherent fibre-optic bundle. In this way, the distal end of coherent fibre bundle acts as a 2D array of wideband ultrasound detectors. In another configuration, an optical relay is used between the distal end face of flexible fibre bundle and the Fabry-Pérot sensor to enlarge the lateral field of view to 6 mm x 6 mm. In both configurations, the pulsed excitation laser beam is full-field coupled into the fibre bundle at the proximal end for uniform backward-mode illumination of the tissue at the probe tip. In order to record the photoacoustic waves arriving at the probe tip, the proximal end of the fibre bundle is optically scanned in 2D with a CW wavelength-tunable interrogation laser beam thereby interrogating different spatial points on the sensor. A time-reversal image reconstruction algorithm was used to reconstruct a 3D image from the detected signals. The 3D field of view of the flexible PAE probe is 6 mm x 6 mm x 6 mm and the axial and lateral spatial resolution is 30 µm and 90 µm, respectively. 3D imaging capability is demonstrated using tissue phantoms, ex vivo tissues and in vivo. To the best of our knowledge, this is the first forward-viewing implementation of a photoacoustic endoscopy probe, and it offers several advantages over previous distal-end scanning probes. These include a high degree of miniaturisation, no moving parts at the distal end and simple and inexpensive fabrication with the potential to realise disposable probes for clinical imaging of the GI tract and other minimally invasive applications.

Tibiofemoral joint contact area and pressure after single- and double-bundle anterior cruciate ligament reconstruction.

PubMed

Morimoto, Yusuke; Ferretti, Mario; Ekdahl, Max; Smolinski, Patrick; Fu, Freddie H

2009-01-01

The purpose of this study was to compare the tibiofemoral contact area and pressure after single-bundle (SB) and double-bundle (DB) anterior cruciate ligament (ACL) reconstruction by use of 2 femoral and 2 tibial tunnels in intact cadaveric knees. Tibiofemoral contact area and mean and maximum pressures were measured by pressure-sensitive film (Fujifilm, Valhalla, NY) inserted between the tibia and femur. The knee was subjected to a 1,000-N axial load by use of a uniaxial testing machine at 0 degrees , 15 degrees , 30 degrees , and 45 degrees of flexion. Three conditions were evaluated: (1) intact ACL, (2) SB ACL reconstruction (n = 10 knees), and (3) DB ACL reconstruction (n = 9 knees). When compared with the intact knee, DB ACL reconstruction showed no significant difference in tibiofemoral contact area and mean and maximum pressures. SB ACL reconstruction had a significantly smaller contact area on the lateral and medial tibiofemoral joints at 30 degrees and 15 degrees of flexion. SB ACL reconstruction also had significantly higher mean pressures at 15 degrees of flexion on the medial tibiofemoral joint and at 0 degrees and 15 degrees of flexion on the lateral tibiofemoral joint, as well as significantly higher maximum pressures at 15 degrees of flexion on the lateral tibiofemoral joint. SB ACL reconstruction resulted in a significantly smaller tibiofemoral contact area and higher pressures. DB ACL more closely restores the normal contact area and pressure mainly at low flexion angles. Our findings suggest that the changes in the contact area and pressures after SB ACL reconstruction may be one of the causes of osteoarthritis on long-term follow-up. DB ACL reconstruction may reduce the incidence of osteoarthritis by closely restoring contact area and pressure.

A nano-microstructured artificial-hair-cell-type sensor based on topologically graded 3D carbon nanotube bundles

NASA Astrophysics Data System (ADS)

Yilmazoglu, O.; Yadav, S.; Cicek, D.; Schneider, J. J.

2016-09-01

A design for a unique artificial-hair-cell-type sensor (AHCTS) based entirely on 3D-structured, vertically aligned carbon nanotube (CNT) bundles is introduced. Standard microfabrication techniques were used for the straightforward micro-nano integration of vertically aligned carbon nanotube arrays composed of low-layer multi-walled CNTs (two to six layers). The mechanical properties of the carbon nanotube bundles were intensively characterized with regard to various substrates and CNT morphology, e.g. bundle height. The CNT bundles display excellent flexibility and mechanical stability for lateral bending, showing high tear resistance. The integrated 3D CNT sensor can detect three-dimensional forces using the deflection or compression of a central CNT bundle which changes the contact resistance to the shorter neighboring bundles. The complete sensor system can be fabricated using a single chemical vapor deposition (CVD) process step. Moreover, sophisticated external contacts to the surroundings are not necessary for signal detection. No additional sensors or external bias for signal detection are required. This simplifies the miniaturization and the integration of these nanostructures for future microsystem set-ups. The new nanostructured sensor system exhibits an average sensitivity of 2100 ppm in the linear regime with the relative resistance change per micron (ppm μm-1) of the individual CNT bundle tip deflection. Furthermore, experiments have shown highly sensitive piezoresistive behavior with an electrical resistance decrease of up to ˜11% at 50 μm mechanical deflection. The detection sensitivity is as low as 1 μm of deflection, and thus highly comparable with the tactile hair sensors of insects, having typical thresholds on the order of 30-50 μm. The AHCTS can easily be adapted and applied as a flow, tactile or acceleration sensor as well as a vibration sensor. Potential applications of the latter might come up in artificial cochlear systems. In particular, the stable mechanical bending of the sensor up to 90° opens up unique application opportunities.

Needle endomicroscope with a plastic, achromatic objective to perform optical biopsies of breast tissue

NASA Astrophysics Data System (ADS)

Kyrish, Matthew; Dobbs, Jessica; Richards-Kortum, Rebecca; Tkaczyk, Tomasz

2013-03-01

In order to diagnose cancer in breast tissue, a sample must be removed, prepared, and examined under a microscope. To provide an alternative to conventional biopsies, an endomicroscope intended to perform optical biopsies is demonstrated. The system provides high resolution, high contrast images in real-time which could allow a diagnosis to be made during surgery without the need for tissue removal. Optical sectioning is achieved via structured illumination to reject out of focus light. An image is relayed between the sample plane and the imaging system by a coherent fiber bundle with an achromatized objective lens at the distal tip of the fiber bundle which is the diameter of a biopsy needle. The custom, plastic objective provides correction for both the excitation and emission wavelengths of proflavine (452 nm and 515 nm, respectively). It also magnifies the object onto the distal tip of the fiber bundle to increase lateral resolution. The lenses are composed of the optical plastics Zeonex E48R, PMMA, and polystyrene. The lenses are fabricated via single point diamond turning and assembled using a zero alignment technique. The lateral resolution and chromatic focal shift were measured and in vitro images of breast carcinoma cells stained with proflavine were captured. The optical biopsy system is able to achieve optical sectioning and to resolve smaller features than the current high resolution microendoscope.

Monitoring growth and movement of Ralstonia solanacearum cells harboring plasmid pRSS12 derived from bacteriophage phiRSS1.

PubMed

Fujie, Makoto; Takamoto, Hirofumi; Kawasaki, Takeru; Fujiwara, Akiko; Yamada, Takashi

2010-02-01

We monitored growth and movement of Ralstonia solanacearum harboring the plasmid pRSS12 in tomato seedlings. The plasmid contains a gene for green fluorescent protein (GFP) and is stably maintained in R. solanacearum cells without selection pressure. Bacteria harboring the plasmid can be tracked in planta by visualizing GFP fluorescence. Stems of seedlings were infected with R. solanacearum cells transformed with pRSS12, and bacterial growth and movement, particularly around the vascular bundles, were monitored for more than 7 days. Our results showed that vascular bundles are independent of each other within the stem, and that it takes a long time for R. solanacearum cells to migrate from one vascular bundle to another. For real-time monitoring of bacteria in planta, tomato seedlings were grown on agar medium and bacterial suspension was applied to the root apex. The bacterial invasion process was monitored by fluorescent microscopy. Bacteria invaded taproots within 6 h, and movement of the bacteria was observed until 144 h after inoculation. In susceptible tomato cultivars, strong GFP fluorescence was observed in hypocotyls and lateral roots as well as the taproot. In resistant cultivars, however, GFP fluorescence was rarely observed on lateral roots. Our results show that this monitoring system can be used to assess bacterial pathogenicity efficiently. Copyright (c) 2009 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Probabilistic vs. deterministic fiber tracking and the influence of different seed regions to delineate cerebellar-thalamic fibers in deep brain stimulation.

PubMed

Schlaier, Juergen R; Beer, Anton L; Faltermeier, Rupert; Fellner, Claudia; Steib, Kathrin; Lange, Max; Greenlee, Mark W; Brawanski, Alexander T; Anthofer, Judith M

2017-06-01

This study compared tractography approaches for identifying cerebellar-thalamic fiber bundles relevant to planning target sites for deep brain stimulation (DBS). In particular, probabilistic and deterministic tracking of the dentate-rubro-thalamic tract (DRTT) and differences between the spatial courses of the DRTT and the cerebello-thalamo-cortical (CTC) tract were compared. Six patients with movement disorders were examined by magnetic resonance imaging (MRI), including two sets of diffusion-weighted images (12 and 64 directions). Probabilistic and deterministic tractography was applied on each diffusion-weighted dataset to delineate the DRTT. Results were compared with regard to their sensitivity in revealing the DRTT and additional fiber tracts and processing time. Two sets of regions-of-interests (ROIs) guided deterministic tractography of the DRTT or the CTC, respectively. Tract distances to an atlas-based reference target were compared. Probabilistic fiber tracking with 64 orientations detected the DRTT in all twelve hemispheres. Deterministic tracking detected the DRTT in nine (12 directions) and in only two (64 directions) hemispheres. Probabilistic tracking was more sensitive in detecting additional fibers (e.g. ansa lenticularis and medial forebrain bundle) than deterministic tracking. Probabilistic tracking lasted substantially longer than deterministic. Deterministic tracking was more sensitive in detecting the CTC than the DRTT. CTC tracts were located adjacent but consistently more posterior to DRTT tracts. These results suggest that probabilistic tracking is more sensitive and robust in detecting the DRTT but harder to implement than deterministic approaches. Although sensitivity of deterministic tracking is higher for the CTC than the DRTT, targets for DBS based on these tracts likely differ. © 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Distribution and co-localization of choline acetyltransferase and p75 neurotrophin receptors in the sheep basal forebrain: implications for the use of a specific cholinergic immunotoxin.

PubMed

Ferreira, G; Meurisse, M; Tillet, Y; Lévy, F

2001-01-01

The basal forebrain cholinergic system is involved in different forms of memory. To study its role in social memory in sheep, an immunotoxin, ME20.4 immunoglobulin G (IgG)-saporin, was developed that is specific to basal forebrain cholinergic neurons bearing the p75 neurotrophin receptor. The distribution of sheep cholinergic neurons was mapped with an antibody against choline acetyltransferase. To assess the localization of the p75 receptor on basal forebrain cholinergic neurons, the distribution of p75 receptor-immunoreactive neurons with ME20.4 IgG was examined, and a double-labeling study with antibodies against choline acetyltransferase and p75 receptor was undertaken. The loss of basal forebrain cholinergic neurons and acetylcholinesterase fibers in basal forebrain projection areas was assessed in ewes that had received intracerebroventricular injections of the immunotoxin (50, 100 or 150 microg) alone, as well as, in some of the ewes treated with the highest dose, with bilateral immunotoxin injections in the nucleus basalis (11 microg/side). Results indicated that choline acetyltransferase- and p75 receptor-immunoreactive cells had similar distributions in the medial septum, the vertical and horizontal limbs of the band of Broca, and the nucleus basalis. The double-labeling procedure revealed that 100% of the cholinergic neurons are also p75 receptor positive in the medial septum and in the vertical and horizontal limbs of the band of Broca, and 82% in the nucleus basalis. Moreover, 100% of the p75 receptor-immunoreactive cells of these four nuclei were cholinergic. Combined immunotoxin injections into ventricles and the nucleus basalis produced a near complete loss (80-95%) of basal forebrain cholinergic neurons and acetylcholinesterase-positive fibers in the hippocampus, olfactory bulb and entorhinal cortex. This study provides the first anatomical data concerning the basal forebrain cholinergic system in ungulates. The availability of a selective cholinergic immunotoxin effective in sheep provides a new tool to probe the involvement of basal forebrain cholinergic neurons in cognitive processes in this species.

Corticostriatal connectivity and its role in disease

PubMed Central

Shepherd, Gordon M. G.

2014-01-01

Corticostriatal projections are essential components of forebrain circuits widely involved in motivated behavior. These axonal projections are formed by two distinct classes of cortical neurons, intratelencephalic (IT) and pyramidal tract (PT) type neurons. Convergent evidence points to IT/PT differentiation of the corticostriatal system at all levels of functional organization, from cellular signaling mechanisms to circuit topology. There is also growing evidence for IT/PT imbalance as an etiological factor in neurodevelopmental, neuropsychiatric, and movement disorders – autism, amyotrophic lateral sclerosis, obsessive-compulsive disorder, schizophrenia, Huntington’s and Parkinson’s diseases, and major depression are highlighted here. PMID:23511908

Comparison of Effects Produced by Nicotine and the α4β2-Selective Agonist 5-I-A-85380 On Intracranial Self-Stimulation in Rats

PubMed Central

Freitas, Kelen; Carroll, F. Ivy; Negus, S. Stevens

2015-01-01

Intracranial self-stimulation (ICSS) is one type of preclinical procedure for research on pharmacological mechanisms that mediate abuse potential of drugs acting at various targets including nicotinic acetylcholine receptors (nAChRs). This study compared effects of the non-selective nAChR agonist nicotine (0.032-1.0 mg/kg) and the α4β2-selective nAChR agonist 5-I-A-85380 (0.01-1.0 mg/kg) on ICSS in male Sprague-Dawley rats. Rats were implanted with electrodes targeting the medial forebrain bundle at the level of the lateral hypothalamus and trained to respond under a fixed-ratio 1 schedule for a range of brain stimulation frequencies (158-56 Hz). A broad range of 5-I-A-85380 doses produced an abuse-related increase (or “facilitation”) of low ICSS rates maintained by low brain-stimulation frequencies, and this effect was blocked by both the nonselective nAChR antagonist mecamylamine and the selective α4β2 antagonist dihyrdo-ß-erythroidine (DHßE). Conversely, nicotine produced weaker ICSS facilitation across a narrower range of doses, and higher nicotine doses decreased high rates of ICSS maintained by high brain- stimulation frequencies. The rate-decreasing effects of a high nicotine dose were blocked by mecamylamine but not DHßE. Chronic nicotine treatment produced selective tolerance to rate-decreasing effects of nicotine but did not alter ICSS rate-increasing effects of nicotine. These results suggest that α4β2 receptors are sufficient to mediate abuse-related rate-increasing effects of nAChR agonists in this ICSS procedure. Conversely, nicotine effects at non-α4β2 nAChRs appear to oppose and limit abuse-related effects mediated by α4β2 receptors, although tolerance can develop to these non-α4β2 effects. Selective α4β2 agonists may have higher abuse potential than nicotine. PMID:26461167

Hemispheric differences in processing of vocalizations depend on early experience.

PubMed

Phan, Mimi L; Vicario, David S

2010-02-02

An intriguing phenomenon in the neurobiology of language is lateralization: the dominant role of one hemisphere in a particular function. Lateralization is not exclusive to language because lateral differences are observed in other sensory modalities, behaviors, and animal species. Despite much scientific attention, the function of lateralization, its possible dependence on experience, and the functional implications of such dependence have yet to be clearly determined. We have explored the role of early experience in the development of lateralized sensory processing in the brain, using the songbird model of vocal learning. By controlling exposure to natural vocalizations (through isolation, song tutoring, and muting), we manipulated the postnatal auditory environment of developing zebra finches, and then assessed effects on hemispheric specialization for communication sounds in adulthood. Using bilateral multielectrode recordings from a forebrain auditory area known to selectively process species-specific vocalizations, we found that auditory responses to species-typical songs and long calls, in both male and female birds, were stronger in the right hemisphere than in the left, and that right-side responses adapted more rapidly to stimulus repetition. We describe specific instances, particularly in males, where these lateral differences show an influence of auditory experience with song and/or the bird's own voice during development.

Some glial progenitors in the neonatal subventricular zone migrate through the corpus callosum to the contralateral cerebral hemisphere.

PubMed

Kakita, Akiyoshi; Zerlin, Marielba; Takahashi, Hitoshi; Goldman, James E

2003-04-14

The great majority of glial cells of the mammalian forebrain are generated in the perinatal period from progenitors in the subventricular zone (SVZ). We investigated the migration of progenitors from the neonatal (postnatal day 0, P0) rat forebrain SVZ by labeling them in vivo with a green fluorescence protein (GFP) retrovirus and monitoring their movements by time-lapse video microscopy in P3 slices. We identified a small number of progenitors that migrated tangentially within the corpus callosum (CC) and crossed the midline. These cells retained a relatively uniform morphology: the leading process was extended toward the contralateral side but showed no process branching or turning away from the migratory direction. Net migration requires the elongation of the leading process and nuclear translocation, and the migrating cells in the CC showed both modes. We confirmed the presence of unmyelinated axon bundles within the P3 CC, but failed to detect any radially directed glial processes (vimentin- or GLAST-immunolabeled fibers) spanning through the CC. Confocal images showed a close proximity between neurofilament-immunolabeled axons and the leading process of the GFP-expressing progenitors in the CC. The destination of the callosal fibers was examined by applying DiI to the right cingulum; the labeled fibers ran throughout the CC and reached the left cingulate and motor areas. The distribution and final fates of the retrovirus-labeled cells were examined in P28 brains. A small proportion of the labeled cells were found in the contralateral hemisphere, where, as oligodendrocytes and astrocytes, they colonized predominantly the cortex and the underlying white matter of the cingulate and secondary motor areas. The distribution pattern appears to coincide well with the projection direction of the callosal fibers. Thus, glial progenitors migrate across the CC, presumably in conjunction with unmyelinated axons, to colonize the contralateral hemisphere. Copyright 2003 Wiley-Liss, Inc.

Distinct Correlation Structure Supporting a Rate-Code for Sound Localization in the Owl’s Auditory Forebrain

PubMed Central

2017-01-01

Abstract While a topographic map of auditory space exists in the vertebrate midbrain, it is absent in the forebrain. Yet, both brain regions are implicated in sound localization. The heterogeneous spatial tuning of adjacent sites in the forebrain compared to the midbrain reflects different underlying circuitries, which is expected to affect the correlation structure, i.e., signal (similarity of tuning) and noise (trial-by-trial variability) correlations. Recent studies have drawn attention to the impact of response correlations on the information readout from a neural population. We thus analyzed the correlation structure in midbrain and forebrain regions of the barn owl’s auditory system. Tetrodes were used to record in the midbrain and two forebrain regions, Field L and the downstream auditory arcopallium (AAr), in anesthetized owls. Nearby neurons in the midbrain showed high signal and noise correlations (RNCs), consistent with shared inputs. As previously reported, Field L was arranged in random clusters of similarly tuned neurons. Interestingly, AAr neurons displayed homogeneous monotonic azimuth tuning, while response variability of nearby neurons was significantly less correlated than the midbrain. Using a decoding approach, we demonstrate that low RNC in AAr restricts the potentially detrimental effect it can have on information, assuming a rate code proposed for mammalian sound localization. This study harnesses the power of correlation structure analysis to investigate the coding of auditory space. Our findings demonstrate distinct correlation structures in the auditory midbrain and forebrain, which would be beneficial for a rate-code framework for sound localization in the nontopographic forebrain representation of auditory space. PMID:28674698

Forebrain-specific expression of monoamine oxidase A reduces neurotransmitter levels, restores the brain structure, and rescues aggressive behavior in monoamine oxidase A-deficient mice.

PubMed

Chen, Kevin; Cases, Olivier; Rebrin, Igor; Wu, Weihua; Gallaher, Timothy K; Seif, Isabelle; Shih, Jean Chen

2007-01-05

Previous studies have established that abrogation of monoamine oxidase (MAO) A expression leads to a neurochemical, morphological, and behavioral specific phenotype with increased levels of serotonin (5-HT), norepinephrine, and dopamine, loss of barrel field structure in mouse somatosensory cortex, and an association with increased aggression in adults. Forebrain-specific MAO A transgenic mice were generated from MAO A knock-out (KO) mice by using the promoter of calcium-dependent kinase IIalpha (CaMKIIalpha). The presence of human MAO A transgene and its expression were verified by PCR of genomic DNA and reverse transcription-PCR of mRNA and Western blot, respectively. Significant MAO A catalytic activity, autoradiographic labeling of 5-HT, and immunocytochemistry of MAO A were found in the frontal cortex, striatum, and hippocampus but not in the cerebellum of the forebrain transgenic mice. Also, compared with MAO A KO mice, lower levels of 5-HT, norepinephrine, and DA and higher levels of MAO A metabolite 5-hydroxyindoleacetic acid were found in the forebrain regions but not in the cerebellum of the transgenic mice. These results suggest that MAO A is specifically expressed in the forebrain regions of transgenic mice. This forebrain-specific differential expression resulted in abrogation of the aggressive phenotype. Furthermore, the disorganization of the somatosensory cortex barrel field structure associated with MAO A KO mice was restored and became morphologically similar to wild type. Thus, the lack of MAO A in the forebrain of MAO A KO mice may underlie their phenotypes.

Afferentation of the lateral nidopallium: A tracing study of a brain area involved in sexual imprinting in the zebra finch (Taeniopygia guttata).

PubMed

Sadananda, Monika; Bischof, Hans-Joachim

2006-08-23

The lateral forebrain of zebra finches that comprises parts of the lateral nidopallium and parts of the lateral mesopallium is supposed to be involved in the storage and processing of visual information acquired by an early learning process called sexual imprinting. This information is later used to select an appropriate sexual partner for courtship behavior. Being involved in such a complicated behavioral task, the lateral nidopallium should be an integrative area receiving input from many other regions of the brain. Our experiments indeed show that the lateral nidopallium receives input from a variety of telencephalic regions including the primary and secondary areas of both visual pathways, the globus pallidus, the caudolateral nidopallium functionally comparable to the prefrontal cortex, the caudomedial nidopallium involved in song perception and storage of song-related memories, and some parts of the arcopallium. There are also a number of thalamic, mesencephalic, and brainstem efferents including the catecholaminergic locus coeruleus and the unspecific activating reticular formation. The spatial distribution of afferents suggests a compartmentalization of the lateral nidopallium into several subdivisions. Based on its connections, the lateral nidopallium should be considered as an area of higher order processing of visual information coming from the tectofugal and the thalamofugal visual pathways. Other sensory modalities and also motivational factors from a variety of brain areas are also integrated here. These findings support the idea of an involvement of the lateral nidopallium in imprinting and the control of courtship behavior.

A centrifugal pathway to the mouse accessory olfactory bulb from the medial amygdala conveys gender-specific volatile pheromonal signals

PubMed Central

Martel, Kristine L.; Baum, Michael J.

2009-01-01

We previously found that female mice exhibited Fos responses in the accessory olfactory bulb (AOB) after exposure to volatile opposite-, but not same-sex, urinary odours. This effect was eliminated by lesioning the main olfactory epithelium, raising the possibility that the AOB receives information about gender via centrifugal inputs originating in the main olfactory system instead of from the vomeronasal organ. We asked which main olfactory forebrain targets send axonal projections to the AOB, and whether these input neurons express Fos in response to opposite-sex urinary volatiles. Female mice received bilateral injections of the retrograde tracer, cholera toxin B (CTB), into the AOB, and were exposed to either same- or opposite-sex volatile urinary odours one week later. We found CTB- labeled cell bodies in several forebrain sites including the bed nucleus of the accessory olfactory tract, the rostral portion of the medial amygdala (MeA), and the posteromedial cortical nucleus of the amygdala. A significant increase in the percentage of CTB/Fos co-labeled cells was seen only in the MeA of female subjects exposed to male but not to female urinary volatiles. In Experiment 2, CTB-injected females were later exposed to volatile odours from male mouse urine, food, or cat urine. Again, a significant increase in the percentage of CTB/Fos co-labeled cells was seen in the MeA of females exposed to male mouse urinary volatiles but not to food or predator odours. Main olfactory - MeA -AOB signaling may motivate approach behaviour to opposite-sex pheromonal signals that ensure successful reproduction. PMID:19077123

Adenosine inhibits activity of hypocretin/orexin neurons via A1 receptor in the lateral hypothalamus: a possible sleep-promoting effect

PubMed Central

Liu, Zhong-Wu; Gao, Xiao-Bing

2006-01-01

Neurons in the lateral hypothalamus (LH) that contain hypocretin/orexin have been established as important promoters of arousal. Deficiencies in the hypocretin/orexin system lead to narcolepsy. The inhibition of hypocretin/orexin neurons by sleep-promoting neurotransmitters has been suggested as one part of the sleep regulation machinery. Adenosine has been identified as a sleep promoter and its role in sleep regulation in the basal forebrain has been well documented. However, the effect of adenosine on arousal-promoting hypocretin/orexin neurons has not been addressed, despite recent evidence that immunocytochemical visualization of adenosine receptors was detected in these neurons. In this study, we examined the hypothesis that adenosine inhibits the activity of hypocretin/orexin neurons by using electrophysiological methods in brain slices from mice expressing green fluorescent protein in hypocretin/orexin neurons. We found that adenosine significantly attenuated the frequency of action potentials without a change in membrane potential in hypocretin/orexin neurons. The adenosine-mediated inhibition is due to depression of excitatory synaptic transmission to hypocretin/orexin neurons, since adenosine depresses the amplitude of evoked excitatory postsynaptic potential and the frequency of spontaneous and miniature excitatory postsynaptic currents in these neurons. At the cell body of the hypocretin/orexin neurons, adenosine inhibits voltage-dependent calcium currents without the induction of GIRK current. The inhibitory effect of adenosine is dose-dependent, pertussis toxin-sensitive and mediated via A1 receptors. In summary, our data suggest that in addition to its effect in the basal forebrain, adenosine exerts its sleep-promoting effect in the LH via inhibition of hypocretin/orexin neurons. PMID:17093123

Assembly of tobacco mosaic virus into fibrous and macroscopic bundled arrays mediated by surface aniline polymerization.

PubMed

Niu, Zhongwei; Bruckman, Michael A; Li, Siqi; Lee, L Andrew; Lee, Byeongdu; Pingali, Sai Venkatesh; Thiyagarajan, P; Wang, Qian

2007-06-05

One-dimensional (1D) polyaniline/tobacco mosaic virus (TMV) composite nanofibers and macroscopic bundles of such fibers were generated via a self-assembly process of TMV assisted by in-situ polymerization of polyaniline on the surface of TMV. At near-neutral reaction pH, branched polyaniline formed on the surface of TMV preventing lateral association. Therefore, long 1D nanofibers were observed with high aspect ratios and excellent processibility. At a lower pH, transmission electron microscopy (TEM) analysis revealed that initially long nanofibers were formed which resulted in bundled structures upon long-time reaction, presumably mediated by the hydrophobic interaction because of the polyaniline on the surface of TMV. In-situ time-resolved small-angle X-ray scattering study of TMV at different reaction conditions supported this mechanism. This novel strategy to assemble TMV into 1D and 3D supramolecular composites could be utilized in the fabrication of advanced materials for potential applications including electronics, optics, sensing, and biomedical engineering.

Dimer model for Tau proteins bound in microtubule bundles

NASA Astrophysics Data System (ADS)

Hall, Natalie; Kluber, Alexander; Hayre, N. Robert; Singh, Rajiv; Cox, Daniel

2013-03-01

The microtubule associated protein tau is important in nucleating and maintaining microtubule spacing and structure in neuronal axons. Modification of tau is implicated as a later stage process in Alzheimer's disease, but little is known about the structure of tau in microtubule bundles. We present preliminary work on a proposed model for tau dimers in microtubule bundles (dimers are the minimal units since there is one microtubule binding domain per tau). First, a model of tau monomer was created and its characteristics explored using implicit solvent molecular dynamics simulation. Multiple simulations yield a partially collapsed form with separate positively/negatively charged clumps, but which are a factor of two smaller than required by observed microtubule spacing. We argue that this will elongate in dimer form to lower electrostatic energy at a cost of entropic ``spring'' energy. We will present preliminary results on steered molecular dynamics runs on tau dimers to estimate the actual force constant. Supported by US NSF Grant DMR 1207624.

Generation of contractile actomyosin bundles depends on mechanosensitive actin filament assembly and disassembly

PubMed Central

Tojkander, Sari; Gateva, Gergana; Husain, Amjad; Krishnan, Ramaswamy; Lappalainen, Pekka

2015-01-01

Adhesion and morphogenesis of many non-muscle cells are guided by contractile actomyosin bundles called ventral stress fibers. While it is well established that stress fibers are mechanosensitive structures, physical mechanisms by which they assemble, align, and mature have remained elusive. Here we show that arcs, which serve as precursors for ventral stress fibers, undergo lateral fusion during their centripetal flow to form thick actomyosin bundles that apply tension to focal adhesions at their ends. Importantly, this myosin II-derived force inhibits vectorial actin polymerization at focal adhesions through AMPK-mediated phosphorylation of VASP, and thereby halts stress fiber elongation and ensures their proper contractility. Stress fiber maturation additionally requires ADF/cofilin-mediated disassembly of non-contractile stress fibers, whereas contractile fibers are protected from severing. Taken together, these data reveal that myosin-derived tension precisely controls both actin filament assembly and disassembly to ensure generation and proper alignment of contractile stress fibers in migrating cells. DOI: http://dx.doi.org/10.7554/eLife.06126.001 PMID:26652273

Generation of contractile actomyosin bundles depends on mechanosensitive actin filament assembly and disassembly.

PubMed

Tojkander, Sari; Gateva, Gergana; Husain, Amjad; Krishnan, Ramaswamy; Lappalainen, Pekka

2015-12-10

Adhesion and morphogenesis of many non-muscle cells are guided by contractile actomyosin bundles called ventral stress fibers. While it is well established that stress fibers are mechanosensitive structures, physical mechanisms by which they assemble, align, and mature have remained elusive. Here we show that arcs, which serve as precursors for ventral stress fibers, undergo lateral fusion during their centripetal flow to form thick actomyosin bundles that apply tension to focal adhesions at their ends. Importantly, this myosin II-derived force inhibits vectorial actin polymerization at focal adhesions through AMPK-mediated phosphorylation of VASP, and thereby halts stress fiber elongation and ensures their proper contractility. Stress fiber maturation additionally requires ADF/cofilin-mediated disassembly of non-contractile stress fibers, whereas contractile fibers are protected from severing. Taken together, these data reveal that myosin-derived tension precisely controls both actin filament assembly and disassembly to ensure generation and proper alignment of contractile stress fibers in migrating cells.

Impact of Maternal Serotonin Transporter Genotype on Placental Serotonin, Fetal Forebrain Serotonin, and Neurodevelopment

PubMed Central

Muller, Christopher L; Anacker, Allison MJ; Rogers, Tiffany D; Goeden, Nick; Keller, Elizabeth H; Forsberg, C Gunnar; Kerr, Travis M; Wender, Carly LA; Anderson, George M; Stanwood, Gregg D; Blakely, Randy D; Bonnin, Alexandre; Veenstra-VanderWeele, Jeremy

2017-01-01

Biomarker, neuroimaging, and genetic findings implicate the serotonin transporter (SERT) in autism spectrum disorder (ASD). Previously, we found that adult male mice expressing the autism-associated SERT Ala56 variant have altered central serotonin (5-HT) system function, as well as elevated peripheral blood 5-HT levels. Early in gestation, before midbrain 5-HT projections have reached the cortex, peripheral sources supply 5-HT to the forebrain, suggesting that altered maternal or placenta 5-HT system function could impact the developing embryo. We therefore used different combinations of maternal and embryo SERT Ala56 genotypes to examine effects on blood, placenta and embryo serotonin levels and neurodevelopment at embryonic day E14.5, when peripheral sources of 5-HT predominate, and E18.5, when midbrain 5-HT projections have reached the forebrain. Maternal SERT Ala56 genotype was associated with decreased placenta and embryonic forebrain 5-HT levels at E14.5. Low 5-HT in the placenta persisted, but forebrain levels normalized by E18.5. Maternal SERT Ala56 genotype effects on forebrain 5-HT levels were accompanied by a broadening of 5-HT-sensitive thalamocortical axon projections. In contrast, no effect of embryo genotype was seen in concepti from heterozygous dams. Blood 5-HT levels were dynamic across pregnancy and were increased in SERT Ala56 dams at E14.5. Placenta RNA sequencing data at E14.5 indicated substantial impact of maternal SERT Ala56 genotype, with alterations in immune and metabolic-related pathways. Collectively, these findings indicate that maternal SERT function impacts offspring placental 5-HT levels, forebrain 5-HT levels, and neurodevelopment. PMID:27550733

Placenta-derived hypo-serotonin situations in the developing forebrain cause autism.

PubMed

Sato, Kohji

2013-04-01

Autism is a pervasive developmental disorder that is characterized by the behavioral traits of impaired social cognition and communication, and repetitive and/or obsessive behavior and interests. Although there are many theories and speculations about the pathogenetic causes of autism, the disruption of the serotonergic system is one of the most consistent and well-replicated findings. Recently, it has been reported that placenta-derived serotonin is the main source in embryonic day (E) 10-15 mouse forebrain, after that period, the serotonergic fibers start to supply serotonin into the forebrain. E 10-15 is the very important developing period, when cortical neurogenesis, migration and initial axon targeting are processed. Since all these events have been considered to be involved in the pathogenesis of autism and they are highly controlled by serotonin signals, the paucity of placenta-derived serotonin should have potential importance when the pathogenesis of autism is considered. I, thus, postulate a hypothesis that placenta-derived hypo-serotonin situations in the developing forebrain cause autism. The hypothesis is as follows. Various factors, such as inflammation, dysfunction of the placenta, together with genetic predispositions cause a decrease of placenta-derived serotonin levels. The decrease of placenta-derived serotonin levels leads to hypo-serotonergic situations in the forebrain of the fetus. The paucity of serotonin in the forebrain leads to mis-wiring in important regions which are responsible for the theory of mind. The paucity of serotonin in the forebrain also causes over-growth of serotonergic fibers. These disturbances result in network deficiency and aberration of the serotonergic system, leading to the autistic phenotypes. Copyright © 2013 Elsevier Ltd. All rights reserved.

Small-angle X-ray scattering and rheological characterization of alginate gels. 2. Time-resolved studies on ionotropic gels

NASA Astrophysics Data System (ADS)

Yuguchi, Y.; Urakawa, H.; Kajiwara, K.; Draget, K. I.; Stokke, B. T.

2000-10-01

Gelation was observed by time-resolved small-angle X-ray scattering and rheology on 10 mg/ml Ca-alginate gels prepared by in situ release of Ca 2+ from CaEGTA or CaCO 3 with total Ca 2+ concentration in the range 10-20 mM. This was carried out for alginates having a fraction of α- L-GulA (G) of FG=0.39 and 0.68, respectively, obtained by the selection of alginates isolated from two different brown algae, Ascophyllum nodosum and Laminaria hyperborea stipe. Correlation between the rheological data and SAXS data shows that a large fraction of the lateral association precedes the formation of a continuous network through the sample cell. Following the initial association of chain segments in junction zones, the analysis using two-component broken rod model indicates the formation of larger bundles, and that the relative weight of these bundles increases with increasing time. The molecular model for the bundles is proposed by associating 2-16 units (G-blocks) composed of 14 (1→4) linked residues of α- L-GulA in parallel according to the available crystallographic data. The storage modulus increases as the bundles composed of associated alginate chains grow during the gel formation. The gel elasticity is mainly sustained by single chains in the alginate sample with a low fraction of α- L-GulA. The alginates with a high fraction of α- L-GulA associate into thicker bundles which join to form a network. Here the gel elasticity seems to be due to the flexible joints between bundles, since the fraction of single chains is extremely low.

Development and aging of a brain neural stem cell niche.

PubMed

Conover, Joanne C; Todd, Krysti L

2017-08-01

In the anterior forebrain, along the lateral wall of the lateral ventricles, a neurogenic stem cell niche is found in a region referred to as the ventricular-subventricular zone (V-SVZ). In rodents, robust V-SVZ neurogenesis provides new neurons to the olfactory bulb throughout adulthood; however, with increasing age stem cell numbers are reduced and neurogenic capacity is significantly diminished, but new olfactory bulb neurons continue to be produced even in old age. Humans, in contrast, show little to no new neurogenesis after two years of age and whether V-SVZ neural stem cells persist in the adult human brain remains unclear. Here, we review functional and organizational differences in the V-SVZ stem cell niche of mice and humans, and examine how aging affects the V-SVZ niche and its associated functions. Copyright © 2016 Elsevier Inc. All rights reserved.

The microtubule end-binding protein EB2 is a central regulator of microtubule reorganisation in apico-basal epithelial differentiation.

PubMed

Goldspink, Deborah A; Gadsby, Jonathan R; Bellett, Gemma; Keynton, Jennifer; Tyrrell, Benjamin J; Lund, Elizabeth K; Powell, Penny P; Thomas, Paul; Mogensen, Mette M

2013-09-01

Microtubule end-binding (EB) proteins influence microtubule dynamic instability, a process that is essential for microtubule reorganisation during apico-basal epithelial differentiation. Here, we establish for the first time that expression of EB2, but not that of EB1, is crucial for initial microtubule reorganisation during apico-basal epithelial differentiation, and that EB2 downregulation promotes bundle formation. EB2 siRNA knockdown during early stages of apico-basal differentiation prevented microtubule reorganisation, whereas its downregulation at later stages promoted microtubule stability and bundle formation. Interestingly, although EB1 is not essential for microtubule reorganisation, its knockdown prevented apico-basal bundle formation and epithelial elongation. siRNA depletion of EB2 in undifferentiated epithelial cells induced the formation of straight, less dynamic microtubules with EB1 and ACF7 lattice association and co-alignment with actin filaments, a phenotype that could be rescued by inhibition with formin. Importantly, in situ inner ear and intestinal crypt epithelial tissue revealed direct correlations between a low level of EB2 expression and the presence of apico-basal microtubule bundles, which were absent where EB2 was elevated. EB2 is evidently important for initial microtubule reorganisation during epithelial polarisation, whereas its downregulation facilitates EB1 and ACF7 microtubule lattice association, microtubule-actin filament co-alignment and bundle formation. The spatiotemporal expression of EB2 thus dramatically influences microtubule organisation, EB1 and ACF7 deployment and epithelial differentiation.

Disruption of SorCS2 reveals differences in the regulation of stereociliary bundle formation between hair cell types in the inner ear

PubMed Central

Taylor, Ruth R.; Lovett, Michael; Jagger, Daniel J.

2017-01-01

Behavioural anomalies suggesting an inner ear disorder were observed in a colony of transgenic mice. Affected animals were profoundly deaf. Severe hair bundle defects were identified in all outer and inner hair cells (OHC, IHC) in the cochlea and in hair cells of vestibular macular organs, but hair cells in cristae were essentially unaffected. Evidence suggested the disorder was likely due to gene disruption by a randomly inserted transgene construct. Whole-genome sequencing identified interruption of the SorCS2 (Sortilin-related VPS-10 domain containing protein) locus. Real-time-qPCR demonstrated disrupted expression of SorCS2 RNA in cochlear tissue from affected mice and this was confirmed by SorCS2 immuno-labelling. In all affected hair cells, stereocilia were shorter than normal, but abnormalities of bundle morphology and organisation differed between hair cell types. Bundles on OHC were grossly misshapen with significantly fewer stereocilia than normal. However, stereocilia were organised in rows of increasing height. Bundles on IHC contained significantly more stereocilia than normal with some longer stereocilia towards the centre, or with minimal height differentials. In early postnatal mice, kinocilia (primary cilia) of IHC and of OHC were initially located towards the lateral edge of the hair cell surface but often became surrounded by stereocilia as bundle shape and apical surface contour changed. In macular organs the kinocilium was positioned in the centre of the cell surface throughout maturation. There was disruption of the signalling pathway controlling intrinsic hair cell apical asymmetry. LGN and Gαi3 were largely absent, and atypical Protein Kinase C (aPKC) lost its asymmetric distribution. The results suggest that SorCS2 plays a role upstream of the intrinsic polarity pathway and that there are differences between hair cell types in the deployment of the machinery that generates a precisely organised hair bundle. PMID:28346477

Larval development of Brachiopod Coptothyris grayi (Davidson, 1852) (Brachiopoda, Rhynchonelliformea).

PubMed

Kuzmina, T V; Temereva, E N; Malakhov, V V

2016-11-01

The larval development of the Brachiopod Coptothyris grayi (Davidson, 1852) from the Sea of Japan is described for the first time. Ciliated blastula proved to represent the first free-swimming stage. The blastopore is initially formed as a rounded hole stretching later along the anteroposterior axis. The larva is first divided into two lobes (the apical lobe and the trunk); the mantle lobe is formed later as two lateral folds. Two pairs of seta bundles appear in the late stage larvae. The apical larval lobe in brachiopods is supposed to match the pre-oral lobe and anterior part of the trunk with tentacles in phoronids.

Midbrain dopamine neurons regulate preprotachykinin-A mRNA expression in the rat forebrain during development.

PubMed

Brené, S; Lindefors, N; Persson, H

1992-06-01

Intracerebroventricular 6-hydroxydopamine injections were performed at postnatal days 3 and 6 in animals pretreated with the norepinephrine uptakeblocker desimipramine in order to generate a selective lesion of dopamine neurons. In situ hybridization was then used to analyze preprotachykinin-A (PPT-A) mRNA expression in the lesioned as well as in saline-injected control animals. The midbrain dopaminergic lesion caused a 22-25% increase in the level of PPT-A mRNA in cingulate cortex and frontoparietal cortex when analysed at 2 weeks of age, compared to saline-injected control animals. In contrast, the lesion caused no change in PPT-A mRNA expression in the neonatal caudate-putamen. These results indicate that dopamine neurons downregulate the expression of PPT-A mRNA specifically in cingulate cortex and frontoparietal cortex during early postnatal brain development. In the adult rat forebrain, lesioned at P3 and P6, no change in the level of PPT-A mRNA was seen in cingulate cortex and frontoparietal cortex. However, a 29% decrease in PPT-A mRNA was seen in the lateral caudate-putamen with no significant change in neurons of medial caudate-putamen. Thus, dopamine neurons appears to exert a region specific influence on PPT-A mRNA expression during brain development.

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

DTIC Science & Technology

1993-05-28

1993 Dissertation and Abstract Approved: Commit tee Chairperson . ,a..w ember ~tee Member tli:u., ;2 9" PQ3 bate Date bate The author...1982; Mesulam et al., 1983; Rye et al., 1984; Saper, 1984). I will refer to the region of the basal forebrain that supplies cholinergic innervation to...topographical organization has been observed for cholinergic projection patterns, with more rostral and medial basal forebrain cell groups supplying

Hair cell regeneration in the bullfrog vestibular otolith organs following aminoglycoside toxicity

NASA Technical Reports Server (NTRS)

Baird, R. A.; Torres, M. A.; Schuff, N. R.

1993-01-01

Adult bullfrog were given single intraotic injections of the aminoglycoside antibiotic gentamicin sulfate and sacrificed at postinjection times ranging from 0.5 to 9 days. The saccular and utricular maculae of normal and injected animals were examined in wholemount and cross-section. Intraotic 200 microM gentamicin concentrations resulted in the uniform destruction of the hair bundles and, at later times, the cell bodies of saccular hair cells. In the utriculus, striolar hair cells were selectively damaged while extrastriolar hair cells were relatively unaffected. Regenerating hair cells, identified in sectioned material by their small cell bodies and short, well-formed hair bundles, were seen in the saccular and utricular maculae as early as 24-48 h postinjection. Immature versions of mature hair cell types in both otolith organs were recognized by the presence or absence of a bulbed kinocilia and the relative lengths of their kinocilia and longest stereocilia. Utricular hair cell types with kinocilia longer than their longest stereocilia were observed at earlier than hair cell types with shorter kinocilia. In the sacculus, the hair bundles of gentamicin-treated animals, even at 9 days postinjection, were significantly smaller than those of normal animals. The hair bundles of utricular hair cells, on the other hand, reached full maturity within the same time period.

Hair cell regeneration in the bullfrog vestibular otolith organs following aminoglycoside toxicity

NASA Technical Reports Server (NTRS)

Baird, Richard A.; Torres, M. A.; Schuff, N. R.

1994-01-01

Adult bullfrogs were given single intraotic injections of the aminoglycoside antibiotic gentamicin sulfate and sacrificed at postinjection times ranging from 0.5 to 9 days. The saccular and utricular maculae of normal and injected animals were examined in wholemount and cross-section. Intraotic 200 (mu) M gentamicin concentrations resulted in the uniform destruction of the hair bundles and, at later times, the cell bodies of saccular hair cells. In the utriculus, striolar hair cells were selectively damaged while extrastriolar hair cells were relatively unaffected. Regenerating hair cells, identified in sectioned material by their small cell bodies and short, well-formed hair bundles, were seen in the saccular and utricular maculae as early as 24-48 h postinjection. Immature versions of mature hair cell types in both otolith organs were recognized by the presence of absence of a bulbed kinocilia and the relative lengths of their kinocilia and longest sterocilia. Utricular hair cell types with kinocilia longer than their longest stereocilia were observed at earlier times than hair cell types with shorter kinocilia. In the same sacculus, the hair bundles of gentamicin-treated animals, even at 9 days postinjection, were significantly smaller than those of normal animals. The hair bundles of utricular hair cells, on the other hand, reached full maturity within the same time period.

Dianthus chinensis L.: The Structural Difference between Vascular Bundles in the Placenta and Ovary Wall Suggests Their Different Origin

PubMed Central

Guo, Xue-Min; Yu, Ying-Ying; Bai, Lan; Gao, Rong-Fu

2017-01-01

Dianthus chinensis is a perennial herbaceous plant with great ornamental, botanical, ecological, and medicinal value. The pistil of D. chinensis is composed of two fused carpels with free central placenta and two separate styles. The placenta is a columnar structure extending about two-thirds the length of the maturing fruit, which is typical of the Caryophyllaceous. Traditionally, free central placenta is thought to have evolved from axial placenta by septal disappearance, and axial placenta to have occurred through fusion of conduplicate carpels with marginal placenta. However, the traditional opinion is becoming more and more inconsistent with the new data gained in recent research of angiosperm systematics. To clarify the origin of D. chinensis pistil, the present anatomical study was carried out. The results show that the vascular system of placenta is independent to that of the ovary wall in D. chinensis. Moreover, in the central part of placenta there are one or two amphicribral bundles, and correspondingly numerous ones in the pistil which supply the ovules/seeds. It is obvious that the central amphicribral bundles in placenta are comparable to the counterparts in branches but not to those in leaves or their derivatives. Therefore, it is reasonable to deduce that the placenta of D. chinensis was not derived from conduplicate carpels through fusion of collateral vascular bundles, and actually a floral axis with ovules/seeds laterally adhering. On the contrary, the ovary wall was the lateral appendages of the floral axis. The result of the present study is completely in agreement with Unifying Theory, in which the placenta is taken as an ovule-bearing branch. Except for D. chinensis, the similar vascular organization has been observed in placenta of numerous isolated taxa. But till now, it is uncertain that whether this vascular organization pattern is popular in the whole angiosperms or not. More intensive and extensive investigations are needed. PMID:29250086

Dianthus chinensis L.: The Structural Difference between Vascular Bundles in the Placenta and Ovary Wall Suggests Their Different Origin.

PubMed

Guo, Xue-Min; Yu, Ying-Ying; Bai, Lan; Gao, Rong-Fu

2017-01-01

Dianthus chinensis is a perennial herbaceous plant with great ornamental, botanical, ecological, and medicinal value. The pistil of D. chinensis is composed of two fused carpels with free central placenta and two separate styles. The placenta is a columnar structure extending about two-thirds the length of the maturing fruit, which is typical of the Caryophyllaceous. Traditionally, free central placenta is thought to have evolved from axial placenta by septal disappearance, and axial placenta to have occurred through fusion of conduplicate carpels with marginal placenta. However, the traditional opinion is becoming more and more inconsistent with the new data gained in recent research of angiosperm systematics. To clarify the origin of D. chinensis pistil, the present anatomical study was carried out. The results show that the vascular system of placenta is independent to that of the ovary wall in D. chinensis . Moreover, in the central part of placenta there are one or two amphicribral bundles, and correspondingly numerous ones in the pistil which supply the ovules/seeds. It is obvious that the central amphicribral bundles in placenta are comparable to the counterparts in branches but not to those in leaves or their derivatives. Therefore, it is reasonable to deduce that the placenta of D. chinensis was not derived from conduplicate carpels through fusion of collateral vascular bundles, and actually a floral axis with ovules/seeds laterally adhering. On the contrary, the ovary wall was the lateral appendages of the floral axis. The result of the present study is completely in agreement with Unifying Theory, in which the placenta is taken as an ovule-bearing branch. Except for D. chinensis , the similar vascular organization has been observed in placenta of numerous isolated taxa. But till now, it is uncertain that whether this vascular organization pattern is popular in the whole angiosperms or not. More intensive and extensive investigations are needed.

Forebrain pathway for auditory space processing in the barn owl.

PubMed

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

1998-02-01

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

Decreased levels of free D-aspartic acid in the forebrain of serine racemase (Srr) knock-out mice.

PubMed

Horio, Mao; Ishima, Tamaki; Fujita, Yuko; Inoue, Ran; Mori, Hisashi; Hashimoto, Kenji

2013-05-01

d-Serine, an endogenous co-agonist of the N-methyl-d-aspartate (NMDA) receptor is synthesized from l-serine by serine racemase (SRR). A previous study of Srr knockout (Srr-KO) mice showed that levels of d-serine in forebrain regions, such as frontal cortex, hippocampus, and striatum, but not cerebellum, of mutant mice are significantly lower than those of wild-type (WT) mice, suggesting that SRR is responsible for d-serine production in the forebrain. In this study, we attempted to determine whether SRR affects the level of other amino acids in brain tissue. We found that tissue levels of d-aspartic acid in the forebrains (frontal cortex, hippocampus and striatum) of Srr-KO mice were significantly lower than in WT mice, whereas levels of d-aspartic acid in the cerebellum were not altered. Levels of d-alanine, l-alanine, l-aspartic acid, taurine, asparagine, arginine, threonine, γ-amino butyric acid (GABA) and methionine, remained the same in frontal cortex, hippocampus, striatum and cerebellum of WT and mutant mice. Furthermore, no differences in d-aspartate oxidase (DDO) activity were detected in the forebrains of WT and Srr-KO mice. These results suggest that SRR and/or d-serine may be involved in the production of d-aspartic acid in mouse forebrains, although further detailed studies will be necessary to confirm this finding. Copyright © 2013 Elsevier Ltd. All rights reserved.

Dissociating basal forebrain and medial temporal amnesic syndromes: insights from classical conditioning.

PubMed

Myer, Catherine E; Bryant, Deborah; DeLuca, John; Gluck, Mark A

2002-01-01

In humans, anterograde amnesia can result from damage to the medial temporal (MT) lobes (including hippocampus), as well as to other brain areas such as basal forebrain. Results from animal classical conditioning studies suggest that there may be qualitative differences in the memory impairment following MT vs. basal forebrain damage. Specifically, delay eyeblink conditioning is spared after MT damage in animals and humans, but impaired in animals with basal forebrain damage. Recently, we have likewise shown delay eyeblink conditioning impairment in humans with amnesia following anterior communicating artery (ACoA) aneurysm rupture, which damages the basal forebrain. Another associative learning task, a computer-based concurrent visual discrimination, also appears to be spared in MT amnesia while ACoA amnesics are slower to learn the discriminations. Conversely, animal and computational models suggest that, even though MT amnesics may learn quickly, they may learn qualitatively differently from controls, and these differences may result in impaired transfer when familiar information is presented in novel combinations. Our initial data suggests such a two-phase learning and transfer task may provide a double dissociation between MT amnesics (spared initial learning but impaired transfer) and ACoA amnesics (slow initial learning but spared transfer). Together, these emerging data suggest that there are subtle but dissociable differences in the amnesic syndrome following damage to the MT lobes vs. basal forebrain, and that these differences may be most visible in non-declarative tasks such as eyeblink classical conditioning and simple associative learning.

Prosomeric map of the lamprey forebrain based on calretinin immunocytochemistry, Nissl stain, and ancillary markers.

PubMed

Pombal, M A; Puelles, L

1999-11-22

The structural organization of the lamprey extratelencephalic forebrain is re-examined from the perspective of the prosomeric segmental paradigm. The question asked was whether the prosomeric forebrain model used for gnathostomes is of material advantage for interpreting subdivisions in the lamprey forebrain. To this aim, the main longitudinal and transverse landmarks recognized by the prosomeric model in other vertebrates were identified in Nissl-stained lamprey material. Lines of cytoarchitectural discontinuity and contours of migrated neuronal groups were mapped in a two-dimensional sagittal representation and were also classified according to their radial position. Immunocytochemical mapping of calretinin expression in adjacent sections served to define particular structural units better, in particular, the dorsal thalamus. These data were complemented by numerous other chemoarchitectonic observations obtained with ancillary markers, which identified additional specific formations, subdivisions, or boundaries. Emphasis was placed on studying whether such chemically defined neuronal groups showed boundaries aligned with the postulated inter- or intraprosomeric boundaries. The course of diverse axonal tracts was studied also with regard to their prosomeric topography. This analysis showed that the full prosomeric model applies straightforwardly to the lamprey forebrain. This finding implies that a common segmental and longitudinal organization of the neural tube may be primitive for all vertebrates. Interesting novel aspects appear in the interpretation of the lamprey pretectum, the dorsal and ventral thalami, and the hypothalamus. The topologic continuity of the prosomeric forebrain regions with evaginated or non-evaginated portions of the telencephalon was also examined. Copyright 1999 Wiley-Liss, Inc.

Tissue distribution and neuroprotective effects of citrus flavonoid tangeretin in a rat model of Parkinson's disease.

PubMed

Datla, K P; Christidou, M; Widmer, W W; Rooprai, H K; Dexter, D T

2001-12-04

Neuroprotective effects of a natural antioxidant tangeretin, a citrus flavonoid, were elucidated in the 6-hydroxydopamine (6-OHDA) lesion rat model of Parkinson's disease (PD), after bioavailability studies. Following the chronic oral administration (10 mg/kg/day for 28 days), significant levels of tangeretin were detected in the hypothalamus, striatum and hippocampus (3.88, 2.36 and 2.00 ng/mg, respectively). The levels in the liver and plasma were 0.59 ng/mg and 0.11 ng/ml respectively. Unilateral infusion of the dopaminergic neurotoxin, 6-hydroxydopamine (6-OHDA; 8 microg), onto medial forebrain bundle significantly reduced the number of tyrosine hydroxylase positive (TH+) cells in the substantia nigra and decreased striatal dopamine content in the vehicle treated rats. Sub-chronic treatment of the rats with high doses of tangeretin (20 mg/kg/day for 4 days; p.o.) before 6-OHDA lesioning markedly reduced the loss of both TH+ cells and striatal dopamine content. These studies, for the first time, give evidence that tangeretin crosses the blood-brain barrier. The significant protection of striato-nigral integrity and functionality by tangeretin suggests its potential use as a neuroprotective agent.

Videofluorographic assessment of deglutitive behaviors in a rat model of aging and Parkinson disease.

PubMed

Russell, John A; Ciucci, Michelle R; Hammer, Michael J; Connor, Nadine P

2013-03-01

Dysphagia is commonly associated with aging and Parkinson disease and can have a significant impact on a person's quality of life. In some cases, dysphagia may be life-threatening. Animal models may be used to study underlying mechanisms of dysphagia, but paradigms that allow adequate imaging of the swallow in combination with measurement of physiological variables have not been forthcoming. To begin development of methods that allow this, we used videofluorography to record the deglutition behaviors of 22 Fisher 344/Brown Norway rats in young adult (9 months old), old (32 months old), and parkinsonian (unilateral lesion to the medial forebrain bundle) groups. We hypothesized that the old and parkinsonian rats would manifest deficits in deglutition behaviors analogous to those found in human clinical populations. Our results supported our hypothesis in that the old group demonstrated reductions in bolus transport speeds and mastication rate while the parkinsonian rats showed impairments in oral processing. Interpretation of these results should consider the particular animal model, lesion type, and videofluorographic protocol used in this work. Future studies will link swallow imaging data of this kind with physiological and anatomical data in a manner not possible with human participants.

An integrative neuroscience model of "significance" processing.

PubMed

Williams, Leanne M

2006-03-01

The Gordon [37-40] framework of Integrative Neuroscience is used to develop a continuum model for understanding the central role of motivationally-determined "significance" in organizing human information processing. Significance is defined as the property which gives a stimulus relevance to our core motivation to minimize danger and maximize pleasure. Within this framework, the areas of cognition and emotion, theories of motivational arousal and orienting, and the current understanding of neural systems are brought together. The basis of integration is a temporal continuum in which significance processing extends from the most rapid millisecond time scale of automatic, nonconscious mechanisms to the time scale of seconds, in which memory is shaped, to the controlled and conscious mechanisms unfolding over minutes. Over this continuum, significant stimuli are associated with a spectrum of defensive (or consumptive) behaviors through to volitional regulatory behaviors for danger (versus pleasure) and associated brainstem, limbic, medial forebrain bundle and prefrontal circuits, all of which reflect a balance of excitatory (predominant at rapid time scales) to inhibitory mechanisms. Across the lifespan, the negative and positive outcomes of significance processing, coupled with constitutional and genetic factors, will contribute to plasticity, shaping individual adaptations and maladaptions in the balance of excitatory-inhibitory mechanisms.

Affective preclinical modeling of psychiatric disorders: taking imbalanced primal emotional feelings of animals seriously in our search for novel antidepressants

PubMed Central

Panksepp, Jaak

2015-01-01

Preclinical animal models of psychiatric disorders are of critical importance for advances in development of new psychiatric medicine. Regrettably, behavior-only models have yielded no novel targeted treatments during the past half-century of vigorous deployment. This may reflect the general neglect of experiential aspects of animal emotions, since affective mental states of animals supposedly cannot be empirically monitored. This supposition is wrong—to the extent that the rewarding and punishing aspects of emotion circuit arousals reflect positive and negative affective states. During the past decade, the use of such affective neuroscience-based animal modeling has yielded three novel antidepressants (i) via the alleviation of psychic pain with low doses of buprenorphine; (ii) via the amplification of enthusiasm by direct stimulation of the medial forebrain bundle); and (iii) via the facilitation of the capacity for social joy with play facilitators such as rapastinel (GLYX13). All have progressed to successful human testing. For optimal progress, it may be useful for preclinical investigators to focus on the evolved affective foundations of psychiatrically relevant brain emotional disorders for optimal animal modeling. PMID:26869838

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

Videofluorographic assessment of deglutitive behaviors in a rat model of aging and Parkinson disease

PubMed Central

Russell, John A.; Ciucci, Michelle R.; Hammer, Michael J.; Connor, Nadine P.

2012-01-01

Dysphagia is commonly associated with aging and Parkinson disease and can have a significant impact on a person’s quality of life. In some cases, dysphagia may be life threatening. Animal models may be used to study underlying mechanisms of dysphagia, but paradigms that allow adequate imaging of the swallow in combination with measurement of physiological variables have not been forthcoming. To begin development of methods that allow this, we used videofluorography to record the deglutition behaviors of 22 Fischer 344-Brown Norway rats in young adult (9 months old), old (32 months old), and parkinsonian (unilateral lesion to the medial forebrain bundle) groups. We hypothesized that the old and parkinsonian rats would manifest deficits in deglutition behaviors analogous to those found in human clinical populations. Our results supported our hypotheses in that the old group demonstrated reductions in bolus transport speeds and mastication rate, while the parkinsonian rats showed impairments in oral processing. Interpretation of these results should consider the particular animal model, lesion type and videoflurographic protocol used in this work. Future studies will link swallow imaging data of this kind with physiological and anatomical data in a manner not possible with human participants. PMID:22763806

Differential functions of NR2A and NR2B in short-term and long-term memory in rats.

PubMed

Jung, Ye-Ha; Suh, Yoo-Hun

2010-08-23

N-methyl-D-aspartate receptors (NMDARs) are glutamate receptors implicated in synaptic plasticity and memory function. The specific functions of NMDA receptor subunits NR2A and NR2B have not yet been fully determined in the different types of memory. Nine Wistar rats (8-weeks-old) were subjected to the Morris water maze task to evaluate the memory behaviorally. Quantitative analysis of NR1, NR2A, and NR2B levels in the right and left forebrain of rats was performed and subunit associations with different types of memory were investigated using the Morris water maze task. Right forebrain NR2A expression was significantly increased and correlated with faster escape time onto a hidden platform, indicating involvement of short-term memory, because of the training time interval. Right forebrain NR2B expression was positively associated with long-term memory lasting 24-h (h). In the left forebrain, NR2B expression was positively related to 72-h long-term memory. In conclusion, the functions of NR2A and NR2B receptors were differentially specialized in short-term and long-term memory, depending on the right or left forebrain.

Task-phase-specific dynamics of basal forebrain neuronal ensembles

PubMed Central

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

2014-01-01

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

Basal Forebrain Cholinergic Deficits Reduce Glucose Metabolism and Function of Cholinergic and GABAergic Systems in the Cingulate Cortex.

PubMed

Jeong, Da Un; Oh, Jin Hwan; Lee, Ji Eun; Lee, Jihyeon; Cho, Zang Hee; Chang, Jin Woo; Chang, Won Seok

2016-01-01

Reduced brain glucose metabolism and basal forebrain cholinergic neuron degeneration are common features of Alzheimer's disease and have been correlated with memory function. Although regions representing glucose hypometabolism in patients with Alzheimer's disease are targets of cholinergic basal forebrain neurons, the interaction between cholinergic denervation and glucose hypometabolism is still unclear. The aim of the present study was to evaluate glucose metabolism changes caused by cholinergic deficits. We lesioned basal forebrain cholinergic neurons in rats using 192 immunoglobulin G-saporin. After 3 weeks, lesioned animals underwent water maze testing or were analyzed by ¹⁸F-2-fluoro-2-deoxyglucose positron emission tomography. During water maze probe testing, performance of the lesioned group decreased with respect to time spent in the target quadrant and platform zone. Cingulate cortex glucose metabolism in the lesioned group decreased, compared with the normal group. Additionally, acetylcholinesterase activity and glutamate decarboxylase 65/67 expression declined in the cingulate cortex. Our results reveal that spatial memory impairment in animals with selective basal forebrain cholinergic neuron damage is associated with a functional decline in the GABAergic and cholinergic system associated with cingulate cortex glucose hypometabolism.

Eph/Ephrin signalling maintains eye field segregation from adjacent neural plate territories during forebrain morphogenesis

PubMed Central

Cavodeassi, Florencia; Ivanovitch, Kenzo; Wilson, Stephen W.

2013-01-01

During forebrain morphogenesis, there is extensive reorganisation of the cells destined to form the eyes, telencephalon and diencephalon. Little is known about the molecular mechanisms that regulate region-specific behaviours and that maintain the coherence of cell populations undergoing specific morphogenetic processes. In this study, we show that the activity of the Eph/Ephrin signalling pathway maintains segregation between the prospective eyes and adjacent regions of the anterior neural plate during the early stages of forebrain morphogenesis in zebrafish. Several Ephrins and Ephs are expressed in complementary domains in the prospective forebrain and combinatorial abrogation of their activity results in incomplete segregation of the eyes and telencephalon and in defective evagination of the optic vesicles. Conversely, expression of exogenous Ephs or Ephrins in regions of the prospective forebrain where they are not usually expressed changes the adhesion properties of the cells, resulting in segregation to the wrong domain without changing their regional fate. The failure of eye morphogenesis in rx3 mutants is accompanied by a loss of complementary expression of Ephs and Ephrins, suggesting that this pathway is activated downstream of the regional fate specification machinery to establish boundaries between domains undergoing different programmes of morphogenesis. PMID:24026122

Chronic hypertension with subsequent congestive heart failure in a western lowland gorilla (Gorilla gorilla gorilla).

PubMed

Miller, C L; Schwartz, A M; Barnhart, J S; Bell, M D

1999-06-01

Chronic severe subclinical systemic hypertension was diagnosed in a 28-yr-old male western lowland gorilla (Gorilla gorilla gorilla). Thoracic radiography, electrocardiography, and echocardiography revealed an enlarged heart with a hypertrophied left ventricle, mitral regurgitation, and a persistent left bundle branch block. Enalapril, later combined with nifedipine, was of some value in reducing the hypertension, with partial reversal of cardiac enlargement and resolution of the bundle branch block. Two years after initiation of treatment, the gorilla developed lethargy and dyspnea. The diagnosis of heart failure was confirmed under anesthesia; the gorilla did not recover and was euthanized. Postmortem examination confirmed congestive heart failure with chronic, fibrosing cardiomyopathy similar to that in other gorillas.

Systemic administration of defined extracts from Withania somnifera (Indian Ginseng) and Shilajit differentially affects cholinergic but not glutamatergic and GABAergic markers in rat brain.

PubMed

Schliebs, R; Liebmann, A; Bhattacharya, S K; Kumar, A; Ghosal, S; Bigl, V

1997-02-01

Although some promising results have been achieved by acetylcholinesterase inhibitors, an effective therapeutic intervention in Alzheimer's disease still remains an important goal. Sitoindosides VII-X, and withaferin-A, isolated from aqueous methanol extract from the roots of cultivated varieties of Withania somnifera (known as Indian Ginseng), as well as Shilajit, a pale-brown to blackish brown exudation from steep rocks of the Himalaya mountain, are used in Indian medicine to attenuate cerebral functional deficits, including amnesia, in geriatric patients. The present investigation was conducted to assess whether the memory-enhancing effects of plant extracts from Withania somnifera and Shilajit are owing to neurochemical alterations of specific transmitter systems. Therefore, histochemistry to analyse acetylcholinesterase activity as well as receptor autoradiography to detect cholinergic, glutamatergic and GABAergic receptor subtypes were performed in brain slices from adult male Wistar rats, injected intraperitoneally daily with an equimolar mixture of sitoindosides VII-X and withaferin-A (prepared from Withania somnifera) or with Shilajit, at doses of 40 mg/kg of body weight for 7 days. Administration of Shilajit led to reduced acetylcholinesterase staining, restricted to the basal forebrain nuclei including medial septum and the vertical limb of the diagonal band. Systemic application of the defined extract from Withania somnifera, however, led to differential effects on AChE activity in basal forebrain nuclei: slightly enhanced AChE activity was found in the lateral septum and globus pallidus, whereas in the vertical diagonal band AChE activity was reduced following treatment with sitoindosides VII-X and withaferin-A. These changes were accompanied by enhanced M1-muscarinic cholinergic receptor binding in lateral and medial septum as well as in frontal cortices, whereas the M2-muscarinic receptor binding sites were increased in a number of cortical regions including cingulate, frontal, piriform, parietal and retrosplenial cortex. Treatment with Shilajit or the defined extract from Withania somnifera affected neither GABAA and benzodiazepine receptor binding nor NMDA and AMPA glutamate receptor subtypes in any of the cortical or subcortical regions studied. The data suggest that Shilajit and the defined extract from Withania somnifera affect preferentially events in the cortical and basal forebrain cholinergic signal transduction cascade. The drug-induced increase in cortical muscarinic acetylcholine receptor capacity might partly explain the cognition-enhancing and memory-improving effects of extracts from Withania somnifera observed in animals and humans.

Single-nucleus analysis of accessible chromatin in developing mouse forebrain reveals cell-type-specific transcriptional regulation.

PubMed

Preissl, Sebastian; Fang, Rongxin; Huang, Hui; Zhao, Yuan; Raviram, Ramya; Gorkin, David U; Zhang, Yanxiao; Sos, Brandon C; Afzal, Veena; Dickel, Diane E; Kuan, Samantha; Visel, Axel; Pennacchio, Len A; Zhang, Kun; Ren, Bing

2018-03-01

Analysis of chromatin accessibility can reveal transcriptional regulatory sequences, but heterogeneity of primary tissues poses a significant challenge in mapping the precise chromatin landscape in specific cell types. Here we report single-nucleus ATAC-seq, a combinatorial barcoding-assisted single-cell assay for transposase-accessible chromatin that is optimized for use on flash-frozen primary tissue samples. We apply this technique to the mouse forebrain through eight developmental stages. Through analysis of more than 15,000 nuclei, we identify 20 distinct cell populations corresponding to major neuronal and non-neuronal cell types. We further define cell-type-specific transcriptional regulatory sequences, infer potential master transcriptional regulators and delineate developmental changes in forebrain cellular composition. Our results provide insight into the molecular and cellular dynamics that underlie forebrain development in the mouse and establish technical and analytical frameworks that are broadly applicable to other heterogeneous tissues.

Optogenetic fMRI and electrophysiological identification of region-specific connectivity between the cerebellar cortex and forebrain.

PubMed

Choe, Katrina Y; Sanchez, Carlos F; Harris, Neil G; Otis, Thomas S; Mathews, Paul J

2018-06-01

Complex animal behavior is produced by dynamic interactions between discrete regions of the brain. As such, defining functional connections between brain regions is critical in gaining a full understanding of how the brain generates behavior. Evidence suggests that discrete regions of the cerebellar cortex functionally project to the forebrain, mediating long-range communication potentially important in motor and non-motor behaviors. However, the connectivity map remains largely incomplete owing to the challenge of driving both reliable and selective output from the cerebellar cortex, as well as the need for methods to detect region specific activation across the entire forebrain. Here we utilize a paired optogenetic and fMRI (ofMRI) approach to elucidate the downstream forebrain regions modulated by activating a region of the cerebellum that induces stereotypical, ipsilateral forelimb movements. We demonstrate with ofMRI, that activating this forelimb motor region of the cerebellar cortex results in functional activation of a variety of forebrain and midbrain areas of the brain, including the hippocampus and primary motor, retrosplenial and anterior cingulate cortices. We further validate these findings using optogenetic stimulation paired with multi-electrode array recordings and post-hoc staining for molecular markers of activated neurons (i.e. c-Fos). Together, these findings demonstrate that a single discrete region of the cerebellar cortex is capable of influencing motor output and the activity of a number of downstream forebrain as well as midbrain regions thought to be involved in different aspects of behavior. Copyright © 2018 Elsevier Inc. All rights reserved.

Forebrain Mechanisms of Nociception and Pain: Analysis through Imaging

NASA Astrophysics Data System (ADS)

Casey, Kenneth L.

1999-07-01

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

Expression of aromatase in the embryonic brain of the olive ridley sea turtle (Lepidochelys olivacea), and the effect of bisphenol-A in sexually differentiated embryos.

PubMed

Gómez-Picos, Patsy; Sifuentes-Romero, Itzel; Merchant-Larios, Horacio; Hernández-Cornejo, Rubí; Díaz-Hernández, Verónica; García-Gasca, Alejandra

2014-01-01

Brain aromatase participates in several biological processes, such as regulation of the reproductive-endocrine axis, memory, stress, sexual differentiation of the nervous system, male sexual behavior, and brain repair. Here we report the isolation and expression of brain aromatase in olive ridley sea turtle (Lepidochelys olivacea) embryos incubated at male- and female-promoting temperatures (MPT and FPT, respectively), at the thermosensitive period (TSP) and the sex-differentiated period. Also, aromatase expression was assessed in differentiated embryos exposed to bisphenol-A (BPA) during the TSP. BPA is a monomer of polycarbonate plastics and is considered an endocrine-disrupting compound. Normal aromatase expression was measured in both forebrain and hindbrain, showing higher expression levels in the forebrain of differentiated embryos at both incubation temperatures. Although no significant differences were detected in the hindbrain, expression was slightly higher at MPT. BPA did not affect aromatase expression neither in forebrains or hindbrains from embryos incubated at MPT, whereas at FPT an inverted U-shape curve was observed in forebrains with significant differences at lower concentrations, whereas in hindbrains a non-significant increment was observed at higher concentrations. Our data indicate that both incubation temperature and developmental stage are critical factors affecting aromatase expression in the forebrain. Because of the timing and location of aromatase expression in the brain, we suggest that brain aromatase may participate in the imprinting of sexual trends related to reproduction and sexual behavior at the onset of sex differentiation, and BPA exposure may impair aromatase function in the female forebrain.

Transcript profiling of a novel plant meristem, the monocot cambium

Treesearch

Matthew Zinkgraf; Suzanne Gerttula; Andrew Groover

2017-01-01

While monocots lack the ability to produce a vascular cambium or woody growth, some monocot lineages evolved a novel lateral meristem, the monocot cambium, which supports secondary radial growth of stems. In contrast to the vascular cambium found in woody angiosperm and gymnosperm species, the monocot cambium produces secondary vascular bundles, which have an...

A Comprehensive Reanalysis of the Distal Iliotibial Band: Quantitative Anatomy, Radiographic Markers, and Biomechanical Properties.

PubMed

Godin, Jonathan A; Chahla, Jorge; Moatshe, Gilbert; Kruckeberg, Bradley M; Muckenhirn, Kyle J; Vap, Alexander R; Geeslin, Andrew G; LaPrade, Robert F

2017-09-01

The qualitative anatomy of the distal iliotibial band (ITB) has previously been described. However, a comprehensive characterization of the quantitative anatomic, radiographic, and biomechanical properties of the Kaplan fibers of the deep distal ITB has not yet been established. It is paramount to delineate these characteristics to fully understand the distal ITB's contribution to rotational knee stability. Purpose/Hypothesis: There were 2 distinct purposes for this study: (1) to perform a quantitative anatomic and radiographic evaluation of the distal ITB's attachment sites and their relationships to pertinent osseous and soft tissue landmarks, and (2) to quantify the biomechanical properties of the deep (Kaplan) fibers of the distal ITB. It was hypothesized that the distal ITB has definable parameters concerning its anatomic attachments and consistent relationships to surgically pertinent landmarks with correlating plain radiographic findings. In addition, it was hypothesized that the biomechanical properties of the Kaplan fibers would support their role as important restraints against internal rotation. Descriptive laboratory study. Ten nonpaired, fresh-frozen human cadaveric knees (mean age, 61.1 years; range, 54-65 years) were dissected for anatomic and radiographic purposes. A coordinate measuring device quantified the attachment areas of the distal ITB to the distal femur, patella, and proximal tibia and their relationships to pertinent bony landmarks. A radiographic analysis was performed by inserting pins into the attachment sites of relevant anatomic structures to assess their location relative to pertinent bony landmarks with fluoroscopic guidance. A further biomechanical assessment of 10 cadaveric knees quantified the load to failure and stiffness of the Kaplan fibers' insertion on the distal femur after a preconditioning protocol. Two separate deep (Kaplan) fiber bundles were identified with attachments to 2 newly identified femoral bony prominences (ridges). The proximal and distal bundles inserted on the distal femur 53.6 mm (95% CI, 50.7-56.6 mm) and 31.4 mm (95% CI, 27.3-35.5 mm) proximal to the lateral epicondyle, respectively. The centers of the bundle insertions were 22.5 mm (95% CI, 19.1-25.9 mm) apart. The total insertion area of the distal ITB on the proximal tibia was 429.1 mm 2 (95% CI, 349.2-509.1 mm 2 ). A distinct capsulo-osseous layer of the distal ITB was also identified that was intimately related to the lateral knee capsule. Its origin was in close proximity to the lateral gastrocnemius tubercle, and it inserted on the proximal tibia at the lateral tibial tubercle between the fibular head and the Gerdy tubercle. Radiographic analysis supported the quantitative anatomic findings. The mean maximum load during pull-to-failure testing was 71.3 N (95% CI, 41.2-101.4 N) and 170.2 N (95% CI, 123.6-216.8 N) for the proximal and distal Kaplan bundles, respectively. The most important finding of this study was that 2 distinct deep bundles (Kaplan fibers) of the distal ITB were identified. Each bundle of the deep layer of the ITB was associated with a newly identified distinct bony ridge. Radiographic analysis confirmed the measurements previously recorded and established reproducible landmarks for the newly described structures. Biomechanical testing revealed that the Kaplan fibers had a strong attachment to the distal femur, thereby supporting a role in rotational knee stability. The identification of 2 distinct deep fiber (Kaplan) attachments clarifies the function of the ITB more definitively. The results also support the role of the ITB in rotatory knee stability because of the fibers' vectors and their identified maximum loads. These findings provide the anatomic and biomechanical foundation needed for the development of reconstruction or repair techniques to anatomically address these deficiencies in knee ligament injuries.

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

Nord, Alex S.; Pattabiraman, Kartik; Visel, Axel

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

Enhanced recognition memory following glycine transporter 1 deletion in forebrain neurons.

PubMed

Singer, Philipp; Boison, Detlev; Möhler, Hanns; Feldon, Joram; Yee, Benjamin K

2007-10-01

Selective deletion of glycine transporter 1 (GlyT1) in forebrain neurons enhances N-methyl-D-aspartate receptor (NMDAR)-dependent neurotransmission and facilitates associative learning. These effects are attributable to increases in extracellular glycine availability in forebrain neurons due to reduced glycine re-uptake. Using a forebrain- and neuron-specific GlyT1-knockout mouse line (CamKIIalphaCre; GlyT1tm1.2fl/fI), the authors investigated whether this molecular intervention can affect recognition memory. In a spontaneous object recognition memory test, enhanced preference for a novel object was demonstrated in mutant mice relative to littermate control subjects at a retention interval of 2 hr, but not at 2 min. Furthermore, mutants were responsive to a switch in the relative spatial positions of objects, whereas control subjects were not. These potential procognitive effects were demonstrated against a lack of difference in contextual novelty detection: Mutant and control subjects showed equivalent preference for a novel over a familiar context. Results therefore extend the possible range of potential promnesic effects of specific forebrain neuronal GlyT1 deletion from associative learning to recognition memory and further support the possibility that mnemonic functions can be enhanced by reducing GlyT1 function. (PsycINFO Database Record (c) 2007 APA, all rights reserved).

Brittle-to-ductile transition in a fiber bundle with strong heterogeneity.

PubMed

Kovács, Kornél; Hidalgo, Raul Cruz; Pagonabarraga, Ignacio; Kun, Ferenc

2013-04-01

We analyze the failure process of a two-component system with widely different fracture strength in the framework of a fiber bundle model with localized load sharing. A fraction 0≤α≤1 of the bundle is strong and it is represented by unbreakable fibers, while fibers of the weak component have randomly distributed failure strength. Computer simulations revealed that there exists a critical composition α(c) which separates two qualitatively different behaviors: Below the critical point, the failure of the bundle is brittle, characterized by an abrupt damage growth within the breakable part of the system. Above α(c), however, the macroscopic response becomes ductile, providing stability during the entire breaking process. The transition occurs at an astonishingly low fraction of strong fibers which can have importance for applications. We show that in the ductile phase, the size distribution of breaking bursts has a power law functional form with an exponent μ=2 followed by an exponential cutoff. In the brittle phase, the power law also prevails but with a higher exponent μ=9/2. The transition between the two phases shows analogies to continuous phase transitions. Analyzing the microstructure of the damage, it was found that at the beginning of the fracture process cracks nucleate randomly, while later on growth and coalescence of cracks dominate, which give rise to power law distributed crack sizes.

Neuronal Circuitry Mechanisms Regulating Adult Mammalian Neurogenesis

PubMed Central

Song, Juan; Olsen, Reid H.J.; Sun, Jiaqi; Ming, Guo-li; Song, Hongjun

2017-01-01

The adult mammalian brain is a dynamic structure, capable of remodeling in response to various physiological and pathological stimuli. One dramatic example of brain plasticity is the birth and subsequent integration of newborn neurons into the existing circuitry. This process, termed adult neurogenesis, recapitulates neural developmental events in two specialized adult brain regions: the lateral ventricles of the forebrain. Recent studies have begun to delineate how the existing neuronal circuits influence the dynamic process of adult neurogenesis, from activation of quiescent neural stem cells (NSCs) to the integration and survival of newborn neurons. Here, we review recent progress toward understanding the circuit-based regulation of adult neurogenesis in the hippocampus and olfactory bulb. PMID:27143698

Control of arousal by the orexin neurons

PubMed Central

Alexandre, Chloe; Andermann, Mark L; Scammell, Thomas E

2013-01-01

The orexin-producing neurons in the lateral hypothalamus play an essential role in promoting arousal and maintaining wakefulness. These neurons receive a broad variety of signals related to environmental, physiological and emotional stimuli; they project to almost every brain region involved in the regulation of wakefulness; and they fire most strongly during active wakefulness, high motor activation, and sustained attention. This review focuses on the specific neuronal pathways through which the orexin neurons promote wakefulness and maintain high level of arousal, and how recent studies using optogenetic and pharmacogenetic methods have demonstrated that the locus coeruleus, the tuberomammillary nucleus, and the basal forebrain are some of the key sites mediating the arousing actions of orexins. PMID:23683477

Spatiotemporal changes in the distribution of LHFPL5 in mice cochlear hair bundles during development and in the absence of PCDH15

PubMed Central

Mahendrasingam, Shanthini; Fettiplace, Robert; Alagramam, Kumar N.; Cross, Ellen

2017-01-01

Mechanosensory transduction by vertebrate hair cells depends on a protein complex at the tips of shorter stereocilia associated with mechanoelectrical transduction channels activated by tip links in the hair bundle. In mammalian hair cells, this complex includes transmembrane channel-like protein subunit 1 (TMC1), lipoma HMGIC fusion partner-like 5 protein (LHFPL5) and protocadherin 15 (PCDH15), a lower-end component of the tip link. TMC1 interacts with LHFPL5 and PCDH15 but how the complex develops to maturity, and the relationships between these proteins, remains uncertain. Here we evaluate the spatiotemporal development of LHFPL5 distributions in mouse cochlear hair bundles by immunofluorescence and immunogold transmission electron microscopy, from postnatal day 0 (P0) through P21 in wild type and PCDH15-deficient mice. At P0, hair bundles contain many short microvilli-like processes which we term unranked stereocilia, and a subset of lengthening rows, adjacent to a kinocilium. LHFPL5 is distributed throughout the bundle, including on stereocilia tips and the kinocilium. At P3, 4-to-6 rows of ranked stereocilia are evident, total LHFPL5 expression peaks, and LHFPL5 is localised to ranked stereocilia tips of all rows and to lower shaft/ankle links. By P12, the bundle has a mature pattern with 3 ranked rows but virtually no unranked stereocilia or kinocilium; LHFPL5 expression has declined and become restricted to the tips of shorter stereocilia. Throughout development from P0, expression of LHFPL5 is greater overall on apical than basal bundles, but there is, on average, an equal amount of labelling per labelled tip. In P3 mice lacking PCDH15, LHFPL5 labelling is not at the tips but is primarily on unranked stereocilia and lower lateral links. These data show that LHFPL5 is already present in the MET apparatus at P0 but requires PCDH15 at P3 to remain there. Shaft/ankle link localisation suggests it interacts with link proteins other than PCDH15. PMID:29069081

[Premature outflow tract ventricular contraction combined with complete bundle branch block: the characteristic electrocardiographic and ablation target potential features].

PubMed

Di, C Y; Wan, Z; Li, K; Ding, Y S; Lin, W H

2017-12-01

Objective: To explore the characteristics of electrocardiogram(ECG) and target potential features of premature ventricular contraction (PVC) in patients with complete left/right bundle branch block (CL/RBBB) and compare with those without CL/RBBB. Methods: A retrospective analysis was done in 8 outflow tract PVC patients with CL/RBBB, who successfully underwent radiofrequency ablation from August 2009 to June 2017. According to the bundle branch block chamber, patients were divided into the complete right bundle branch block (CRBBB) group ( n= 4) and the complete left bundle branch block (CLBBB) group ( n= 4). The control group were those who successfully underwent ablation at the same position as the above two groups but without CL/RBBB. The characteristics of ECG and target potential features were compared among groups. Results: One case in the CRBBB group was successfully ablated in the great cardiac vein with precordial R/S>1 transition at V(1) and one case in the CLBBB group was successfully ablated in the right coronary cusp with precordial R/S>1 transition at V(2), while other 6 cases were all with precordial R/S>1 transition at lead V(4). Precordial R/S>1 transition was not later than sinus rhythm (SR) in the CLBBB group. No statistical difference was found in the QRS complex duration between SR and PVC in the CL/RBBB patients [(134.38±23.80)ms vs (156.75±25.93)ms, P> 0.05], while statistical difference was shown in the control group [(92.63±5.76)ms vs (140.25±15.97)ms, P< 0.05]. Conclusion: Bundle branch block can lead to misjudgment of PVC origin with CL/RBBB during sinus rhythm, thus the origin chamber of the PVC should be determined according to the mapping and ablation result.

Development of the nervous system in Phoronopsis harmeri (Lophotrochozoa, Phoronida) reveals both deuterostome- and trochozoan-like features

PubMed Central

2012-01-01

Background Inferences concerning the evolution of invertebrate nervous systems are often hampered by the lack of a solid data base for little known but phylogenetically crucial taxa. In order to contribute to the discussion concerning the ancestral neural pattern of the Lophotrochozoa (a major clade that includes a number of phyla that exhibit a ciliated larva in their life cycle), we investigated neurogenesis in Phoronopsis harmeri, a member of the poorly studied Phoronida, by using antibody staining against serotonin and FMRFamide in combination with confocal microscopy and 3D reconstruction software. Results The larva of Phoronopsis harmeri exhibits a highly complex nervous system, including an apical organ that consists of four different neural cell types, such as numerous serotonin-like immunoreactive flask-shaped cells. In addition, serotonin- and FMRFamide-like immunoreactive bi- or multipolar perikarya that give rise to a tentacular neurite bundle which innervates the postoral ciliated band are found. The preoral ciliated band is innervated by marginal serotonin-like as well as FMRFamide-like immunoreactive neurite bundles. The telotroch is innervated by two neurite bundles. The oral field is the most densely innervated area and contains ventral and ventro-lateral neurite bundles as well as several groups of perikarya. The digestive system is innervated by both serotonin- and FMRFamide-like immunoreactive neurites and perikarya. Importantly, older larvae of P. harmeri show a paired ventral neurite bundle with serial commissures and perikarya. Conclusions Serotonin-like flask-shaped cells such as the ones described herein for Phoronopsis harmeri are found in the majority of lophotrochozoan larvae and therefore most likely belong to the ground pattern of the last common lophotrochozoan ancestor. The finding of a transitory paired ventral neurite bundle with serially repeated commissures that disappears during metamorphosis suggests that such a structure was part of the “ur-phoronid” nervous system, but was lost in the adult stage, probably due to its acquired sessile benthic lifestyle. PMID:22827441

Habenula functional resting-state connectivity in pediatric CRPS.

PubMed

Erpelding, Nathalie; Sava, Simona; Simons, Laura E; Lebel, Alyssa; Serrano, Paul; Becerra, Lino; Borsook, David

2014-01-01

The habenula (Hb) is a small brain structure located in the posterior end of the medial dorsal thalamus and through medial (MHb) and lateral (LHb) Hb connections, it acts as a conduit of information between forebrain and brainstem structures. The role of the Hb in pain processing is well documented in animals and recently also in acute experimental pain in humans. However, its function remains unknown in chronic pain disorders. Here, we investigated Hb resting-state functional connectivity (rsFC) in patients with complex regional pain syndrome (CRPS) compared with healthy controls. Twelve pediatric patients with unilateral lower-extremity CRPS (9 females; 10-17 yr) and 12 age- and sex-matched healthy controls provided informed consent to participate in the study. In healthy controls, Hb functional connections largely overlapped with previously described anatomical connections in cortical, subcortical, and brainstem structures. Compared with controls, patients exhibited an overall Hb rsFC reduction with the rest of the brain and, specifically, with the anterior midcingulate cortex, dorsolateral prefrontal cortex, supplementary motor cortex, primary motor cortex, and premotor cortex. Our results suggest that Hb rsFC parallels anatomical Hb connections in the healthy state and that overall Hb rsFC is reduced in patients, particularly connections with forebrain areas. Patients' decreased Hb rsFC to brain regions implicated in motor, affective, cognitive, and pain inhibitory/modulatory processes may contribute to their symptomatology.

Functional topography of serotonergic systems supports the Deakin/Graeff hypothesis of anxiety and affective disorders.

PubMed

Paul, Evan D; Lowry, Christopher A

2013-12-01

Over 20 years ago, Deakin and Graeff hypothesized about the role of different serotonergic pathways in controlling the behavioral and physiologic responses to aversive stimuli, and how compromise of these pathways could lead to specific symptoms of anxiety and affective disorders. A growing body of evidence suggests these serotonergic pathways arise from topographically organized subpopulations of serotonergic neurons located in the dorsal and median raphe nuclei. We argue that serotonergic neurons in the dorsal/caudal parts of the dorsal raphe nucleus project to forebrain limbic regions involved in stress/conflict anxiety-related processes, which may be relevant for anxiety and affective disorders. Serotonergic neurons in the "lateral wings" of the dorsal raphe nucleus provide inhibitory control over structures controlling fight-or-flight responses. Dysfunction of this pathway could be relevant for panic disorder. Finally, serotonergic neurons in the median raphe nucleus, and the developmentally and functionally-related interfascicular part of the dorsal raphe nucleus, give rise to forebrain limbic projections that are involved in tolerance and coping with aversive stimuli, which could be important for affective disorders like depression. Elucidating the mechanisms through which stress activates these topographically and functionally distinct serotonergic pathways, and how dysfunction of these pathways leads to symptoms of neuropsychiatric disorders, may lead to the development of novel approaches to both the prevention and treatment of anxiety and affective disorders.

Is There Evidence for Myelin Modeling by Astrocytes in the Normal Adult Brain?

PubMed Central

Varela-Echevarría, Alfredo; Vargas-Barroso, Víctor; Lozano-Flores, Carlos; Larriva-Sahd, Jorge

2017-01-01

A set of astrocytic process associated with altered myelinated axons is described in the forebrain of normal adult rodents with confocal, electron microscopy, and 3D reconstructions. Each process consists of a protuberance that contains secretory organelles including numerous lysosomes which polarize and open next to disrupted myelinated axons. Because of the distinctive asymmetric organelle distribution and ubiquity throughout the forebrain neuropil, this enlargement is named paraxial process (PAP). The myelin envelope contiguous to the PAP displays focal disruption or disintegration. In routine electron microscopy clusters of large, confluent, lysosomes proved to be an effective landmark for PAP identification. In 3D assemblies lysosomes organize a series of interconnected saccules that open up to the plasmalemma next to the disrupted myelin envelope(s). Activity for acid hydrolases was visualized in lysosomes, and extracellularly at the PAP-myelin interface and/or between the glial and neuronal outer aspects. Organelles in astrocytic processes involved in digesting pyknotic cells and debris resemble those encountered in PAPs supporting a likewise lytic function of the later. Conversely, processes entangling tripartite synapses and glomeruli were devoid of lysosomes. Both oligodendrocytic and microglial processes were not associated with altered myelin envelopes. The possible roles of the PAP in myelin remodeling in the context of the oligodendrocyte-astrocyte interactions and in the astrocyte's secretory pathways are discussed. PMID:28932188

THE DEVELOPMENT OF SLEEP-WAKE RHYTHMS AND THE SEARCH FOR ELEMENTAL CIRCUITS IN THE INFANT BRAIN

PubMed Central

Blumberg, Mark S.; Gall, Andrew J.; Todd, William D.

2014-01-01

Despite the predominance of sleep in early infancy, developmental science has yet to play a major role in shaping concepts and theories about sleep and its associated ultradian and circadian rhythms. Here we argue that developmental analyses help us to elucidate the relative contributions of the brainstem and forebrain to sleep-wake control and to dissect the neural components of sleep-wake rhythms. Developmental analysis also makes it clear that sleep-wake processes in infants are the foundation for those of adults. For example, the infant brainstem alone contains a fundamental sleep-wake circuit that is sufficient to produce transitions among wakefulness, quiet sleep, and active sleep. Also, consistent with the requirements of a “flip-flop” model of sleep-wake processes, this brainstem circuit supports rapid transitions between states. Later in development, strengthening bidirectional interactions between the brainstem and forebrain contribute to the consolidation of sleep and wake bouts, the elaboration of sleep homeostatic processes, and the emergence of diurnal or nocturnal circadian rhythms. The developmental perspective promoted here critically constrains theories of sleep-wake control and provides a needed framework for the creation of fully realized computational models. Finally, with a better understanding of how this system is constructed developmentally, we will gain insight into the processes that govern its disintegration due to aging and disease. PMID:24708298

The development of sleep-wake rhythms and the search for elemental circuits in the infant brain.

PubMed

Blumberg, Mark S; Gall, Andrew J; Todd, William D

2014-06-01

Despite the predominance of sleep in early infancy, developmental science has yet to play a major role in shaping concepts and theories about sleep and its associated ultradian and circadian rhythms. Here we argue that developmental analyses help us to elucidate the relative contributions of the brainstem and forebrain to sleep-wake control and to dissect the neural components of sleep-wake rhythms. Developmental analysis also makes it clear that sleep-wake processes in infants are the foundation for those of adults. For example, the infant brainstem alone contains a fundamental sleep-wake circuit that is sufficient to produce transitions among wakefulness, quiet sleep, and active sleep. In addition, consistent with the requirements of a "flip-flop" model of sleep-wake processes, this brainstem circuit supports rapid transitions between states. Later in development, strengthening bidirectional interactions between the brainstem and forebrain contribute to the consolidation of sleep and wake bouts, the elaboration of sleep homeostatic processes, and the emergence of diurnal or nocturnal circadian rhythms. The developmental perspective promoted here critically constrains theories of sleep-wake control and provides a needed framework for the creation of fully realized computational models. Finally, with a better understanding of how this system is constructed developmentally, we will gain insight into the processes that govern its disintegration due to aging and disease.

Zebrafish zic2a patterns the forebrain through modulation of Hedgehog-activated gene expression

PubMed Central

Sanek, Nicholas A.; Taylor, Aaron A.; Nyholm, Molly K.; Grinblat, Yevgenya

2009-01-01

Summary Holoprosencephaly (HPE) is the most common congenital malformation of the forebrain in human. Several genes with essential roles during forebrain development have been identified because they cause HPE when mutated. Among these are genes that encode the secreted growth factor Sonic hedgehog (Shh) and the transcription factors Six3 and Zic2. In the mouse, Six3 and Shh activate each other's transcription, but a role for Zic2 in this interaction has not been tested. We demonstrate that in zebrafish, as in mouse, Hh signaling activates transcription of six3b in the developing forebrain. zic2a is also activated by Hh signaling, and represses six3b non-cell-autonomously, i.e. outside of its own expression domain, probably through limiting Hh signaling. Zic2a repression of six3b is essential for the correct formation of the prethalamus. The diencephalon-derived optic stalk (OS) and neural retina are also patterned in response to Hh signaling. We show that zebrafish Zic2a limits transcription of the Hh targets pax2a and fgf8a in the OS and retina. The effects of Zic2a depletion in the forebrain and in the OS and retina are rescued by blocking Hh signaling or by increasing levels of the Hh antagonist Hhip, suggesting that in both tissues Zic2a acts to attenuate the effects of Hh signaling. These data uncover a novel, essential role for Zic2a as a modulator of Hh-activated gene expression in the developing forebrain and advance our understanding of a key gene regulatory network that, when disrupted, causes HPE. PMID:19855021

Zebrafish zic2a patterns the forebrain through modulation of Hedgehog-activated gene expression.

PubMed

Sanek, Nicholas A; Taylor, Aaron A; Nyholm, Molly K; Grinblat, Yevgenya

2009-11-01

Holoprosencephaly (HPE) is the most common congenital malformation of the forebrain in human. Several genes with essential roles during forebrain development have been identified because they cause HPE when mutated. Among these are genes that encode the secreted growth factor Sonic hedgehog (Shh) and the transcription factors Six3 and Zic2. In the mouse, Six3 and Shh activate each other's transcription, but a role for Zic2 in this interaction has not been tested. We demonstrate that in zebrafish, as in mouse, Hh signaling activates transcription of six3b in the developing forebrain. zic2a is also activated by Hh signaling, and represses six3b non-cell-autonomously, i.e. outside of its own expression domain, probably through limiting Hh signaling. Zic2a repression of six3b is essential for the correct formation of the prethalamus. The diencephalon-derived optic stalk (OS) and neural retina are also patterned in response to Hh signaling. We show that zebrafish Zic2a limits transcription of the Hh targets pax2a and fgf8a in the OS and retina. The effects of Zic2a depletion in the forebrain and in the OS and retina are rescued by blocking Hh signaling or by increasing levels of the Hh antagonist Hhip, suggesting that in both tissues Zic2a acts to attenuate the effects of Hh signaling. These data uncover a novel, essential role for Zic2a as a modulator of Hh-activated gene expression in the developing forebrain and advance our understanding of a key gene regulatory network that, when disrupted, causes HPE.

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

PubMed Central

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

2015-01-01

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

The effects of increasing PGE2 on translocation of labeled albumin into rat brain.

PubMed

Messripour, M; Mesripour, A; Mashayekhie, F J

2015-01-01

Under pathophysiological conditions, infiltration of leukocyte plays a key role in the progression of the neuroinflammatory reaction in the CNS. Prostaglandin E2 (PGE2) is known to accumulate at lesion sites of the post-ischemic brain. Although post-ischemic treatments with cyclooxygenase-2 inhibitors reduce blood-brain barrier (BBB) leukocyte infiltration, the direct effect of PGE2 on BBB has not been fully implemented. Therefore, the direct effect of increasing PGE2 infusion on translocation of labeled albumin into the brain was assessed. Under anesthesia rats were drilled stereo-taxicaly a burr hole in the right forebrain and PGE2 was infused into the forebrain and the hole was occluded. The animals were then injected with fluorescent labeled albumin (FA), via internal right jugular vein and decapitated at different infusion time points. The forebrain was removed and each forebrain hemisphere was homogenized and fluorescence intensities were measured in the supernatant. The fluorescence intensities measured in the right and left forebrain hemispheres of the control group (0.0 μg PGE2) were almost identical. Four hours after infusion of PGE2 at doses higher than 250 μg, fluorescence intensity increased in the right forebrain supernatant, even if it was not statistically significant. The fluorescence intensity was detectable in the brain supernatant 4 h after infusion of PGE2 in doses higher than 250 μg PGE2. The highest fluorescence intensity was 16 h after infusion of 500 μg PGE2, which returned to near control values after 48 h. Increased fluorescence intensity in the brain following PGE2 infusion is concluded to be associated with disruption of the BBB.

Improvement in process of care and outcome after a multicenter severe sepsis educational program in Spain.

PubMed

Ferrer, Ricard; Artigas, Antonio; Levy, Mitchell M; Blanco, Jesús; González-Díaz, Gumersindo; Garnacho-Montero, José; Ibáñez, Jordi; Palencia, Eduardo; Quintana, Manuel; de la Torre-Prados, María Victoria

2008-05-21

Concern exists that current guidelines for care of patients with severe sepsis and septic shock are followed variably, possibly due to a lack of adequate education. To determine whether a national educational program based on the Surviving Sepsis Campaign guidelines affected processes of care and hospital mortality for severe sepsis. Before and after design in 59 medical-surgical intensive care units (ICUs) located throughout Spain. All ICU patients were screened daily and enrolled if they fulfilled severe sepsis or septic shock criteria. A total of 854 patients were enrolled in the preintervention period (November-December 2005), 1465 patients during the postintervention period (March-June 2006), and 247 patients during the long-term follow-up period 1 year later (November-December 2006) in a subset of 23 ICUs. The educational program consisted of training physicians and nursing staff from the emergency department, wards, and ICU in the definition, recognition, and treatment of severe sepsis and septic shock as outlined in the guidelines. Treatment was organized in 2 bundles: a resuscitation bundle (6 tasks to begin immediately and be accomplished within 6 hours) and a management bundle (4 tasks to be completed within 24 hours). Hospital mortality, differences in adherence to the bundles' process-of-care variables, ICU mortality, 28-day mortality, hospital length of stay, and ICU length of stay. Patients included before and after the intervention were similar in terms of age, sex, and Acute Physiology and Chronic Health Evaluation II score. At baseline, only 3 process-of-care measurements (blood cultures before antibiotics, early administration of broad-spectrum antibiotics, and mechanical ventilation with adequate inspiratory plateau pressure) we had compliance rates higher than 50%. Patients in the postintervention cohort had a lower risk of hospital mortality (44.0% vs 39.7%; P = .04). The compliance with process-of-care variables also improved after the intervention in the sepsis resuscitation bundle (5.3% [95% confidence interval [CI], 4%-7%] vs 10.0% [95% CI, 8%-12%]; P < .001) and in the sepsis management bundle (10.9% [95% CI, 9%-13%] vs 15.7% [95% CI, 14%-18%]; P = .001). Hospital length of stay and ICU length of stay did not change after the intervention. During long-term follow-up, compliance with the sepsis resuscitation bundle returned to baseline but compliance with the sepsis management bundle and mortality remained stable with respect to the postintervention period. A national educational effort to promote bundles of care for severe sepsis and septic shock was associated with improved guideline compliance and lower hospital mortality. However, compliance rates were still low, and the improvement in the resuscitation bundle lapsed by 1 year.

Reversible chronic acquired complete atrioventricular block.

PubMed

Rakovec, P; Milcinski, G; Voga, G; Korsic, L

1982-01-01

The return of atrioventricular conduction is reported in a case after nearly four years of complete acquired heart block. After recovery from atrioventricular block, right bundle branch block persisted, but P-R interval and H-V interval were normal. Three months later a relapse of second degree infranodal atrioventricular block was noted. A short review of similar cases from the literature is given.

Effect of basal forebrain stimulation on extracellular acetylcholine release and blood flow in the olfactory bulb.

PubMed

Uchida, Sae; Kagitani, Fusako

2017-05-12

The olfactory bulb receives cholinergic basal forebrain input, as does the neocortex; however, the in vivo physiological functions regarding the release of extracellular acetylcholine and regulation of regional blood flow in the olfactory bulb are unclear. We used in vivo microdialysis to measure the extracellular acetylcholine levels in the olfactory bulb of urethane-anesthetized rats. Focal chemical stimulation by microinjection of L-glutamate into the horizontal limb of the diagonal band of Broca (HDB) in the basal forebrain, which is the main source of cholinergic input to the olfactory bulb, increased extracellular acetylcholine release in the ipsilateral olfactory bulb. When the regional cerebral blood flow was measured using laser speckle contrast imaging, the focal chemical stimulation of the HDB did not significantly alter the blood flow in the olfactory bulb, while increases were observed in the neocortex. Our results suggest a functional difference between the olfactory bulb and neocortex regarding cerebral blood flow regulation through the release of acetylcholine by cholinergic basal forebrain input.

Downregulation of ribosome biogenesis during early forebrain development

PubMed Central

Chau, Kevin F; Shannon, Morgan L; Fame, Ryann M; Fonseca, Erin; Mullan, Hillary; Johnson, Matthew B; Sendamarai, Anoop K; Springel, Mark W; Laurent, Benoit

2018-01-01

Forebrain precursor cells are dynamic during early brain development, yet the underlying molecular changes remain elusive. We observed major differences in transcriptional signatures of precursor cells from mouse forebrain at embryonic days E8.5 vs. E10.5 (before vs. after neural tube closure). Genes encoding protein biosynthetic machinery were strongly downregulated at E10.5. This was matched by decreases in ribosome biogenesis and protein synthesis, together with age-related changes in proteomic content of the adjacent fluids. Notably, c-MYC expression and mTOR pathway signaling were also decreased at E10.5, providing potential drivers for the effects on ribosome biogenesis and protein synthesis. Interference with c-MYC at E8.5 prematurely decreased ribosome biogenesis, while persistent c-MYC expression in cortical progenitors increased transcription of protein biosynthetic machinery and enhanced ribosome biogenesis, as well as enhanced progenitor proliferation leading to subsequent macrocephaly. These findings indicate large, coordinated changes in molecular machinery of forebrain precursors during early brain development. PMID:29745900

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

NASA Technical Reports Server (NTRS)

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

1994-01-01

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

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

PubMed

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

1998-01-01

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

The imaging features of the meniscal roots on isotropic 3D MRI in young asymptomatic volunteers.

PubMed

Wang, Ping; Zhang, Cheng-Zhou; Zhang, Di; Liu, Quan-Yuan; Zhong, Xiao-Fei; Yin, Zhi-Jie; Wang, Bin

2018-05-01

This study aimed to describe clearly the normal imaging features of the meniscal roots on the magnetic resonance imaging (MRI) with a 3-dimensional (3D) proton density-weighted (PDW) sequence at 3T. A total of 60 knees of 31 young asymptomatic volunteers were examined using a 3D MRI. The insertion patterns, constitution patterns, and MR signals of the meniscal roots were recorded. The anterior root of the medial meniscus (ARMM), the anterior root of the lateral meniscus (ARLM), and the posterior root of the medial meniscus (PRMM) had 1 insertion site, whereas the posterior root of the lateral meniscus (PRLM) can be divided into major and minor insertion sites. The ARLM and the PRMM usually consisted of multiple fiber bundles (≥3), whereas the ARMM and the PRLM often consisted of a single fiber bundle. The ARMM and the PRLM usually appeared as hypointense, whereas the ARLM and the PRMM typically exhibited mixed signals. The meniscal roots can be complex and diverse, and certain characteristics of them were observed on 3D MRI. Understanding the normal imaging features of the meniscal roots is extremely beneficial for further diagnosis of root tears.

Risks to the Superior Gluteal Neurovascular Bundle During Iliosacral and Transsacral Screw Fixation: A Computed Tomogram Arteriography Study.

PubMed

Maslow, Jed; Collinge, Cory A

2017-12-01

Iliosacral (IS) and transsacral (TS) screws are popular techniques to repair complicated injuries to the pelvis. The anatomy of the superior gluteal neurovasculature (SG NV bundle) is well described as running along the posterior ilium, providing innervation and perfusion to important abductor muscles. The method of pelvis fixation least likely to injure the SG NV bundle is unknown. Twenty uninjured patients with a contrasted computed tomogram of the pelvis and lower extremities (CTA) were evaluated. Starting points for an S1 IS screw and S1 and S2 TS screws were estimated on the "ghost" lateral CTA image for those pelvi with safe corridors (>9 mm diameter). The distance from the projected screw to the SG artery was measured. A distance of <3.65 mm (half of a 7.3-mm screw's diameter) was considered likely for NV bundle injury. Of 40 pelvi CTAs (single sides), 10 pelvi (25%) were determined to be inappropriate for an S1 TS screw. The average distances from the screw starting point and the artery were 25.3 mm (±9.2) for S1 IS, 12.4 mm (±9.0) for S1 TS, and 23.5 mm (±10.7) for S2 TS screws, respectively. Ten S1 TS screws (25%) and no S1 IS or S2 TS screws were projected to have caused injury to the SG NV bundle (P < 0.001). Inserting S1 IS and S2 TS screws put the SG NV anatomy at significantly less risk than S1 TS screws. This information may aid in choosing the "best" fixation option for patients with pelvic ring trauma requiring surgery.

Altered white matter microarchitecture in the cingulum bundle in women with primary dysmenorrhea: A tract-based analysis study.

PubMed

Liu, Jixin; Liu, Hongjuan; Mu, Junya; Xu, Qing; Chen, Tao; Dun, Wanghuan; Yang, Jing; Tian, Jie; Hu, Li; Zhang, Ming

2017-09-01

Primary dysmenorrhea (PD), as characterized by painful menstrual cramps without organic causes, is associated with central sensitization and brain function changes. Previous studies showed the integrated role of the default mode network (DMN) in the pain connectome and its key contribution on how an individual perceives and copes with pain disorders. Here, we aimed to investigate whether the cingulum bundle connecting hub regions of the DMN was disrupted in young women with PD. Diffusion tensor imaging was obtained in 41 PD patients and 41 matched healthy controls (HC) during their periovulatory phase. The production of prostaglandins (PGs) was obtained in PD patients during their pain-free and pain phases. As compared with HC, PD patients had similar scores of pain intensity, anxiety, and depression in their pain-free phase. However, altered white matter properties mainly located in the posterior section of the cingulum bundle were observed in PD. Besides PGs being related to menstrual pain, a close relationship was found between the white matter properties of the cingulum bundle during the pain-free phase and the severity of the menstrual pain in PD patients. Our study suggested that PD had trait changes of white matter integrities in the cingulum bundle that persisted beyond the time of menstruation. We inferred that altered anatomical connections may lead to less-flexible communication within the DMN, and/or between the DMN and other pain-related brain networks, which may result in the central susceptibility to develop chronic pain conditions in PD's later life. Hum Brain Mapp 38:4430-4443, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Posed versus spontaneous facial expressions are modulated by opposite cerebral hemispheres.

PubMed

Ross, Elliott D; Pulusu, Vinay K

2013-05-01

Clinical research has indicated that the left face is more expressive than the right face, suggesting that modulation of facial expressions is lateralized to the right hemisphere. The findings, however, are controversial because the results explain, on average, approximately 4% of the data variance. Using high-speed videography, we sought to determine if movement-onset asymmetry was a more powerful research paradigm than terminal movement asymmetry. The results were very robust, explaining up to 70% of the data variance. Posed expressions began overwhelmingly on the right face whereas spontaneous expressions began overwhelmingly on the left face. This dichotomy was most robust for upper facial expressions. In addition, movement-onset asymmetries did not predict terminal movement asymmetries, which were not significantly lateralized. The results support recent neuroanatomic observations that upper versus lower facial movements have different forebrain motor representations and recent behavioral constructs that posed versus spontaneous facial expressions are modulated preferentially by opposite cerebral hemispheres and that spontaneous facial expressions are graded rather than non-graded movements. Published by Elsevier Ltd.

Generalization of rapidly recurring seizures is suppressed in mice lacking glial cell line-derived neurotrophic factor family receptor alpha2.

PubMed

Nanobashvili, A; Kokaia, Z; Lindvall, O

2003-01-01

Recent experimental evidence indicates that neurotrophic factors play a role in the pathophysiology of epilepsy. The objective of this study was to explore whether signaling through one of the glial cell line-derived neurotrophic factor family receptors, GFRalpha2, influences the severity of kindling-evoked, rapidly recurring seizures and the subsequent development of permanent hyperexcitability. We applied the rapid kindling model to adult mice, using 40 threshold stimulations delivered with 5-min interval in the ventral hippocampus. Generalized seizures were fewer and developed later in response to kindling stimulations in mice lacking GFRalpha2. However, GFRalpha2 gene deletion did not influence the acquisition of the permanent abnormal excitability as assessed 4 weeks later. In situ hybridization revealed marked and dynamic changes of GFRalpha2 mRNA levels in several forebrain areas following the stimulus-evoked seizures. Our findings provide evidence that signaling through the GFRalpha2 receptor contributes to seizure generalization in rapid kindling.

Influence of Oxygen Tension on Dopaminergic Differentiation of Human Fetal Stem Cells of Midbrain and Forebrain Origin

PubMed Central

Krabbe, Christina; Bak, Sara Thornby; Jensen, Pia; von Linstow, Christian; Martínez Serrano, Alberto; Hansen, Claus; Meyer, Morten

2014-01-01

Neural stem cells (NSCs) constitute a promising source of cells for transplantation in Parkinson's disease (PD), but protocols for controlled dopaminergic differentiation are not yet available. Here we investigated the influence of oxygen on dopaminergic differentiation of human fetal NSCs derived from the midbrain and forebrain. Cells were differentiated for 10 days in vitro at low, physiological (3%) versus high, atmospheric (20%) oxygen tension. Low oxygen resulted in upregulation of vascular endothelial growth factor and increased the proportion of tyrosine hydroxylase-immunoreactive (TH-ir) cells in both types of cultures (midbrain: 9.1±0.5 and 17.1±0.4 (P<0.001); forebrain: 1.9±0.4 and 3.9±0.6 (P<0.01) percent of total cells). Regardless of oxygen levels, the content of TH-ir cells with mature neuronal morphologies was higher for midbrain as compared to forebrain cultures. Proliferative Ki67-ir cells were found in both types of cultures, but the relative proportion of these cells was significantly higher for forebrain NSCs cultured at low, as compared to high, oxygen tension. No such difference was detected for midbrain-derived cells. Western blot analysis revealed that low oxygen enhanced β-tubulin III and GFAP expression in both cultures. Up-regulation of β-tubulin III was most pronounced for midbrain cells, whereas GFAP expression was higher in forebrain as compared to midbrain cells. NSCs from both brain regions displayed less cell death when cultured at low oxygen tension. Following mictrotransplantation into mouse striatal slice cultures predifferentiated midbrain NSCs were found to proliferate and differentiate into substantial numbers of TH-ir neurons with mature neuronal morphologies, particularly at low oxygen. In contrast, predifferentiated forebrain NSCs microtransplanted using identical conditions displayed little proliferation and contained few TH-ir cells, all of which had an immature appearance. Our data may reflect differences in dopaminergic differentiation capacity and region-specific requirements of NSCs, with the dopamine-depleted striatum cultured at low oxygen offering an attractive micro-environment for midbrain NSCs. PMID:24788190

11C-4DST PET/CT Imaging of Cardiac Sarcoidosis: Comparison With 18F-FDG and Cardiac MRI.

PubMed

Hotta, Masatoshi; Minamimoto, Ryogo; Kubota, Shuji; Awaya, Toru; Hiroi, Yukio

2018-06-01

A 75-year-old woman with a history of sarcoidosis presenting with low cardiac output and complete right bundle-branch block underwent 4'-[methyl-C]-thiothymidine (4DST) PET/CT after cardiac MRI and FDG PET/CT for the evaluation of suspected cardiac sarcoidosis (CS) before treatment. Cardiac MRI revealed late gadolinium enhancement on the anterior-to-lateral and posterior wall, indicating CS. FDG uptake was shown on the anterior-to-lateral wall, but not on the posterior wall. In contrast, 4DST uptake was demonstrated on both anterior-to-lateral and posterior walls. Use of 4DST appears promising for detecting CS without dietary restriction, due to the lack of physiological uptake in myocardium.

Lobar holoprosencephaly in a Miniature Schnauzer with hypodipsic hypernatremia.

PubMed

Sullivan, Stacey A; Harmon, Barry G; Purinton, P Thomas; Greene, Craig E; Glerum, Leigh E

2003-12-15

A 9-month-old male Miniature Schnauzer was examined because of a lifelong history of behavioral abnormalities, including hypodipsia. Diagnostic evaluation revealed marked hypernatremia and a single forebrain ventricle. The behavioral abnormalities did not resolve with correction of the hypernatremia, and the dog was euthanatized. At necropsy, midline forebrain structures were absent or reduced in size, and normally paired forebrain structures were incompletely separated. Findings were diagnostic for holoprosencephaly, a potentially genetic disorder and the likely cause of the hypodipsia. Similar evaluation of affected Miniature Schnauzer dogs may reveal whether holoprosencephaly routinely underlies the thirst deficiency that may be seen in dogs of this breed.

TASK Channels on Basal Forebrain Cholinergic Neurons Modulate Electrocortical Signatures of Arousal by Histamine

PubMed Central

Vu, Michael T.; Du, Guizhi; Bayliss, Douglas A.

2015-01-01

Basal forebrain cholinergic neurons are the main source of cortical acetylcholine, and their activation by histamine elicits cortical arousal. TWIK-like acid-sensitive K+ (TASK) channels modulate neuronal excitability and are expressed on basal forebrain cholinergic neurons, but the role of TASK channels in the histamine-basal forebrain cholinergic arousal circuit is unknown. We first expressed TASK channel subunits and histamine Type 1 receptors in HEK cells. Application of histamine in vitro inhibited the acid-sensitive K+ current, indicating a functionally coupled signaling mechanism. We then studied the role of TASK channels in modulating electrocortical activity in vivo using freely behaving wild-type (n = 12) and ChAT-Cre:TASKf/f mice (n = 12), the latter lacking TASK-1/3 channels on cholinergic neurons. TASK channel deletion on cholinergic neurons significantly altered endogenous electroencephalogram oscillations in multiple frequency bands. We then identified the effect of TASK channel deletion during microperfusion of histamine into the basal forebrain. In non-rapid eye movement sleep, TASK channel deletion on cholinergic neurons significantly attenuated the histamine-induced increase in 30–50 Hz activity, consistent with TASK channels contributing to histamine action on basal forebrain cholinergic neurons. In contrast, during active wakefulness, histamine significantly increased 30–50 Hz activity in ChAT-Cre:TASKf/f mice but not wild-type mice, showing that the histamine response depended upon the prevailing cortical arousal state. In summary, we identify TASK channel modulation in response to histamine receptor activation in vitro, as well as a role of TASK channels on cholinergic neurons in modulating endogenous oscillations in the electroencephalogram and the electrocortical response to histamine at the basal forebrain in vivo. SIGNIFICANCE STATEMENT Attentive states and cognitive function are associated with the generation of γ EEG activity. Basal forebrain cholinergic neurons are important modulators of cortical arousal and γ activity, and in this study we investigated the mechanism by which these neurons are activated by the wake-active neurotransmitter histamine. We found that histamine inhibited a class of K+ leak channels called TASK channels and that deletion of TASK channels selectively on cholinergic neurons modulated baseline EEG activity as well as histamine-induced changes in γ activity. By identifying a discrete brain circuit where TASK channels can influence γ activity, these results represent new knowledge that enhances our understanding of how subcortical arousal systems may contribute to the generation of attentive states. PMID:26446210

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

PubMed

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

2012-11-01

Precise axon pathfinding is crucial for establishment of the initial neuronal network during development. Pioneer axons navigate without the help of preexisting axons and pave the way for follower axons that project later. Voltage-gated ion channels make up the intrinsic electrical activity of pioneer axons and regulate axon pathfinding. To elucidate which channel molecules are present in pioneer axons, immunohistochemical analysis was performed to examine 14 voltage-gated ion channels (Kv1.1-Kv1.3, Kv3.1-Kv3.4, Kv4.3, Cav1.2, Cav1.3, Cav2.2, Nav1.2, Nav1.6, and Nav1.9) in nine axonal tracts in the developing rat forebrain, including the optic nerve, corpus callosum, corticofugal fibers, thalamocortical axons, lateral olfactory tract, hippocamposeptal projection, anterior commissure, hippocampal commissure, and medial longitudinal fasciculus. We found A-type K⁺ channel Kv3.4 in both pioneer axons and early follower axons and L-type Ca²⁺ channel Cav1.2 in pioneer axons and early and late follower axons. Spatially, Kv3.4 and Cav1.2 were colocalized with markers of pioneer neurons and pioneer axons, such as deleted in colorectal cancer (DCC), in most fiber tracts examined. Temporally, Kv3.4 and Cav1.2 were expressed abundantly in most fiber tracts during axon pathfinding but were downregulated beginning in synaptogenesis. By contrast, delayed rectifier Kv channels (e.g., Kv1.1) and Nav channels (e.g., Nav1.2) were absent from these fiber tracts (except for the corpus callosum) during pathfinding of pioneer axons. These data suggest that Kv3.4 and Cav1.2, two high-voltage-activated ion channels, may act together to control Ca²⁺ -dependent electrical activity of pioneer axons and play important roles during axon pathfinding. Copyright © 2012 Wiley Periodicals, Inc.

Response to deep hypoglycemia does not involve glucoreceptors in carotid perfused tissue

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

Cane, P.; Haun, C.K.; Evered, J.

1988-11-01

In the present study the authors examined whether the magnified hormonal counter-regulatory response seen during deep hypoglycemia (40 mg/dl) could be attenuated by supplying the forebrain with glucose furnished through carotid infusion. Two protocols were performed in conscious dogs. In the first protocol they infused glucose bilaterally into the carotid circulation to produce a forebrain glycemia of 55 {plus minus} 1 mg/dl whereas systemic glycemia declined to 39 {plus minus} 2 mg/dl. In the second protocol as a control they infused glucose into the systemic circulation at a rate matched to protocol 1 so that both systemic and jugular plasmamore » glucose concentrations were equivalent to the systemic glucose concentrations in protocol 1. In spite of a substantial difference in forebrain glycemia there were no differences in the counter-regulatory responses of catecholamines or glucagon. In addition, through the use of radiolabeled microspheres, they defined the precise regions of the forebrain irrigated during bilateral intracarotid glucose infusions. The concentration of microspheres was high in the forebrain but very low in the hindbrain. The results indicate that glucoreceptor cells in tissues perfused by carotid arteries may play a tautological role in the sympathetic response to hypoglycemia and imply that glucose-sensitive receptors must also be located elsewhere in the central nervous system or in the periphery.« less

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

PubMed Central

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

2013-01-01

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

Postnatal chlorpyrifos exposure and apolipoprotein E (APOE) genotype differentially affect cholinergic expression and developmental parameters in transgenic mice.

PubMed

Basaure, Pia; Guardia-Escote, Laia; Cabré, Maria; Peris-Sampedro, Fiona; Sánchez-Santed, Fernando; Domingo, José L; Colomina, Maria Teresa

2018-05-03

Chlorpyrifos (CPF) is one of the most commonly used organophosphate pesticides in the world. Our previous results described that apolipoprotein E (APOE) polymorphisms are a source of individual differences in susceptibility to CPF. The aim of this study was to assess the physical and biochemical effects of postnatal exposure to CPF in the apoE targeted replacement mouse model. Mice were exposed to CPF at 0 or 1 mg/kg/day from postnatal day 10-15. Physical development, plasma and forebrain cholinesterase (ChE) activity and gene expression in liver and forebrain were evaluated. CPF exposure delays physical maturation and decreases the expression of choline acetyltransferase, α4-subunit and the α7 receptor. CPF decreases the expression of vesicular acetylcholine transporter (VAChT) mRNA in the forebrain only in apoE3 mice. The expression of paraoxonase-2 in the forebrain was also influenced by APOE genotype and CPF. Differences between genotypes were observed in litter size, ChE activity, expression of butyrylcholinesterase and paraoxonase-1 in liver and variants of acetylcholinesterase, VAChT and the α7 receptor in the forebrain. These results support that there are different vulnerabilities to postnatal CPF exposure according to the APOE polymorphism, which in turn affects the cholinergic system and defenses to oxidative stress. Copyright © 2018 Elsevier Ltd. All rights reserved.

Morphology of the bryozoan Cinctipora elegans (Cyclostomata, Cinctiporidae) with first data on its sexual reproduction and the cyclostome neuro-muscular system.

PubMed

Schwaha, Thomas F; Handschuh, Stephan; Ostrovsky, Andrew N; Wanninger, Andreas

2018-06-14

Cyclostome bryozoans are an ancient group of marine colonial suspension-feeders comprising approximately 700 extant species. Previous morphological studies are mainly restricted to skeletal characters whereas data on soft tissues obtained by state-of-the-art methods are still lacking. In order to contribute to issues related to cyclostome ground pattern reconstruction, we analyzed the morphology of the neuromuscular system Cinctipora elegans by means of immunocytochemical staining, confocal laser scanning microscopy, histological sections and microCT imaging. Polypides of C. elegans are located in elongated tubular skeletal cystids. Distally, the orifice leads into a prominent vestibulum which is lined by an epithelium that joins an almost complete perimetrical attachment organ, both containing radially arranged neurite bundles and muscles. Centrally, the prominent atrial sphincter separates the vestibulum from the atrium. The latter is enclosed by the tentacle sheath which contains few longitudinal muscle fibers and two principal neurite bundles. These emerge from the cerebral ganglion, which is located at the lophophoral base. Lateral ganglia are located next to the cerebral ganglion from which the visceral neurite bundles emerge that extend proximally towards the foregut. There are four tentacle neurite bundles that emerge from the ganglia and the circum-oral nerve ring, which encompasses the pharynx. The tentacles possess two striated longitudinal muscles. Short buccal dilatators are situated at the lophophoral base and short muscular sets are present at the abfrontal and frontal side of the tentacle base. The pharynx is myoepithelial and triradiate in cross-section. Oocytes are found inside the pharyngeal myoepithelium. The digestive tract contains dense circular musculature and few longitudinal muscles. The membranous sac contains regular, thin, circular and diagonal muscles and neurites in its epithelial lining. The general structure of the neuro-muscular system is more reminiscent of the condition found in Gymnolaemata rather than Phylactolaemata, which supports a close relationship between Cyclostomata and Gymnolaemata. Several characters of C. elegans such as the lateral ganglia or loss of the cardia are probably apomorphic for this species. For the first time, oocytes that surprisingly develop in the pharyngeal wall are reported for this species.

Anatomic double-bundle anterior cruciate ligament reconstruction restores patellofemoral contact areas and pressures more closely than nonanatomic single-bundle reconstruction.

PubMed

Tajima, Goro; Iriuchishima, Takanori; Ingham, Sheila J M; Shen, Wei; van Houten, Albert H; Aerts, Maarten M; Shimamura, Tadashi; Smolinski, Patrick; Fu, Freddie H

2010-10-01

To investigate the effects of anterior cruciate ligament (ACL) deficiency and nonanatomic single-bundle (SB) and anatomic double-bundle (DB) ACL reconstruction on the contact characteristics of the patellofemoral (PF) joint. By use of a materials testing system, 7 fresh-frozen human cadaveric knees were tested. The following states were tested: ACL-intact knee, nonanatomic SB ACL reconstruction, anatomic DB ACL reconstruction, and ACL-deficient knee. Hamstring autografts were used. PF contact pressures and areas were measured with pressure-sensitive film at 30°, 60°, and 90° of knee flexion with a constant 100-N load on the quadriceps tendon. The total contact area of ACL-deficient and nonanatomic SB ACL-reconstructed knees (123.8 ± 63.9 and 149.6 ± 79.3 mm(2), respectively) significantly decreased when compared with those of the intact knee (206.1 ± 83.6 mm(2)) at 30° of knee flexion. The lateral-facet peak pressure of ACL-deficient and nonanatomic SB ACL-reconstructed knees (1.12 ± 0.52 and 1.22 ± 0.54 MPa, respectively) significantly decreased when compared with those of the intact knee (0.68 ± 0.38 MPa) at 90° of knee flexion. Anatomic DB ACL reconstruction restored the contact pressures and areas to values similar to those of the intact knee (no significant difference). ACL deficiency resulted in a significant decrease in the total and medial PF contact areas and in an increase in the lateral PF contact pressure. Anatomic DB ACL reconstruction more closely restored normal PF contact area and pressure than did nonanatomic SB ACL reconstruction. Our findings suggest that the changes in the PF contact area and pressures in ACL deficiency and after nonanatomic SB ACL reconstruction may be one of the causes of PF osteoarthritis or other related PF problems found at long-term follow-up. Anatomic DB ACL reconstruction may reduce the incidence of PF problems by closely restoring the contact area and pressure. Copyright © 2010 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

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

EPA Science Inventory

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

Distribution of 3H-GABA uptake sites in the nematode Ascaris

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

Guastella, J.; Stretton, A.O.

1991-05-22

The distribution of uptake sites for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the nematode Ascaris suum was examined by autoradiography of 3H-GABA uptake. Single neural processes in both the ventral and dorsal nerve cords were labeled with 3H-GABA. Serial section analysis identified the cells of origin of these processes as the RMEV-like and RMED-like neurons. These cells belong to a set of four neurons in the nerve ring, all of which are labeled by 3H-GABA. 3H-GABA labeling of at least two other sets of cephalic neurons was seen. One of these pairs consists of medium-sized lateral ganglia neurons, locatedmore » at the level of the amphid commissure bundle. A second pair is located in the lateral ganglia at the level of the deirid commissure bundle. The position and size of these lateral ganglia cells suggest that they are the GABA-immunoreactive lateral ganglia cells frequently seen in whole-mount immunocytochemical preparations. Four neuronal cell bodies located in the retrovesicular ganglion were also labeled with 3H-GABA. These cells, which are probably cholinergic excitatory motor neurons, do not contain detectable GABA-like immunoreactivity. Heavy labeling of muscle cells was also observed. The ventral and dorsal nerve cord inhibitory motor neurons, which are known to contain GABA-like immunoreactivity, were not labeled above background with 3H-GABA. Together with the experiments reported previously, these results define three classes of GABA-associated neurons in Ascaris: (1) neurons that contain endogenous GABA and possess a GABA uptake system; (2) neurons that contain endogenous GABA, but that either lack a GABA uptake system or possess a GABA uptake system of low activity; (3) neurons that possess a GABA uptake system, but that lack endogenous GABA.« less

Evidence for a role for α6* nAChRs in L-dopa-induced dyskinesias using parkinsonian α6* nAChR gain-of-function mice

PubMed Central

Bordia, Tanuja; McGregor, Matthew; McIntosh, J.M.; Drenan, Ryan M.; Quik, Maryka

2015-01-01

L-Dopa-induced dyskinesias (LIDs) are a serious side effect of dopamine replacement therapy for Parkinson's disease. The mechanisms that underlie LIDs are currently unclear. However, preclinical studies indicate that nicotinic acetylcholine receptors (nAChRs) play a role, suggesting that drugs targeting these receptors may be of therapeutic benefit. To further understand the involvement of α6β2* nAChRs in LIDs, we used gain-of-function α6* nAChR (α6L9S) mice that exhibit a 20-fold enhanced sensitivity to nAChR agonists. Wildtype (WT) and α6L9S mice were lesioned by unilateral injection of 6-hydroxydopamine (6-OHDA, 3 μg/ml) into the medial forebrain bundle. Three to 4 wk later, they were administered L-dopa (3 mg/kg) plus benserazide (15 mg/kg) until stably dyskinetic. L-dopa-induced abnormal involuntary movements (AIMs) were similar in α6L9S and WT mice. WT mice were then given nicotine in the drinking water in gradually increasing doses to a final 300 μg/ml, which resulted in a 40% decline AIMs. By contrast, there was no decrease in AIMs in α6L9S mice at a maximally tolerated nicotine dose of 20 μg/ml. However, the nAChR antagonist mecamylamine (1 mg/kg ip 30 min before L-dopa) reduced L-dopa-induced AIMs in both α6L9S and WT mice. Thus, both a nAChR agonist and antagonist decreased AIMs in WT mice, but only the antagonist was effective in α6L9S mice. Since nicotine appears to reduce LIDs via desensitization, hypersensitive α6β2* nAChRs may desensitize less readily. The present data show that α6β2* nAChRs are key regulators of LIDs, and may be useful therapeutic targets for their management in Parkinson's disease. PMID:25813704

Comparison of effects produced by nicotine and the α4β2-selective agonist 5-I-A-85380 on intracranial self-stimulation in rats.

PubMed

Freitas, Kelen; Carroll, F Ivy; Negus, S Stevens

2016-02-01

Intracranial self-stimulation (ICSS) is one type of preclinical procedure for research on pharmacological mechanisms that mediate abuse potential of drugs acting at various targets, including nicotinic acetylcholine receptors (nAChRs). This study compared effects of the nonselective nAChR agonist nicotine (0.032-1.0 mg/kg) and the α4β2-selective nAChR agonist 5-I-A-85380 (0.01-1.0 mg/kg) on ICSS in male Sprague-Dawley rats. Rats were implanted with electrodes targeting the medial forebrain bundle at the level of the lateral hypothalamus and trained to respond under a fixed-ratio 1 schedule for a range of brain stimulation frequencies (158-56 Hz). A broad range of 5-I-A-85380 doses produced an abuse-related increase (or "facilitation") of low ICSS rates maintained by low brain-stimulation frequencies, and this effect was blocked by both the nonselective nAChR antagonist mecamylamine and the selective α4β2 antagonist dihyrdo-β-erythroidine (DHβE). Conversely, nicotine produced weaker ICSS facilitation across a narrower range of doses, and higher nicotine doses decreased high rates of ICSS maintained by high brain-stimulation frequencies. The rate-decreasing effects of a high nicotine dose were blocked by mecamylamine but not DHβE. Chronic nicotine treatment produced selective tolerance to rate-decreasing effects of nicotine but did not alter ICSS rate-increasing effects of nicotine. These results suggest that α4β2 receptors are sufficient to mediate abuse-related rate-increasing effects of nAChR agonists in this ICSS procedure. Conversely, nicotine effects at non-α4β2 nAChRs appear to oppose and limit abuse-related effects mediated by α4β2 receptors, although tolerance can develop to these non-α4β2 effects. Selective α4β2 agonists may have higher abuse potential than nicotine. PsycINFO Database Record (c) 2016 APA, all rights reserved.

Development of serotonin-like immunoreactivity in the embryos and larvae of nudibranch mollusks with emphasis on the structure and possible function of the apical sensory organ.

PubMed

Kempf, S C; Page, L R; Pires, A

1997-09-29

This investigation provides a light and electron microscopic examination of the development of serotonin-like immunoreactivity and structure of the apical sensory organ (ASO) in embryos and/or larvae of four nudibranch species: Berghia verrucicornis, Phestilla sibogae, Melibe leonina, and Tritonia diomedea. Serotonin-like immunoreactivity is first expressed in somata, dendrites, and axons of a group of five distinct neurons within the ASO. These neurons extend axons into an apical neuropil, a structure that is situated centrally and immediately dorsal to the cerebral commissure. Three of these neurons possess sensory dendrites that extend through the pretrochal epithelium, each supporting two cilia at their distal ends. Later development of serotonin-like immunoreactivity includes 1) axons from the apical neuropil that extend into each of the velar lobes; 2) neuron perikarya in the cerebral and pedal ganglia; 3) axons that extend through the cerebral commissure, cerebral-pedal connectives, pedal commissure, and possibly the visceral loop connective; and 4) axons extending from each pedal ganglion into the larval foot. Ultrastructurally, the ASO can be seen to be composed of three lobes and an apical neuropil that is separately delineated from the cerebral commissure. Four cell types are present within the ASO: ciliary tuft cells, type I and type II parampullary neurons, and ampullary neurons. Immunofluorescence and 3,3' diaminobenzidine tetrahydrochloride (DAB) labeling verify that the serotonergic neurons of the ASO are type I and type II parampullary neurons. The ampullary and type I parampullary neurons possess dendrites that extend through the pretrochal epithelium. These dendrites are partitioned into three bundles, one on either side of the ciliary tuft cells and a third bundle penetrating the pretrochal epithelium centrally between the ciliary tuft cells. One serotonergic type I parampullary neuron is associated with each of these bundles. Two ampullary neurons are associated with each of the lateral dendritic bundles, while the central bundle includes only one. Ultrastructural analyses of serotonergic axonal innervation arising from the ASO agree with those determined from fluorescently labeled material. The structure of the ASO and its associated serotonergic axons suggest that the serotonergic component of this structure senses environmental stimuli affecting velar function, possibly the contractility of muscle fibers in the velar lobes. Similarities and differences among the ASOs of embryos and larvae from various invertebrate phyla may provide useful data that will assist in the reconstruction of phylogenetic relationships.

Voltammetric and Mathematical Evidence for Dual Transport Mediation of Serotonin Clearance In Vivo

PubMed Central

Wood, Kevin M.; Zeqja, Anisa; Nijhout, H. Frederik; Reed, Michael C.; Best, Janet; Hashemi, Parastoo

2014-01-01

The neurotransmitter serotonin underlies many of the brain’s functions. Understanding serotonin neurochemistry is important for improving treatments for neuropsychiatric disorders such as depression. Antidepressants commonly target serotonin clearance via serotonin transporters (SERTs) and have variable clinical effects. Adjunctive therapies, targeting other systems including serotonin autoreceptors, also vary clinically and carry adverse consequences. Fast scan cyclic voltammetry (FSCV) is particularly well suited for studying antidepressant effects on serotonin clearance and autoreceptors by providing real-time chemical information on serotonin kinetics in vivo. However, the complex nature of in vivo serotonin responses makes it difficult to interpret experimental data with established kinetic models. Here, we electrically stimulated the mouse medial forebrain bundle (MFB) to provoke and detect terminal serotonin in the substantia nigra reticulata (SNr). In response to MFB stimulation we found three dynamically distinct serotonin signals. To interpret these signals we developed a computational model that supports two independent serotonin reuptake mechanisms (high affinity, low efficiency reuptake mechanism and low affinity, high efficiency reuptake system) and bolsters an important inhibitory role for the serotonin autoreceptors. Our data and analysis, afforded by the powerful combination of voltammetric and theoretical methods, gives new understanding of the chemical heterogeneity of serotonin dynamics in the brain. This diverse serotonergic matrix likely contributes to clinical variability of antidepressants. PMID:24702305

Appropriate Bmp7 levels are required for the differentiation of midline guidepost cells involved in corpus callosum formation.

PubMed

Sánchez-Camacho, Cristina; Ortega, Juan Alberto; Ocaña, Inmaculada; Alcántara, Soledad; Bovolenta, Paola

2011-05-01

Guidepost cells are essential structures for the establishment of major axonal tracts. How these structures are specified and acquire their axon guidance properties is still poorly understood. Here, we show that in mouse embryos appropriate levels of Bone Morphogenetic Protein 7 (Bmp7), a member of the TGF-β superfamily of secreted proteins, are required for the correct development of the glial wedge, the indusium griseum, and the subcallosal sling, three groups of cells that act as guidepost cells for growing callosal axons. Bmp7 is expressed in the region occupied by these structures and its genetic inactivation in mouse embryos caused a marked reduction and disorganization of these cell populations. On the contrary, infusion of recombinant Bmp7 in the developing forebrain induced their premature differentiation. In both cases, changes were associated with the disruption of callosal axon growth and, in most animals fibers did not cross the midline forming typical Probst bundles. Addition of Bmp7 to cortical explants did not modify the extent of their outgrowth nor their directionality, when explants were exposed to a focalized source of the protein. Together, these results indicate that Bmp7 is indirectly required for corpus callosum formation by controlling the timely differentiation of its guidepost cells. Copyright © 2010 Wiley Periodicals, Inc.

Pre-frontal control of closed-loop limbic neurostimulation by rodents using a brain-computer interface

NASA Astrophysics Data System (ADS)

Widge, Alik S.; Moritz, Chet T.

2014-04-01

Objective. There is great interest in closed-loop neurostimulators that sense and respond to a patient's brain state. Such systems may have value for neurological and psychiatric illnesses where symptoms have high intraday variability. Animal models of closed-loop stimulators would aid preclinical testing. We therefore sought to demonstrate that rodents can directly control a closed-loop limbic neurostimulator via a brain-computer interface (BCI). Approach. We trained rats to use an auditory BCI controlled by single units in prefrontal cortex (PFC). The BCI controlled electrical stimulation in the medial forebrain bundle, a limbic structure involved in reward-seeking. Rigorous offline analyses were performed to confirm volitional control of the neurostimulator. Main results. All animals successfully learned to use the BCI and neurostimulator, with closed-loop control of this challenging task demonstrated at 80% of PFC recording locations. Analysis across sessions and animals confirmed statistically robust BCI control and specific, rapid modulation of PFC activity. Significance. Our results provide a preliminary demonstration of a method for emotion-regulating closed-loop neurostimulation. They further suggest that activity in PFC can be used to control a BCI without pre-training on a predicate task. This offers the potential for BCI-based treatments in refractory neurological and mental illness.

Biphasic and bilateral changes in striatal VGLUT1 and 2 protein expression in hemi-Parkinson rats.

PubMed

Massie, Ann; Schallier, Anneleen; Vermoesen, Katia; Arckens, Lutgarde; Michotte, Yvette

2010-09-01

Parkinson's disease is characterized by disturbed glutamatergic neurotransmission in the striatum. Important mediators of extracellular glutamate levels are the vesicular glutamate transporters VGLUT1 and VGLUT2 in respectively corticostriatal and thalamostriatal afferents, next to the high-affinity Na(+)/K(+)-dependent glutamate transporters and the cystine/glutamate antiporter. In the present study, we compared bilateral striatal VGLUT1 and VGLUT2 protein expression as well as VGLUT1 and VGLUT2 transcript levels in the neocortex and parafascicular nucleus of hemi-Parkinson rats at different time intervals post unilateral 6-OHDA injection into the medial forebrain bundle versus controls. Three weeks post-injection we detected increased striatal VGLUT1 expression together with decreased VGLUT2 expression. On the other hand, after twelve weeks, the expression of VGLUT1 was decreased in hemi-Parkinson rats whereas the striatal expression of VGLUT2 was comparable to control rats. No effect could be seen on VGLUT transcript levels in the respective projection areas at any time. In conclusion, we observed a biphasic and bilateral change in the protein expression levels of both VGLUTs in the striatum of hemi-Parkinson rats indicative for a different and time-dependent change in glutamatergic neurotransmission from the two types of striatal afferents. Copyright 2010 Elsevier Ltd. All rights reserved.

Anatomic structures at risk: curved hindfoot arthrodesis nail--a cadaveric approach.

PubMed

Knight, Timothy; Rosenfeld, Peter; Jones, Ioan Tudur; Clark, Callum; Savva, Nick

2014-01-01

Retrograde intramedullary nailing of the hindfoot and ankle is an established procedure for salvage of severe foot and ankle deformity, arthritis, tumor, and instability. In the present study, retrograde hindfoot (tibiotalocalcaneal) arthrodesis nailing was performed using a standardized technique on 7 cadaver specimens by trained senior surgeons. The specimens were then dissected to determine the distance of the subcalcaneal structures at risk from the insertion point of the nail. The findings showed that the distance of the lateral neurovascular bundle from the edge of the nail was 6.5 (range 3.5 to 8, 95% confidence interval 5.9 to 7.1) mm. No neurovascular bundle was compromised, and all were within a previously described "safe window." Copyright © 2014 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.

Control of arousal by the orexin neurons.

PubMed

Alexandre, Chloe; Andermann, Mark L; Scammell, Thomas E

2013-10-01

The orexin-producing neurons in the lateral hypothalamus play an essential role in promoting arousal and maintaining wakefulness. These neurons receive a broad variety of signals related to environmental, physiological and emotional stimuli; they project to almost every brain region involved in the regulation of wakefulness; and they fire most strongly during active wakefulness, high motor activation, and sustained attention. This review focuses on the specific neuronal pathways through which the orexin neurons promote wakefulness and maintain high level of arousal, and how recent studies using optogenetic and pharmacogenetic methods have demonstrated that the locus coeruleus, the tuberomammillary nucleus, and the basal forebrain are some of the key sites mediating the arousing actions of orexins. Copyright © 2013 Elsevier Ltd. All rights reserved.

Vascular-Derived Vegfa Promotes Cortical Interneuron Migration and Proximity to the Vasculature in the Developing Forebrain

PubMed Central

Barber, Melissa; Andrews, William D; Memi, Fani; Gardener, Phillip; Ciantar, Daniel; Tata, Mathew; Ruhrberg, Christiana; Parnavelas, John G

2018-01-01

Abstract Vascular endothelial growth factor (Vegfa) is essential for promoting the vascularization of the embryonic murine forebrain. In addition, it directly influences neural development, although its role in the forming forebrain is less well elucidated. It was recently suggested that Vegfa may influence the development of GABAergic interneurons, inhibitory cells with crucial signaling roles in cortical neuronal circuits. However, the mechanism by which it affects interneuron development remains unknown. Here we investigated the developmental processes by which Vegfa may influence cortical interneuron development by analyzing transgenic mice that ubiquitously express the Vegfa120 isoform to perturb its signaling gradient. We found that interneurons reach the dorsal cortex at mid phases of corticogenesis despite an aberrant vascular network. Instead, endothelial ablation of Vegfa alters cortical interneuron numbers, their intracortical distribution and spatial proximity to blood vessels. We show for the first time that vascular-secreted guidance factors promote early-migrating interneurons in the intact forebrain in vivo and identify a novel role for vascular-Vegfa in this process. PMID:29901792

Selective immunotoxic lesions of basal forebrain cholinergic neurons: twenty years of research and new directions.

PubMed

Baxter, Mark G; Bucci, David J

2013-10-01

The advent of the selective cholinergic toxin, 192 IgG-saporin, dramatically shaped subsequent research on the role of the basal forebrain in learning and memory. In particular, several articles (including the authors' 1995 Behavioral Neuroscience paper; M. G. Baxter, D. J. Bucci, L. K., Gorman, R. G. Wiley, & M. Gallagher, 1995) revealed that selective removal of basal forebrain cholinergic neurons had surprisingly little effect on spatial learning and memory. Here, as part of the series commemorating the 30th anniversary of Behavioral Neuroscience, we describe how our earlier findings prompted a reconsideration of the cholinergic contribution to cognitive function and also led to several new research directions, including renewed interest in basal forebrain GABA-ergic neurons and cholinergic contributions to neurocognitive development. The authors also describe how the successful use of 192 IgG-saporin led to the development and popularity of a wide range of selective new neurotoxic agents. Finally, they consider the utility of the permanent lesion approach in the wake of new transgenic and optogenetic methods. 2013 APA, all rights reserved

Visual training paired with electrical stimulation of the basal forebrain improves orientation-selective visual acuity in the rat.

PubMed

Kang, Jun Il; Groleau, Marianne; Dotigny, Florence; Giguère, Hugo; Vaucher, Elvire

2014-07-01

The cholinergic afferents from the basal forebrain to the primary visual cortex play a key role in visual attention and cortical plasticity. These afferent fibers modulate acute and long-term responses of visual neurons to specific stimuli. The present study evaluates whether this cholinergic modulation of visual neurons results in cortical activity and visual perception changes. Awake adult rats were exposed repeatedly for 2 weeks to an orientation-specific grating with or without coupling this visual stimulation to an electrical stimulation of the basal forebrain. The visual acuity, as measured using a visual water maze before and after the exposure to the orientation-specific grating, was increased in the group of trained rats with simultaneous basal forebrain/visual stimulation. The increase in visual acuity was not observed when visual training or basal forebrain stimulation was performed separately or when cholinergic fibers were selectively lesioned prior to the visual stimulation. The visual evoked potentials show a long-lasting increase in cortical reactivity of the primary visual cortex after coupled visual/cholinergic stimulation, as well as c-Fos immunoreactivity of both pyramidal and GABAergic interneuron. These findings demonstrate that when coupled with visual training, the cholinergic system improves visual performance for the trained orientation probably through enhancement of attentional processes and cortical plasticity in V1 related to the ratio of excitatory/inhibitory inputs. This study opens the possibility of establishing efficient rehabilitation strategies for facilitating visual capacity.

Decreased akt activity is associated with activation of forkhead transcription factor after transient forebrain ischemia in gerbil hippocampus.

PubMed

Kawano, Takayuki; Morioka, Motohiro; Yano, Shigetoshi; Hamada, Jun-Ichiro; Ushio, Yukitaka; Miyamoto, Eishichi; Fukunaga, Kohji

2002-08-01

The authors recently reported that sodium orthovanadate rescues cells from delayed neuronal death in gerbil hippocampus after transient forebrain ischemia through phosphatidylinositol 3-kinase-protein kinase B (Akt) pathway (Kawano et al., 2001). In the current study, they demonstrated that the activation of FKHR, a Forkhead transcription factor and a substrate for Akt, preceded delayed neuronal death in CA1 regions after transient forebrain ischemia. Adult Mongolian gerbils were subjected to 5-minute forebrain ischemia. Immunoblotting analysis with anti-phospho-FKHR antibody showed that phosphorylation of FKHR at serine-256 in the CA1 region decreased immediately after and 0.5 and 1 hour after reperfusion. The dephosphorylation of FKHR was correlated with the decreased Akt activity. Intracerebroventricular injection of orthovanadate 30 minutes before ischemia inhibited dephosphorylation of FKHR after reperfusion, and blocked delayed neuronal death in the CA1 region. Gel mobility shift analysis using nuclear extracts from the CA1 region prepared immediately after reperfusion revealed increases in DNA binding activity for the FKHR-responsive element on the Fas ligand promoter. The orthovanadate injection administered before ischemia inhibited its binding activity. Two days after reperfusion, expression of Fas ligand increased in the CA1 region and the orthovanadate injection inhibited this increased expression. These results suggest that the inactivation of Akt results in the activation of FKHR and, in turn, relates to the expression of Fas ligand in the CA1 region after transient forebrain ischemia.

GABAergic terminals are a source of galanin to modulate cholinergic neuron development in the neonatal forebrain.

PubMed

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

2014-12-01

The distribution and (patho-)physiological role of neuropeptides in the adult and aging brain have been extensively studied. Galanin is an inhibitory neuropeptide that can coexist with γ-aminobutyric acid (GABA) in the adult forebrain. However, galanin's expression sites, mode of signaling, impact on neuronal morphology, and colocalization with amino acid neurotransmitters during brain development are less well understood. Here, we show that galaninergic innervation of cholinergic projection neurons, which preferentially express galanin receptor 2 (GalR2) in the neonatal mouse basal forebrain, develops by birth. Nerve growth factor (NGF), known to modulate cholinergic morphogenesis, increases GalR2 expression. GalR2 antagonism (M871) in neonates reduces the in vivo expression and axonal targeting of the vesicular acetylcholine transporter (VAChT), indispensable for cholinergic neurotransmission. During cholinergic neuritogenesis in vitro, GalR2 can recruit Rho-family GTPases to induce the extension of a VAChT-containing primary neurite, the prospective axon. In doing so, GalR2 signaling dose-dependently modulates directional filopodial growth and antagonizes NGF-induced growth cone differentiation. Galanin accumulates in GABA-containing nerve terminals in the neonatal basal forebrain, suggesting its contribution to activity-driven cholinergic development during the perinatal period. Overall, our data define the cellular specificity and molecular complexity of galanin action in the developing basal forebrain. © The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Adult forebrain NMDA receptors gate social motivation and social memory.

PubMed

Jacobs, Stephanie; Tsien, Joe Z

2017-02-01

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

Neuronal morphology in the lateral geniculate nucleus of the porpoise (Phocoena phocoena).

PubMed

Revishchin, A V; Garey, L J

1993-01-01

The Golgi and Nissl methods and cytochrome oxidase (CO) histochemistry were used to study the overall structure and neuronal morphology of the lateral geniculate nucleus (LGN) of the Black Sea porpoise (Phocoena phocoena). Differences were observed between dorsal and ventral portions of the nucleus in terms of cell size and CO staining. In addition to prominent fibre bundles crossing the LGN horizontally, vertically oriented variations of CO staining were apparent. Neuronal types in the LGN corresponded broadly to those observed in land mammals. The commonest were variants of multipolar cells, and may represent thalamocortical relay cells. Various other types were probably interneuronal.

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

PubMed Central

Alhadeff, Amber L.; Holland, Ruby A.; Zheng, Huiyuan; Rinaman, Linda; Grill, Harvey J.

2017-01-01

Cisplatin chemotherapy is commonly used to treat cancer despite severe energy balance side effects. In rats, cisplatin activates nucleus tractus solitarius (NTS) projections to the lateral parabrachial nucleus (lPBN) and calcitonin-gene related peptide (CGRP) projections from the lPBN to the central nucleus of the amygdala (CeA). We demonstrated previously that CeA glutamate receptor signaling mediates cisplatin-induced anorexia and body weight loss. Here, we used neuroanatomical tracing, immunofluorescence, and confocal imaging to demonstrate that virtually all NTS→lPBN and lPBN→CeA CGRP projections coexpress vesicular glutamate transporter 2 (VGLUT2), providing evidence that excitatory projections mediate cisplatin-induced energy balance dysregulation. To test whether lPBN→CeA projection neurons are required for cisplatin-induced anorexia and weight loss, we inhibited these neurons chemogenetically using a retrograde Cre-recombinase-expressing canine adenovirus-2 in combination with Cre-dependent inhibitory Designer Receptors Exclusive Activated by Designer Drugs (DREADDs) before cisplatin treatment. Inhibition of lPBN→CeA neurons attenuated cisplatin-induced anorexia and body weight loss significantly. Using a similar approach, we additionally demonstrated that inhibition of NTS→lPBN neurons attenuated cisplatin-induced anorexia and body weight loss significantly. Together, our data support the view that excitatory hindbrain–forebrain projections are necessary for cisplatin's untoward effects on energy intake, elucidating a key neuroanatomical circuit driving pathological anorexia and weight loss that accompanies chemotherapy treatment. SIGNIFICANCE STATEMENT Chemotherapy treatments are commonly used to treat cancers despite accompanying anorexia and weight loss that may limit treatment adherence and reduce patient quality of life. Strikingly, we lack a neural understanding of, and effective treatments for, chemotherapy-induced anorexia and weight loss. The current data characterize the excitatory nature of neural projections activated by cisplatin in rats and reveal the necessity of specific hindbrain–forebrain projections for cisplatin-induced anorexia and weight loss. Together, these findings help to characterize the neural mechanisms mediating cisplatin-induced anorexia, advancing opportunities to develop better-tolerated chemotherapies and adjuvant therapies to prevent anorexia and concurrent nutritional deficiencies during cancer treatment. PMID:28077715

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

PubMed

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

2017-01-11

Cisplatin chemotherapy is commonly used to treat cancer despite severe energy balance side effects. In rats, cisplatin activates nucleus tractus solitarius (NTS) projections to the lateral parabrachial nucleus (lPBN) and calcitonin-gene related peptide (CGRP) projections from the lPBN to the central nucleus of the amygdala (CeA). We demonstrated previously that CeA glutamate receptor signaling mediates cisplatin-induced anorexia and body weight loss. Here, we used neuroanatomical tracing, immunofluorescence, and confocal imaging to demonstrate that virtually all NTS→lPBN and lPBN→CeA CGRP projections coexpress vesicular glutamate transporter 2 (VGLUT2), providing evidence that excitatory projections mediate cisplatin-induced energy balance dysregulation. To test whether lPBN→CeA projection neurons are required for cisplatin-induced anorexia and weight loss, we inhibited these neurons chemogenetically using a retrograde Cre-recombinase-expressing canine adenovirus-2 in combination with Cre-dependent inhibitory Designer Receptors Exclusive Activated by Designer Drugs (DREADDs) before cisplatin treatment. Inhibition of lPBN→CeA neurons attenuated cisplatin-induced anorexia and body weight loss significantly. Using a similar approach, we additionally demonstrated that inhibition of NTS→lPBN neurons attenuated cisplatin-induced anorexia and body weight loss significantly. Together, our data support the view that excitatory hindbrain-forebrain projections are necessary for cisplatin's untoward effects on energy intake, elucidating a key neuroanatomical circuit driving pathological anorexia and weight loss that accompanies chemotherapy treatment. Chemotherapy treatments are commonly used to treat cancers despite accompanying anorexia and weight loss that may limit treatment adherence and reduce patient quality of life. Strikingly, we lack a neural understanding of, and effective treatments for, chemotherapy-induced anorexia and weight loss. The current data characterize the excitatory nature of neural projections activated by cisplatin in rats and reveal the necessity of specific hindbrain-forebrain projections for cisplatin-induced anorexia and weight loss. Together, these findings help to characterize the neural mechanisms mediating cisplatin-induced anorexia, advancing opportunities to develop better-tolerated chemotherapies and adjuvant therapies to prevent anorexia and concurrent nutritional deficiencies during cancer treatment. Copyright © 2017 the authors 0270-6474/17/370362-09$15.00/0.

Cytotoxicity of synthetic cannabinoids on primary neuronal cells of the forebrain: the involvement of cannabinoid CB{sub 1} receptors and apoptotic cell death

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

Tomiyama, Ken-ichi; Funada, Masahiko, E-mail: mfunada@ncnp.go.jp

2014-01-01

The abuse of herbal products containing synthetic cannabinoids has become an issue of public concern. The purpose of this paper was to evaluate the acute cytotoxicity of synthetic cannabinoids on mouse brain neuronal cells. Cytotoxicity induced by synthetic cannabinoid (CP-55,940, CP-47,497, CP-47,497-C8, HU-210, JWH-018, JWH-210, AM-2201, and MAM-2201) was examined using forebrain neuronal cultures. These synthetic cannabinoids induced cytotoxicity in the forebrain cultures in a concentration-dependent manner. The cytotoxicity was suppressed by preincubation with the selective CB{sub 1} receptor antagonist AM251, but not with the selective CB{sub 2} receptor antagonist AM630. Furthermore, annexin-V-positive cells were found among the treated forebrainmore » cells. Synthetic cannabinoid treatment induced the activation of caspase-3, and preincubation with a caspase-3 inhibitor significantly suppressed the cytotoxicity. These synthetic cannabinoids induced apoptosis through a caspase-3-dependent mechanism in the forebrain cultures. Our results indicate that the cytotoxicity of synthetic cannabinoids towards primary neuronal cells is mediated by the CB{sub 1} receptor, but not by the CB{sub 2} receptor, and further suggest that caspase cascades may play an important role in the apoptosis induced by these synthetic cannabinoids. In conclusion, excessive synthetic cannabinoid abuse may present a serious acute health concern due to neuronal damage or deficits in the brain. - Highlights: • Synthetic cannabinoids (classical cannabinoids, non-classical cannabinoids, and aminoalkylindole derivatives) induce cytotoxicity in mouse forebrain cultures. • Synthetic cannabinoid-induced cytotoxicity towards forebrain cultures is mediated by the CB{sub 1} receptor, but not by the CB{sub 2} receptor, and involves caspase-dependent apoptosis. • A high concentration of synthetic cannabinoids may be toxic to neuronal cells that express CB{sub 1} receptors.« less

Role of Shp2 in forebrain neurons in regulating metabolic and cardiovascular functions and responses to leptin.

PubMed

do Carmo, J M; da Silva, A A; Sessums, P O; Ebaady, S H; Pace, B R; Rushing, J S; Davis, M T; Hall, J E

2014-06-01

We examined whether deficiency of Src homology 2 containing phosphatase (Shp2) signaling in forebrain neurons alters metabolic and cardiovascular regulation under various conditions and if it attenuates the anorexic and cardiovascular effects of leptin. We also tested whether forebrain Shp2 deficiency alters blood pressure (BP) and heart rate (HR) responses to acute stress. Forebrain Shp2(-/-) mice were generated by crossing Shp2(flox/flox) mice with CamKIIα-cre mice. At 22-24 weeks of age, the mice were instrumented for telemetry for measurement of BP, HR and body temperature (BT). Oxygen consumption (VO2), energy expenditure and motor activity were monitored by indirect calorimetry. Shp2/CamKIIα-cre mice were heavier (46±3 vs 32±1 g), hyperglycemic, hyperleptinemic, hyperinsulinemic and hyperphagic compared to Shp2(flox/flox) control mice. Shp2/CamKIIα-cre mice exhibited reduced food intake responses to fasting/refeeding and impaired regulation of BT when exposed to 15 and 30 °C ambient temperatures. Despite being obese and having many features of metabolic syndrome, Shp2/CamKIIα-cre mice had similar daily average BP and HR compared to Shp2(flox/flox) mice (112±2 vs 113±1 mm Hg and 595±34 vs 650±40 b.p.m.), but exhibited increased BP and HR responses to cold exposure and acute air-jet stress test. Leptin's ability to reduce food intake and to raise BP were markedly attenuated in Shp2/CamKIIα-cre mice. These results suggest that forebrain Shp2 signaling regulates food intake, appetite responses to caloric deprivation and thermogenic control of body temperature during variations in ambient temperature. Deficiency of Shp2 signaling in the forebrain is associated with augmented cardiovascular responses to cold and acute stress but attenuated BP responses to leptin.

Adolescent binge drinking alters adult brain neurotransmitter gene expression, behavior, brain regional volumes, and neurochemistry in mice

PubMed Central

Coleman, Leon G.; He, Jun; Lee, Joohwi; Styner, Martin; Crews, Fulton T.

2013-01-01

Background Binge-drinking is common in human adolescents. The adolescent brain is undergoing structural maturation and has a unique sensitivity to alcohol neurotoxicity. Therefore, adolescent binge ethanol may have long-term effects on the adult brain that alter brain structure and behaviors that are relevant to alcohol use disorders. Methods In order to determine if adolescent ethanol binge drinking alters the adult brain, male C57BL/6 mice were treated with either water or ethanol during adolescence (5g/kg/day i.g., post-natal days P28-37) and assessed during adulthood (P60-P88). An array of neurotransmitter-specific genes, behavioral tests (i.e. reversal learning, prepulse inhibition, and open field), and post-mortem brain structure using MRI and immunohistochemistry, were employed to assess persistent alterations in adult brain. Results At P38, 24 hours after adolescent ethanol (AE) binge, many neurotransmitter genes, particularly cholinergic and dopaminergic, were reduced by ethanol treatment. Interestingly, dopamine receptor type 4 mRNA was reduced and confirmed using immunohistochemistry. Normal control maturation (P38-P88) resulted in decreased neurotransmitter mRNA, e.g. an average decrease of 56%. Following adolescent ethanol treatment, adults showed greater gene expression reductions than controls, averaging 73%. Adult spatial learning assessed in the Morris water maze was not changed by adolescent ethanol treatment, but reversal learning experiments revealed deficits. Assessment of adult brain region volumes using MRI indicated that the olfactory bulb and basal forebrain were smaller in adults following adolescent ethanol. Immunohistochemical analyses found reduced basal forebrain area and fewer basal forebrain cholinergic neurons. Conclusions Adolescent binge ethanol treatment reduces adult neurotransmitter gene expression, particularly cholinergic genes, reduces basal forebrain and olfactory bulb volumes, and causes a reduction in the density of basal forebrain acetylcholine neurons. Loss of cholinergic neurons and forebrain structure could underlie adult reversal learning deficits following adolescent binge drinking. PMID:21223304

Double-Bundle Anterior Cruciate Ligament Reconstruction Using Hamstring Tendon Hybrid Grafts in Patients Over 40 Years of Age: Comparisons Between Different Age Groups.

PubMed

Nishio, Yusuke; Kondo, Eiji; Onodera, Jun; Onodera, Tomohiro; Yagi, Tomonori; Iwasaki, Norimasa; Yasuda, Kazunori

2018-05-01

Several recent studies have reported that favorable clinical results and a high level of patient satisfaction can generally be obtained with no increased risk of complications after single-bundle anterior cruciate ligament (ACL) reconstruction performed in patients >40 years of age. However, no studies have yet clarified the age-based differences in clinical outcomes after double-bundle reconstruction. To compare clinical outcomes after double-bundle ACL reconstruction using hamstring tendon hybrid grafts between patients in 2 different age groups: ≥40 years and <40 years. Cohort study; Level of evidence, 3. A retrospective study was conducted using 96 patients (48 men, 48 women ; mean age, 37 years) who underwent unilateral ACL reconstruction between 2008 and 2011. These patients were divided into 2 groups: group M included patients ≥40 years of age (n = 40 patients), and group Y included patients <40 years of age (n = 56 patients). All patients underwent the same anatomic double-bundle ACL reconstruction procedure. Clinical outcomes were evaluated at 2 years after surgery. Tunnel enlargement was also evaluated by computed digital radiography at 1 week and 2 years after surgery. Mean postoperative side-to-side differences in anterior laxity were 0.5 ± 1.9 mm and 1.2 ± 1.5 mm in groups M and Y, respectively; there was a significant difference between the 2 groups ( P = .039). There were no significant differences between the groups in Lysholm knee scores, International Knee Documentation Committee (IKDC) scores, or peak muscle torque of the hamstring. On the other hand, peak muscle torque of the quadriceps was significantly lower in group M (81%) than in group Y (89%) ( P = .025). With respect to femoral tunnel enlargement, the posterolateral tunnel in group M was significantly larger than that in group Y on anteroposterior and lateral radiographs ( P = .015 and P = .002, respectively). Equivalent clinical outcomes were seen between the 2 age groups after double-bundle ACL reconstruction. Postoperative anterior laxity was significantly less in older patients than in younger patients, however, older patients had significantly less quadriceps muscle strength than younger patients. Surgeons should be aware of residual muscle weakness and tunnel enlargement when performing double-bundle ACL reconstruction in older patients.

The acquisition of mechano-electrical transducer current adaptation in auditory hair cells requires myosin VI.

PubMed

Marcotti, Walter; Corns, Laura F; Goodyear, Richard J; Rzadzinska, Agnieszka K; Avraham, Karen B; Steel, Karen P; Richardson, Guy P; Kros, Corné J

2016-07-01

The transduction of sound into electrical signals occurs at the hair bundles atop sensory hair cells in the cochlea, by means of mechanosensitive ion channels, the mechano-electrical transducer (MET) channels. The MET currents decline during steady stimuli; this is termed adaptation and ensures they always work within the most sensitive part of their operating range, responding best to rapidly changing (sound) stimuli. In this study we used a mouse model (Snell's waltzer) for hereditary deafness in humans that has a mutation in the gene encoding an unconventional myosin, myosin VI, which is present in the hair bundles. We found that in the absence of myosin VI the MET current fails to acquire its characteristic adaptation as the hair bundles develop. We propose that myosin VI supports the acquisition of adaptation by removing key molecules from the hair bundle that serve a temporary, developmental role. Mutations in Myo6, the gene encoding the (F-actin) minus end-directed unconventional myosin, myosin VI, cause hereditary deafness in mice (Snell's waltzer) and humans. In the sensory hair cells of the cochlea, myosin VI is expressed in the cell bodies and along the stereocilia that project from the cells' apical surface. It is required for maintaining the structural integrity of the mechanosensitive hair bundles formed by the stereocilia. In this study we investigate whether myosin VI contributes to mechano-electrical transduction. We report that Ca(2+) -dependent adaptation of the mechano-electrical transducer (MET) current, which serves to keep the transduction apparatus operating within its most sensitive range, is absent in outer and inner hair cells from homozygous Snell's waltzer mutant mice, which fail to express myosin VI. The operating range of the MET channels is also abnormal in the mutants, resulting in the absence of a resting MET current. We found that cadherin 23, a component of the hair bundle's transient lateral links, fails to be downregulated along the length of the stereocilia in maturing Myo6 mutant mice. MET currents of heterozygous littermates appear normal. We propose that myosin VI, by removing key molecules from developing hair bundles, is required for the development of the MET apparatus and its Ca(2+) -dependent adaptation. © 2016 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.

Zic-Proteins Are Repressors of Dopaminergic Forebrain Fate in Mice and C. elegans.

PubMed

Tiveron, Marie-Catherine; Beclin, Christophe; Murgan, Sabrina; Wild, Stefan; Angelova, Alexandra; Marc, Julie; Coré, Nathalie; de Chevigny, Antoine; Herrera, Eloisa; Bosio, Andreas; Bertrand, Vincent; Cremer, Harold

2017-11-01

In the postnatal forebrain regionalized neural stem cells along the ventricular walls produce olfactory bulb (OB) interneurons with varying neurotransmitter phenotypes and positions. To understand the molecular basis of this region-specific variability we analyzed gene expression in the postnatal dorsal and lateral lineages in mice of both sexes from stem cells to neurons. We show that both lineages maintain transcription factor signatures of their embryonic site of origin, the pallium and subpallium. However, additional factors, including Zic1 and Zic2, are postnatally expressed in the dorsal stem cell compartment and maintained in the lineage that generates calretinin-positive GABAergic neurons for the OB. Functionally, we show that Zic1 and Zic2 induce the generation of calretinin-positive neurons while suppressing dopaminergic fate in the postnatal dorsal lineage. We investigated the evolutionary conservation of the dopaminergic repressor function of Zic proteins and show that it is already present in C. elegans SIGNIFICANCE STATEMENT The vertebrate brain generates thousands of different neuron types. In this work we investigate the molecular mechanisms underlying this variability. Using a genomics approach we identify the transcription factor signatures of defined neural stem cells and neuron populations. Based thereon we show that two related transcription factors, Zic1 and Zic2, are essential to control the balance between two defined neuron types in the postnatal brain. We show that this mechanism is conserved in evolutionary very distant species. Copyright © 2017 the authors 0270-6474/17/3710611-13$15.00/0.

Possible involvement of SINEs in mammalian-specific brain formation

PubMed Central

Sasaki, Takeshi; Nishihara, Hidenori; Hirakawa, Mika; Fujimura, Koji; Tanaka, Mikiko; Kokubo, Nobuhiro; Kimura-Yoshida, Chiharu; Matsuo, Isao; Sumiyama, Kenta; Saitou, Naruya; Shimogori, Tomomi; Okada, Norihiro

2008-01-01

Retroposons, such as short interspersed elements (SINEs) and long interspersed elements (LINEs), are the major constituents of higher vertebrate genomes. Although there are many examples of retroposons' acquiring function, none has been implicated in the morphological innovations specific to a certain taxonomic group. We previously characterized a SINE family, AmnSINE1, members of which constitute a part of conserved noncoding elements (CNEs) in mammalian genomes. We proposed that this family acquired genomic functionality or was exapted after retropositioning in a mammalian ancestor. Here we identified 53 new AmnSINE1 loci and refined 124 total loci, two of which were further analyzed. Using a mouse enhancer assay, we demonstrate that one SINE locus, AS071, 178 kbp from the gene FGF8 (fibroblast growth factor 8), is an enhancer that recapitulates FGF8 expression in two regions of the developing forebrain, namely the diencephalon and the hypothalamus. Our gain-of-function analysis revealed that FGF8 expression in the diencephalon controls patterning of thalamic nuclei, which act as a relay center of the neocortex, suggesting a role for FGF8 in mammalian-specific forebrain patterning. Furthermore, we demonstrated that the locus, AS021, 392 kbp from the gene SATB2, controls gene expression in the lateral telencephalon, which is thought to be a signaling center during development. These results suggest important roles for SINEs in the development of the mammalian neuronal network, a part of which was initiated with the exaptation of AmnSINE1 in a common mammalian ancestor. PMID:18334644

Possible involvement of SINEs in mammalian-specific brain formation.

PubMed

Sasaki, Takeshi; Nishihara, Hidenori; Hirakawa, Mika; Fujimura, Koji; Tanaka, Mikiko; Kokubo, Nobuhiro; Kimura-Yoshida, Chiharu; Matsuo, Isao; Sumiyama, Kenta; Saitou, Naruya; Shimogori, Tomomi; Okada, Norihiro

2008-03-18

Retroposons, such as short interspersed elements (SINEs) and long interspersed elements (LINEs), are the major constituents of higher vertebrate genomes. Although there are many examples of retroposons' acquiring function, none has been implicated in the morphological innovations specific to a certain taxonomic group. We previously characterized a SINE family, AmnSINE1, members of which constitute a part of conserved noncoding elements (CNEs) in mammalian genomes. We proposed that this family acquired genomic functionality or was exapted after retropositioning in a mammalian ancestor. Here we identified 53 new AmnSINE1 loci and refined 124 total loci, two of which were further analyzed. Using a mouse enhancer assay, we demonstrate that one SINE locus, AS071, 178 kbp from the gene FGF8 (fibroblast growth factor 8), is an enhancer that recapitulates FGF8 expression in two regions of the developing forebrain, namely the diencephalon and the hypothalamus. Our gain-of-function analysis revealed that FGF8 expression in the diencephalon controls patterning of thalamic nuclei, which act as a relay center of the neocortex, suggesting a role for FGF8 in mammalian-specific forebrain patterning. Furthermore, we demonstrated that the locus, AS021, 392 kbp from the gene SATB2, controls gene expression in the lateral telencephalon, which is thought to be a signaling center during development. These results suggest important roles for SINEs in the development of the mammalian neuronal network, a part of which was initiated with the exaptation of AmnSINE1 in a common mammalian ancestor.

The Tlx gene regulates the timing of neurogenesis in the cortex.

PubMed

Roy, Kristine; Kuznicki, Kathleen; Wu, Qiang; Sun, Zhuoxin; Bock, Dagmar; Schutz, Gunther; Vranich, Nancy; Monaghan, A Paula

2004-09-22

The tailless (tlx) gene is a forebrain-restricted transcription factor. Tlx mutant animals exhibit a reduction in the size of the cerebral hemispheres and associated structures (Monaghan et al., 1997). Superficial cortical layers are specifically reduced, whereas deep layers are relatively unaltered (Land and Monaghan, 2003). To determine whether the adult laminar phenotype has a developmental etiology and whether it is associated with a change in proliferation/differentiation decisions, we examined the cell cycle and neurogenesis in the embryonic cortex. We found that there is a temporal and regional requirement for the Tlx protein in progenitor cells (PCs). Neurons prematurely differentiate at all rostrocaudal levels up to mid-neurogenesis in mutant animals. Heterozygote animals have an intermediate phenotype indicating there is a threshold requirement for Tlx in early cortical neurogenesis. Our studies indicate that PCs in the ventricular zone are sensitive to loss of Tlx in caudal regions only; however, PCs in the subventricular zone are altered at all rostrocaudal levels in tlx-deficient animals. Furthermore, we found that the cell cycle is shorter from embryonic day 9.5 in tlx-/- embryos. At mid-neurogenesis, the PC population becomes depleted, and late PCs have a longer cell cycle in tlx-deficient animals. Consequently, later generated structures, such as upper cortical layers, the dentate gyrus, and the olfactory bulbs, are severely reduced. These studies indicate that tlx is an essential intrinsic regulator in the decision to proliferate or differentiate in the developing forebrain.

The Tlx Gene Regulates the Timing of Neurogenesis in the Cortex

PubMed Central

Roy, Kristine; Kuznicki, Kathleen; Wu, Qiang; Sun, Zhuoxin; Bock, Dagmar; Schutz, Gunther; Vranich, Nancy; Monaghan, A. Paula

2009-01-01

The tailless (tlx) gene is a forebrain-restricted transcription factor. Tlx mutant animals exhibit a reduction in the size of the cerebral hemispheres and associated structures (Monaghan et al., 1997). Superficial cortical layers are specifically reduced, whereas deep layers are relatively unaltered (Land and Monaghan, 2003). To determine whether the adult laminar phenotype has a developmental etiology and whether it is associated with a change in proliferation/differentiation decisions, we examined the cell cycle and neurogenesis in the embryonic cortex. We found that there is a temporal and regional requirement for the Tlx protein in progenitor cells (PCs). Neurons prematurely differentiate at all rostrocaudal levels up to mid-neurogenesis in mutant animals. Heterozygote animals have an intermediate phenotype indicating there is a threshold requirement for Tlx in early cortical neurogenesis. Our studies indicate that PCs in the ventricular zone are sensitive to loss of Tlx in caudal regions only; however, PCs in the subventricular zone are altered at all rostrocaudal levels in tlx-deficient animals. Furthermore, we found that the cell cycle is shorter from embryonic day 9.5 in tlx−/− embryos. At mid-neurogenesis, the PC population becomes depleted, and late PCs have a longer cell cycle in tlx-deficient animals. Consequently, later generated structures, such as upper cortical layers, the dentate gyrus, and the olfactory bulbs, are severely reduced. These studies indicate that tlx is an essential intrinsic regulator in the decision to proliferate or differentiate in the developing forebrain. PMID:15385616

Adolescent, but Not Adult, Binge Ethanol Exposure Leads to Persistent Global Reductions of Choline Acetyltransferase Expressing Neurons in Brain

PubMed Central

Vetreno, Ryan P.; Broadwater, Margaret; Liu, Wen; Spear, Linda P.; Crews, Fulton T.

2014-01-01

During the adolescent transition from childhood to adulthood, notable maturational changes occur in brain neurotransmitter systems. The cholinergic system is composed of several distinct nuclei that exert neuromodulatory control over cognition, arousal, and reward. Binge drinking and alcohol abuse are common during this stage, which might alter the developmental trajectory of this system leading to long-term changes in adult neurobiology. In Experiment 1, adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g., 2-day on/2-day off from postnatal day [P] 25 to P55) treatment led to persistent, global reductions of choline acetyltransferase (ChAT) expression. Administration of the Toll-like receptor 4 agonist lipopolysaccharide to young adult rats (P70) produced a reduction in ChAT+IR that mimicked AIE. To determine if the binge ethanol-induced ChAT decline was unique to the adolescent, Experiment 2 examined ChAT+IR in the basal forebrain following adolescent (P28–P48) and adult (P70–P90) binge ethanol exposure. Twenty-five days later, ChAT expression was reduced in adolescent, but not adult, binge ethanol-exposed animals. In Experiment 3, expression of ChAT and vesicular acetylcholine transporter expression was found to be significantly reduced in the alcoholic basal forebrain relative to moderate drinking controls. Together, these data suggest that adolescent binge ethanol decreases adult ChAT expression, possibly through neuroimmune mechanisms, which might impact adult cognition, arousal, or reward sensitivity. PMID:25405505

Targeted Deletion of the Gene Encoding the La Autoantigen (Sjögren's Syndrome Antigen B) in B Cells or the Frontal Brain Causes Extensive Tissue Loss

PubMed Central

Gaidamakov, Sergei; Maximova, Olga A.; Chon, Hyongi; Blewett, Nathan H.; Wang, Hongsheng; Crawford, Amanda K.; Day, Amanda; Tulchin, Natalie; Crouch, Robert J.; Morse, Herbert C.; Blitzer, Robert D.

2014-01-01

La antigen (Sjögren's syndrome antigen B) is a phosphoprotein associated with nascent precursor tRNAs and other RNAs, and it is targeted by autoantibodies in patients with Sjögren's syndrome, systemic lupus erythematosus, and neonatal lupus. Increased levels of La are associated with leukemias and other cancers, and various viruses usurp La to promote their replication. Yeast cells (Saccharomyces cerevisiae and Schizosaccharomyces pombe) genetically depleted of La grow and proliferate, whereas deletion from mice causes early embryonic lethality, raising the question of whether La is required by mammalian cells generally or only to surpass a developmental stage. We developed a conditional La allele and used it in mice that express Cre recombinase in either B cell progenitors or the forebrain. B cell Mb1Cre La-deleted mice produce no B cells. Consistent with αCamKII Cre, which induces deletion in hippocampal CA1 cells in the third postnatal week and later throughout the neocortex, brains develop normally in La-deleted mice until ∼5 weeks and then lose a large amount of forebrain cells and mass, with evidence of altered pre-tRNA processing. The data indicate that La is required not only in proliferating cells but also in nondividing postmitotic cells. Thus, La is essential in different cell types and required for normal development of various tissue types. PMID:24190965

Adolescent, but not adult, binge ethanol exposure leads to persistent global reductions of choline acetyltransferase expressing neurons in brain.

PubMed

Vetreno, Ryan P; Broadwater, Margaret; Liu, Wen; Spear, Linda P; Crews, Fulton T

2014-01-01

During the adolescent transition from childhood to adulthood, notable maturational changes occur in brain neurotransmitter systems. The cholinergic system is composed of several distinct nuclei that exert neuromodulatory control over cognition, arousal, and reward. Binge drinking and alcohol abuse are common during this stage, which might alter the developmental trajectory of this system leading to long-term changes in adult neurobiology. In Experiment 1, adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g., 2-day on/2-day off from postnatal day [P] 25 to P55) treatment led to persistent, global reductions of choline acetyltransferase (ChAT) expression. Administration of the Toll-like receptor 4 agonist lipopolysaccharide to young adult rats (P70) produced a reduction in ChAT+IR that mimicked AIE. To determine if the binge ethanol-induced ChAT decline was unique to the adolescent, Experiment 2 examined ChAT+IR in the basal forebrain following adolescent (P28-P48) and adult (P70-P90) binge ethanol exposure. Twenty-five days later, ChAT expression was reduced in adolescent, but not adult, binge ethanol-exposed animals. In Experiment 3, expression of ChAT and vesicular acetylcholine transporter expression was found to be significantly reduced in the alcoholic basal forebrain relative to moderate drinking controls. Together, these data suggest that adolescent binge ethanol decreases adult ChAT expression, possibly through neuroimmune mechanisms, which might impact adult cognition, arousal, or reward sensitivity.

Neuro-economics in chicks: foraging choices based on amount, delay and cost.

PubMed

Matsushima, Toshiya; Kawamori, Ai; Bem-Sojka, Tiaza

2008-06-15

Studies on the foraging choices are reviewed, with an emphasis on the neural representations of elementary factors of food (i.e., amount, delay and consumption time) in the avian brain. Domestic chicks serve as an ideal animal model in this respect, as they quickly associate cue colors with subsequently supplied food rewards, and their choices are quantitatively linked with the rewards. When a pair of such color cues was simultaneously presented, the trained chicks reliably made choices according to the profitability of food associated with each color. Two forebrain regions are involved in distinct aspects of choices; i.e., nucleus accumbens-medial striatum (Ac-MSt) and arcopallium intermedium (AI), an association area in the lateral forebrain. Localized lesions of Ac-MSt enhanced delay aversion, and the ablated chicks made impulsive choices of immediate reward more frequently than sham controls. On the other hand, lesions of AI enhanced consumption-time aversion, and the ablated chicks shifted their choices toward easily consumable reward with their impulsiveness unchanged; delay and consumption time are thus doubly dissociated. Furthermore, chicks showed distinct patterns of risk-sensitive choices depending on the factor that varied at trials. Risk aversion occurred when food amount varied, whereas consistent risk sensitivity was not found when the delay varied; amount and delay were not interchangeable. Choices are thus deviated from those predicted as optima. Instead, factors such as amount, delay and consumption time could be separately represented and processed to yield economically sub-optimal choices.

Induction of Fos expression in the rat forebrain after intragastric administration of monosodium L-glutamate, glucose and NaCl.

PubMed

Otsubo, H; Kondoh, T; Shibata, M; Torii, K; Ueta, Y

2011-11-24

l-glutamate, an umami taste substance, is a key molecule coupled to a food intake signaling pathway. Furthermore, recent studies have unveiled new roles for dietary glutamate on gut-brain axis communication via activation of gut glutamate receptors and subsequent vagus nerve. In the present study, we mapped activation sites of the rat forebrain after intragastric load of 60 mM monosodium l-glutamate (MSG) by measurement of Fos protein, a functional marker of neuronal activation. The same concentration of d-glucose (sweet) and NaCl (salty) was used as controls. MSG administration exclusively produced enhanced Fos expression in four hypothalamic regions (the medial preoptic area, lateral hypothalamic area, dorsomedial nucleus, and arcuate nucleus). On the other hand, glucose administration exclusively enhanced Fos induction in the nucleus accumbens. Both MSG and glucose enhanced Fos induction in three brain regions (the habenular nucleus, paraventricular nucleus, and central nucleus of the amygdala). However, MSG induced Fos inductions were more potent than those of glucose in the habenular nucleus and paraventricular nucleus. Importantly, the present study identified for the first time two brain areas (the paraventricular and arcuate hypothalamic nuclei) that are more potently activated by intragastric MSG loads compared with glucose and NaCl. Overall, our results suggest significant activation of a neural network comprising the habenular nucleus, amygdala, and the hypothalamic subnuclei following intragastric load with glutamate. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

Regional neural tube closure defined by the Grainy head-like transcription factors.

PubMed

Rifat, Yeliz; Parekh, Vishwas; Wilanowski, Tomasz; Hislop, Nikki R; Auden, Alana; Ting, Stephen B; Cunningham, John M; Jane, Stephen M

2010-09-15

Primary neurulation in mammals has been defined by distinct anatomical closure sites, at the hindbrain/cervical spine (closure 1), forebrain/midbrain boundary (closure 2), and rostral end of the forebrain (closure 3). Zones of neurulation have also been characterized by morphologic differences in neural fold elevation, with non-neural ectoderm-induced formation of paired dorso-lateral hinge points (DLHP) essential for neural tube closure in the cranial and lower spinal cord regions, and notochord-induced bending at the median hinge point (MHP) sufficient for closure in the upper spinal region. Here we identify a unifying molecular basis for these observations based on the function of the non-neural ectoderm-specific Grainy head-like genes in mice. Using a gene-targeting approach we show that deletion of Grhl2 results in failed closure 3, with mutants exhibiting a split-face malformation and exencephaly, associated with failure of neuro-epithelial folding at the DLHP. Loss of Grhl3 alone defines a distinct lower spinal closure defect, also with defective DLHP formation. The two genes contribute equally to closure 2, where only Grhl gene dosage is limiting. Combined deletion of Grhl2 and Grhl3 induces severe rostral and caudal neural tube defects, but DLHP-independent closure 1 proceeds normally in the upper spinal region. These findings provide a molecular basis for non-neural ectoderm mediated formation of the DLHP that is critical for complete neuraxis closure. (c) 2010 Elsevier Inc. All rights reserved.

Mechanical Effects of the Surface Ectoderm on Optic Vesicle Morphogenesis in the Chick Embryo

PubMed Central

Hosseini, Hadi S.; Beebe, David C.; Taber, Larry A.

2014-01-01

Precise shaping of the eye is crucial for proper vision. Here, we use experiments on chick embryos along with computational models to examine the mechanical factors involved in the formation of the optic vesicles (OVs), which grow outward from the forebrain of the early embryo. First, mechanical dissections were used to remove the surface ectoderm (SE), a membrane that contacts the outer surfaces of the OVs. Principal components analysis of OV shapes suggests that the SE exerts asymmetric loads that cause the OVs to flatten and shear caudally during the earliest stages of eye development and later to bend in the caudal and dorsal directions. These deformations cause the initially spherical OVs to become pear-shaped. Exposure to the myosin II inhibitor blebbistatin reduced these effects, suggesting that cytoskeletal contraction controls OV shape by regulating tension in the SE. To test the physical plausibility of these interpretations, we developed 2-D finite-element models for frontal and transverse cross-sections of the forebrain, including frictionless contact between the SE and OVs. With geometric data used to specify differential growth in the OVs, these models were used to simulate each experiment (control, SE removed, no contraction). For each case, the predicted shape of the OV agrees reasonably well with experiments. The results of this study indicate that differential growth in the OV and external pressure exerted by the SE are suffcient to cause the global changes in OV shape observed during the earliest stages of eye development. PMID:25458577

Conserved pattern of tangential neuronal migration during forebrain development.

PubMed

Métin, Christine; Alvarez, Chantal; Moudoux, David; Vitalis, Tania; Pieau, Claude; Molnár, Zoltán

2007-08-01

Origin, timing and direction of neuronal migration during brain development determine the distinct organization of adult structures. Changes in these processes might have driven the evolution of the forebrain in vertebrates. GABAergic neurons originate from the ganglionic eminence in mammals and migrate tangentially to the cortex. We are interested in differences and similarities in tangential migration patterns across corresponding telencephalic territories in mammals and reptiles. Using morphological criteria and expression patterns of Darpp-32, Tbr1, Nkx2.1 and Pax6 genes, we show in slice cultures of turtle embryos that early cohorts of tangentially migrating cells are released from the medial ganglionic eminence between stages 14 and 18. Additional populations migrate tangentially from the dorsal subpallium. Large cohorts of tangentially migrating neurons originate ventral to the dorsal ventricular ridge at stage 14 and from the lateral ganglionic eminence from stage 15. Release of GABAergic cells from these regions was investigated further in explant cultures. Tangential migration in turtle proceeds in a fashion similar to mammals. In chimeric slice culture and in ovo graft experiments, the tangentially migrating cells behaved according to the host environment - turtle cells responded to the available cues in mouse slices and mouse cells assumed characteristic migratory routes in turtle brains, indicating highly conserved embryonic signals between these distant species. Our study contributes to the evaluation of theories on the origin of the dorsal cortex and indicates that tangential migration is universal in mammals and sauropsids.

Two distinct modes of forebrain circuit dynamics underlie temporal patterning in the vocalizations of young songbirds

PubMed Central

Aronov, Dmitriy; Veit, Lena; Goldberg, Jesse H.; Fee, Michale S.

2011-01-01

Accurate timing is a critical aspect of motor control, yet the temporal structure of many mature behaviors emerges during learning from highly variable exploratory actions. How does a developing brain acquire the precise control of timing in behavioral sequences? To investigate the development of timing, we analyzed the songs of young juvenile zebra finches. These highly variable vocalizations, akin to human babbling, gradually develop into temporally-stereotyped adult songs. We find that the durations of syllables and silences in juvenile singing are formed by a mixture of two distinct modes of timing – a random mode producing broadly-distributed durations early in development, and a stereotyped mode underlying the gradual emergence of stereotyped durations. Using lesions, inactivations, and localized brain cooling we investigated the roles of neural dynamics within two premotor cortical areas in the production of these temporal modes. We find that LMAN (lateral magnocellular nucleus of the nidopallium) is required specifically for the generation of the random mode of timing, and that mild cooling of LMAN causes an increase in the durations produced by this mode. On the contrary, HVC (used as a proper name) is required specifically for producing the stereotyped mode of timing, and its cooling causes a slowing of all stereotyped components. These results show that two neural pathways contribute to the timing of juvenile songs, and suggest an interesting organization in the forebrain, whereby different brain areas are specialized for the production of distinct forms of neural dynamics. PMID:22072687

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

ERIC Educational Resources Information Center

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

2004-01-01

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

The phylogenetic significance of the carpophore in Apiaceae

PubMed Central

Liu, Mei; Plunkett, Gregory M.; Van Wyk, Ben-Erik; Tilney, Patricia M.; Lowry, Porter P.

2012-01-01

Background and aims Fruit structural characters have traditionally been important in the taxonomy of the family Apiaceae. Previous investigations using a limited number of taxa have shown that the carpophore may be especially useful in helping to circumscribe subfamily Azorelloideae. The present study examines, for the first time, carpophore structure in 92 species from 43 genera, representing all subfamilies of Apiaceae, and including all genera assigned to subfamily Azorelloideae. Phylogenetic interpretations are made for the first time, using all available information, and a standard terminology is proposed to describe the various character states found in carpophores. Methods Carpophore structure was studied in detail using light microscopy. Key Results Carpophores, when present, may be categorized into two main groups (B and C) based mainly on the arrangement of the vascular bundles in transverse section, and further divided into six sub-types according to the length of the carpophore (short in B1 and C1) and whether they are entire (B1–B3 and C1) or bifurcate (B4 and C2). Free carpophores are absent in subfamily Mackinlayoideae, and in tribes Lichtensteinieae and Phlyctidocarpeae, which have two opposite vascular bundles (Group A). Entire carpophores with one or two vascular bundles, or bifurcate carpophores with lateral vascular bundles (arranged side by side within the commissural plane), are the main types characterizing Azorelloideae. The short, hygroscopic carpophores found in Choritaenia are unique in Apiaceae and provide additional evidence for the exclusion of this genus from Azorelloideae. Carpophore type C2 is typical for most Apioideae sensu lato (exceptions are, for example, Arctopus and Alepidea, which have type B2). Conclusions A single carpophore and ventral vascular bundles not forming free carpophores are proposed to be the ancestral conditions in Apiaceae, while bifurcate carpophores with opposite vascular bundles are the derived state, present in most Apioideae. Secondary reductions seem to have occurred in several unrelated lineages in all major groups, e.g. many Azorelloideae, several protoapioids (including nearly all members of the tribe Saniculeae) and 29 euapioid genera (e.g. some Oenantheae). PMID:22966116

The Evolutionary Basis of Naturally Diverse Rice Leaves Anatomy

PubMed Central

Chatterjee, Jolly; Dionora, Jacqueline; Elmido-Mabilangan, Abigail; Wanchana, Samart; Thakur, Vivek; Bandyopadhyay, Anindya; Brar, Darshan S.; Quick, William Paul

2016-01-01

Rice contains genetically and ecologically diverse wild and cultivated species that show a wide variation in plant and leaf architecture. A systematic characterization of leaf anatomy is essential in understanding the dynamics behind such diversity. Therefore, leaf anatomies of 24 Oryza species spanning 11 genetically diverse rice genomes were studied in both lateral and longitudinal directions and possible evolutionary trends were examined. A significant inter-species variation in mesophyll cells, bundle sheath cells, and vein structure was observed, suggesting precise genetic control over these major rice leaf anatomical traits. Cellular dimensions, measured along three growth axes, were further combined proportionately to construct three-dimensional (3D) leaf anatomy models to compare the relative size and orientation of the major cell types present in a fully expanded leaf. A reconstruction of the ancestral leaf state revealed that the following are the major characteristics of recently evolved rice species: fewer veins, larger and laterally elongated mesophyll cells, with an increase in total mesophyll area and in bundle sheath cell number. A huge diversity in leaf anatomy within wild and domesticated rice species has been portrayed in this study, on an evolutionary context, predicting a two-pronged evolutionary pathway leading to the ‘sativa leaf type’ that we see today in domesticated species. PMID:27792743

New understanding of the complex structure of knee menisci: implications for injury risk and repair potential for athletes.

PubMed

Rattner, J B; Matyas, J R; Barclay, L; Holowaychuk, S; Sciore, P; Lo, I K Y; Shrive, N G; Frank, C B; Achari, Y; Hart, D A

2011-08-01

Menisci help maintain the structural integrity of the knee. However, the poor healing potential of the meniscus following a knee injury can not only end a career in sports but lead to osteoarthritis later in life. Complete understanding of meniscal structure is essential for evaluating its risk for injury and subsequent successful repair. This study used novel approaches to elucidate meniscal architecture. The radial and circumferential collagen fibrils in the meniscus were investigated using novel tissue-preparative techniques for light and electron microscopic studies. The results demonstrate a unique architecture based on differences in the packaging of the fundamental collagen fibrils. For radial arrays, the collagen fibrils are arranged in parallel into ∼10 μm bundles, which associate laterally to form flat sheets of varying dimensions that bifurcate and come together to form a honeycomb network within the body of the meniscus. In contrast, the circumferential arrays display a complex network of collagen fibrils arranged into ∼5 μm bundles. Interestingly, both types of architectural organization of collagen fibrils in meniscus are conserved across mammalian species and are age and sex independent. These findings imply that disruptions in meniscal architecture following an injury contribute to poor prognosis for functional repair. © 2010 John Wiley & Sons A/S.

The Evolutionary Basis of Naturally Diverse Rice Leaves Anatomy.

PubMed

Chatterjee, Jolly; Dionora, Jacqueline; Elmido-Mabilangan, Abigail; Wanchana, Samart; Thakur, Vivek; Bandyopadhyay, Anindya; Brar, Darshan S; Quick, William Paul

2016-01-01

Rice contains genetically and ecologically diverse wild and cultivated species that show a wide variation in plant and leaf architecture. A systematic characterization of leaf anatomy is essential in understanding the dynamics behind such diversity. Therefore, leaf anatomies of 24 Oryza species spanning 11 genetically diverse rice genomes were studied in both lateral and longitudinal directions and possible evolutionary trends were examined. A significant inter-species variation in mesophyll cells, bundle sheath cells, and vein structure was observed, suggesting precise genetic control over these major rice leaf anatomical traits. Cellular dimensions, measured along three growth axes, were further combined proportionately to construct three-dimensional (3D) leaf anatomy models to compare the relative size and orientation of the major cell types present in a fully expanded leaf. A reconstruction of the ancestral leaf state revealed that the following are the major characteristics of recently evolved rice species: fewer veins, larger and laterally elongated mesophyll cells, with an increase in total mesophyll area and in bundle sheath cell number. A huge diversity in leaf anatomy within wild and domesticated rice species has been portrayed in this study, on an evolutionary context, predicting a two-pronged evolutionary pathway leading to the 'sativa leaf type' that we see today in domesticated species.

Evaluation of the marsh deer stifle joint by imaging studies and gross anatomy.

PubMed

Shigue, D A; Rahal, S C; Schimming, B C; Santos, R R; Vulcano, L C; Linardi, J L; Teixeira, C R

2015-12-01

This study aimed to evaluate the stifle joint of marsh deer using imaging studies and in comparison with gross anatomy. Ten hindlimbs from 5 marsh deer (Blastocerus dichotomus) were used. Radiography, computed tomography (CT) and magnetic resonance imaging (MRI) were performed in each stifle joint. Two hindlimbs were dissected to describe stifle gross anatomy. The other limbs were sectioned in sagittal, dorsal or transverse planes. In the craniocaudal radiographic view, the lateral femoral condyle was broader than the medial femoral condyle. The femoral trochlea was asymmetrical. Subsequent multiplanar reconstruction revealed in the cranial view that the external surface of the patella was roughened, the medial trochlea ridge was larger than the lateral one, and the extensor fossa at the lateral condyle was next to the lateral ridge. The popliteal fossa was better visualized via the lateral view. Sagittal MRI images identified lateral and medial menisci, caudolateral and craniomedial bundles of cranial cruciate ligament, caudal cruciate ligament, patellar ligament and common extensor tendon. In conclusion, the marsh deer stifle presents some anatomical characteristics of the ovine stifle joint. © 2014 Blackwell Verlag GmbH.

Fast optically sectioned fluorescence HiLo endomicroscopy.

PubMed

Ford, Tim N; Lim, Daryl; Mertz, Jerome

2012-02-01

We describe a nonscanning, fiber bundle endomicroscope that performs optically sectioned fluorescence imaging with fast frame rates and real-time processing. Our sectioning technique is based on HiLo imaging, wherein two widefield images are acquired under uniform and structured illumination and numerically processed to reject out-of-focus background. This work is an improvement upon an earlier demonstration of widefield optical sectioning through a flexible fiber bundle. The improved device features lateral and axial resolutions of 2.6 and 17 μm, respectively, a net frame rate of 9.5 Hz obtained by real-time image processing with a graphics processing unit (GPU) and significantly reduced motion artifacts obtained by the use of a double-shutter camera. We demonstrate the performance of our system with optically sectioned images and videos of a fluorescently labeled chorioallantoic membrane (CAM) in the developing G. gallus embryo. HiLo endomicroscopy is a candidate technique for low-cost, high-speed clinical optical biopsies.

Fast optically sectioned fluorescence HiLo endomicroscopy

NASA Astrophysics Data System (ADS)

Ford, Tim N.; Lim, Daryl; Mertz, Jerome

2012-02-01

We describe a nonscanning, fiber bundle endomicroscope that performs optically sectioned fluorescence imaging with fast frame rates and real-time processing. Our sectioning technique is based on HiLo imaging, wherein two widefield images are acquired under uniform and structured illumination and numerically processed to reject out-of-focus background. This work is an improvement upon an earlier demonstration of widefield optical sectioning through a flexible fiber bundle. The improved device features lateral and axial resolutions of 2.6 and 17 μm, respectively, a net frame rate of 9.5 Hz obtained by real-time image processing with a graphics processing unit (GPU) and significantly reduced motion artifacts obtained by the use of a double-shutter camera. We demonstrate the performance of our system with optically sectioned images and videos of a fluorescently labeled chorioallantoic membrane (CAM) in the developing G. gallus embryo. HiLo endomicroscopy is a candidate technique for low-cost, high-speed clinical optical biopsies.

Neuromuscular control of the glottis in a primitive air-breathing fish, Amia calva.

PubMed

Davies, P J; Hedrick, M S; Jones, D R

1993-01-01

The neuromuscular control of the glottis, a muscular sphincter that controls air flow to and from the swim bladder, was investigated using in vitro preparations from bowfin (Amia calva). Stimulation of the ramus intestinalis branch of the vagus nerve caused an increase in isometric tension of the glottal musculature, indicating active closure. The glottis could be actively opened only by direct stimulation of muscle bundles lying lateral to the glottis. In 19 of 24 preparations supramaximal nerve stimulation (20 Hz, 10 V) caused a two-phase increase in muscle tension. Immediately after the onset of stimulation there was a rapid increase in muscle tension. After the end of the train of stimuli, the tension decreased and then again increased briefly followed by a slow return to baseline lasting approximately 60 s. The addition of hyoscine reduced maximum tension of the response by 63 +/- 7% and abolished the second slower element of the response to vagal stimulation. The remaining faster response to nerve stimulation was abolished by tubocurarine. Applied acetylcholine or carbachol mimicked the slow response, causing a slow-onset sustained contraction that was abolished by hyoscine. Hence, the musculature showed physiological characteristics of both skeletal and smooth muscle. Histological examination of the glottis confirmed the physiological results: smooth muscle fibers were found lining the pneumatic duct and lumen of the glottis arranged in a circular fashion around the lateral margins of the glottis. Distinct skeletal muscle bundles were found lateral to the smooth muscle and also arranged in parallel with the glottal lumen, forming a skeletal muscle sphincter.(ABSTRACT TRUNCATED AT 250 WORDS)

Fascial structures and autonomic nerves in the female pelvis: a study using macroscopic slices and their corresponding histology.

PubMed

Tamakawa, Mitsuharu; Murakami, Gen; Takashima, Ken; Kato, Tomoyasu; Hareyama, Masato

2003-12-01

We investigated the topographical anatomy of the pelvic fasciae and autonomic nerves using macroscopic slices of five decalcified female pelves. The lateral aspect of the supravaginal cervix uteri and superior-most vagina issued abundant thick fiber bundles. These visceral fibrous tissues extended dorsolaterally, joined another fibrous tissue from the rectum (the actual lateral ligament of the rectum) and attached to the parietal fibrous tissues at and around the sciatic foramina (i.e. the sacrospinous ligament, thick fasciae of the coccygeus and piriformis and dorsal end of the covering fascia of the levator ani). The inferior or ventral vagina also issued thick fiber bundles communicating with the levator ani fascia. This connection between the vagina and levator fascia, when stretched, seemed to provide a macroscopic morphology called the arcus tendineus fasciae pelvis. The overall morphology of the visceroparietal fascial bridge exhibited a bilateral wing-like shape. The fascial bridge complex was adjacent but dorso-inferior to the internal iliac vascular sheath and located slightly ventral to the pelvic splanchnic nerve. However, the pelvic plexus and its peripheral branches were embedded in the fascial complex. The hypogastric nerve ran along and beneath the uterosacral peritoneal fold, which did not contain thick fibrous tissue. During surgery, in combination with the superficially located vascular sheath, the morphology of the visceroparietal fascial bridge and associated nerves seemed to be artificially changed and developed into the so-called cardinal, uterosacral, uterovesical and/or rectal lateral ligaments. The classical and original concepts of these pelvic fascial structures may need to be altered to adjust to these surgical observations.

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

PubMed Central

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

2014-01-01

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

Forebrain CRHR1 deficiency attenuates chronic stress-induced cognitive deficits and dendritic remodeling

PubMed Central

Wang, Xiao-Dong; Chen, Yuncai; Wolf, Miriam; Wagner, Klaus V.; Liebl, Claudia; Scharf, Sebastian H.; Harbich, Daniela; Mayer, Bianca; Wurst, Wolfgang; Holsboer, Florian; Deussing, Jan M.; Baram, Tallie Z.; Müller, Marianne B.; Schmidt, Mathias V.

2011-01-01

Chronic stress evokes profound structural and molecular changes in the hippocampus, which may underlie spatial memory deficits. Corticotropin-releasing hormone (CRH) and CRH receptor 1 (CRHR1) mediate some of the rapid effects of stress on dendritic spine morphology and modulate learning and memory, thus providing a potential molecular basis for impaired synaptic plasticity and spatial memory by repeated stress exposure. Using adult male mice with CRHR1 conditionally inactivated in the forebrain regions, we investigated the role of CRH-CRHR1 signaling in the effects of chronic social defeat stress on spatial memory, the dendritic morphology of hippocampal CA3 pyramidal neurons, and the hippocampal expression of nectin-3, a synaptic cell adhesion molecule important in synaptic remodeling. In chronically stressed wild-type mice, spatial memory was disrupted, and the complexity of apical dendrites of CA3 neurons reduced. In contrast, stressed mice with forebrain CRHR1 deficiency exhibited normal dendritic morphology of CA3 neurons and mild impairments in spatial memory. Additionally, we showed that the expression of nectin-3 in the CA3 area was regulated by chronic stress in a CRHR1-dependent fashion and associated with spatial memory and dendritic complexity. Moreover, forebrain CRHR1 deficiency prevented the down-regulation of hippocampal glucocorticoid receptor expression by chronic stress but induced increased body weight gain during persistent stress exposure. These findings underscore the important role of forebrain CRH-CRHR1 signaling in modulating chronic stress-induced cognitive, structural and molecular adaptations, with implications for stress-related psychiatric disorders. PMID:21296667

Cholinergic Inputs from Basal Forebrain Add an Excitatory Bias to Odor Coding in the Olfactory Bulb

PubMed Central

Rothermel, Markus; Carey, Ryan M.; Puche, Adam; Shipley, Michael T.

2014-01-01

Cholinergic modulation of central circuits is associated with active sensation, attention, and learning, yet the neural circuits and temporal dynamics underlying cholinergic effects on sensory processing remain unclear. Understanding the effects of cholinergic modulation on particular circuits is complicated by the widespread projections of cholinergic neurons to telencephalic structures that themselves are highly interconnected. Here we examined how cholinergic projections from basal forebrain to the olfactory bulb (OB) modulate output from the first stage of sensory processing in the mouse olfactory system. By optogenetically activating their axons directly in the OB, we found that cholinergic projections from basal forebrain regulate OB output by increasing the spike output of presumptive mitral/tufted cells. Cholinergic stimulation increased mitral/tufted cell spiking in the absence of inhalation-driven sensory input and further increased spiking responses to inhalation of odorless air and to odorants. This modulation was rapid and transient, was dependent on local cholinergic signaling in the OB, and differed from modulation by optogenetic activation of cholinergic neurons in basal forebrain, which led to a mixture of mitral/tufted cell excitation and suppression. Finally, bulbar cholinergic enhancement of mitral/tufted cell odorant responses was robust and occurred independent of the strength or even polarity of the odorant-evoked response, indicating that cholinergic modulation adds an excitatory bias to mitral/tufted cells as opposed to increasing response gain or sharpening response spectra. These results are consistent with a role for the basal forebrain cholinergic system in dynamically regulating the sensitivity to or salience of odors during active sensing of the olfactory environment. PMID:24672011

Neuropeptide Y in the forebrain of the adult male cichlid fish Oreochromis mossambicus: distribution, effects of castration and testosterone replacement.

PubMed

Sakharkar, Amul J; Singru, Praful S; Sarkar, Koustav; Subhedar, Nishikant K

2005-08-22

We studied the organization of the neuropeptide Y (NPY)-immunoreactive system in the forebrain of adult male cichlid fish Oreochromis mossambicus and its response to castration and testosterone replacement by using morphometric methods. Immunoreactivity for NPY was widely distributed in the forebrain, and the pattern generally resembled that in other teleosts. Whereas immunoreactivity was conspicuous in the ganglia of nervus terminalis (NT; or nucleus olfactoretinalis), a weak reaction was detected in some granule cells in the olfactory bulb and in the cells of area ventralis telencephali pars lateralis (Vl). Moderately to intensely immunoreactive cells were distinctly seen in the nucleus entopeduncularis (NE), nucleus preopticus (NPO), nucleus lateralis tuberis (NLT), paraventricular organ (PVO), and midbrain tegmentum (MT). NPY fibers were widely distributed in the forebrain. Castration for 10/15 days resulted in a drastic loss of immunoreactivity in the cells of NE (P<0.001) and a significant decrease (P<0.01) in their cell nuclear size. However, cell nuclei of the NT neurons showed a significant increase in size. A highly significant reduction in the NPY-immunoreactive fiber density (P<0.001) was observed in several areas of the forebrain. Although testosterone replacement reversed these changes, fibers in some areas showed supranormal responses. Immunoreactive cells in Vl, NPO, NLT, PVO, and MT and fiber density in some other areas did not respond to castration. We suggest that the NPY-immunoreactive elements that respond to castration and testosterone replacement may serve as the substrate for processing the positive feedback action of the steroid hormone. (c) 2005 Wiley-Liss, Inc.

Dynamic gene and protein expression patterns of the autism-associated met receptor tyrosine kinase in the developing mouse forebrain.

PubMed

Judson, Matthew C; Bergman, Mica Y; Campbell, Daniel B; Eagleson, Kathie L; Levitt, Pat

2009-04-10

The establishment of appropriate neural circuitry depends on the coordination of multiple developmental events across space and time. These events include proliferation, migration, differentiation, and survival-all of which can be mediated by hepatocyte growth factor (HGF) signaling through the Met receptor tyrosine kinase. We previously found a functional promoter variant of the MET gene to be associated with autism spectrum disorder, suggesting that forebrain circuits governing social and emotional function may be especially vulnerable to developmental disruptions in HGF/Met signaling. However, little is known about the spatiotemporal distribution of Met expression in the forebrain during the development of such circuits. To advance our understanding of the neurodevelopmental influences of Met activation, we employed complementary Western blotting, in situ hybridization, and immunohistochemistry to comprehensively map Met transcript and protein expression throughout perinatal and postnatal development of the mouse forebrain. Our studies reveal complex and dynamic spatiotemporal patterns of expression during this period. Spatially, Met transcript is localized primarily to specific populations of projection neurons within the neocortex and in structures of the limbic system, including the amygdala, hippocampus, and septum. Met protein appears to be principally located in axon tracts. Temporally, peak expression of transcript and protein occurs during the second postnatal week. This period is characterized by extensive neurite outgrowth and synaptogenesis, supporting a role for the receptor in these processes. Collectively, these data suggest that Met signaling may be necessary for the appropriate wiring of forebrain circuits, with particular relevance to the social and emotional dimensions of behavior. (c) 2009 Wiley-Liss, Inc.

Reassessment of the structural basis of the ascending arousal system

PubMed Central

Fuller, Patrick M.; Sherman, David; Pedersen, Nigel P.; Saper, Clifford B.; Lu, Jun

2011-01-01

The “ascending reticular activating system” theory proposed that neurons in the upper brainstem reticular formation projected to forebrain targets that promoted wakefulness. More recent formulations have emphasized that most neurons at the pontomesencepahlic junction that participate in these pathways are actually in monoaminergic and cholinergic cell groups. However, cell-specific lesions of these cell groups have never been able to reproduce the deep coma seen after acute paramedian midbrain lesions that transect ascending axons at the caudal midbrain level. To determine whether the cortical afferents from the thalamus or the basal forebrain were more important in maintaining arousal, we first place large cell-body specific lesions in these targets. Surprisingly, extensive thalamic lesions had little effect on EEG or behavioral measures of wakefulness or on c-Fos expression by cortical neurons during wakefulness. In contrast, animals with large basal forebrain lesions were behaviorally unresponsive, had a monotonous sub-1 Hz EEG, and little cortical c-Fos expression during continuous gentle handling. We then retrogradely labeled inputs to the basal forebrain from the upper brainstem, and found a substantial input from glutamatergic neurons in the parabrachial nucleus and adjacent pre-coeruleus area. Cell specific lesions of the parabrachial-precoeruleus complex produced behavioral unresponsiveness, a monotonous sub-1Hz cortical EEG, and loss of cortical c-Fos expression during gentle handling. These experiments indicate that in rats the reticulo-thalamo-cortical pathway may play a very limited role in behavioral or electrocortical arousal, while the projection from the parabrachial nucleus and precoeruleus region, relayed by the basal forebrain to the cerebral cortex, may be critical for this process. PMID:21280045

Forebrain-specific CRF overproduction during development is sufficient to induce enduring anxiety and startle abnormalities in adult mice.

PubMed

Toth, Mate; Gresack, Jodi E; Bangasser, Debra A; Plona, Zach; Valentino, Rita J; Flandreau, Elizabeth I; Mansuy, Isabelle M; Merlo-Pich, Emilio; Geyer, Mark A; Risbrough, Victoria B

2014-05-01

Corticotropin releasing factor (CRF) regulates physiological and behavioral responses to stress. Trauma in early life or adulthood is associated with increased CRF in the cerebrospinal fluid and heightened anxiety. Genetic variance in CRF receptors is linked to altered risk for stress disorders. Thus, both heritable differences and environmentally induced changes in CRF neurotransmission across the lifespan may modulate anxiety traits. To test the hypothesis that CRF hypersignaling is sufficient to modify anxiety-related phenotypes (avoidance, startle, and conditioned fear), we induced transient forebrain-specific overexpression of CRF (CRFOE) in mice (1) during development to model early-life stress, (2) in adulthood to model adult-onset stress, or (3) across the entire postnatal lifespan to model heritable increases in CRF signaling. The consequences of these manipulations on CRF peptide levels and behavioral responses were examined in adulthood. We found that transient CRFOE during development decreased startle habituation and prepulse inhibition, and increased avoidance (particularly in females) recapitulating the behavioral effects of lifetime CRFOE despite lower CRF peptide levels at testing. In contrast, CRFOE limited to adulthood reduced contextual fear learning in females and increased startle reactivity in males but did not change avoidance or startle plasticity. These findings suggest that forebrain CRFOE limited to development is sufficient to induce enduring alterations in startle plasticity and anxiety, while forebrain CRFOE during adulthood results in a different phenotype profile. These findings suggest that startle circuits are particularly sensitive to forebrain CRFOE, and that the impact of CRFOE may be dependent on the time of exposure.

Lentiviral Infection of Rhesus Macaques Causes Long-Term Injury to Cortical and Hippocampal Projections of Prostaglandin-Expressing Cholinergic Basal Forebrain Neurons

PubMed Central

Depboylu, Candan; Weihe, Eberhard; Eiden, Lee E.

2011-01-01

The simian immunodeficiency virus (SIV) macaque model resembles human HIV-AIDS and associated brain dysfunction. Altered expression of synaptic markers and transmitters in neuro-AIDS has been reported, but limited data exist for the cholinergic system and lipid mediators such as prostaglandins. Here, we analyzed cholinergic basal forebrain neurons with their telencephalic projections and the rate-limiting enzymes for prostaglandin synthesis, cyclooxygenases 1 and 2 (COX1 and 2) in brains of SIV-infected macaques with and without encephalitis and antiretroviral therapy, and uninfected controls. COX1 but not COX2 was co-expressed with markers of cholinergic phenotype, i.e. choline acetyltransferase and vesicular acetylcholine transporter (VAChT), in basal forebrain neurons of monkey, as well as human samples. COX1 was decreased in basal forebrain neurons in macaques with AIDS vs. uninfected and asymptomatic SIV-infected macaques. VAChT-positive fiber density was reduced in frontal, parietal and hippocampal-entorhinal cortex. Although brain SIV burden and associated COX1- and COX2-positive mononuclear and endothelial inflammatory reactions were mostly reversed in AIDS-diseased macaques that received 6-chloro-2′,3′-dideoxyguanosine treatment, decreased VAChT-positive terminal density and reduced cholinergic COX1 expression were not. Thus, COX1 expression is a feature of primate cholinergic basal forebrain neurons; it may be functionally important and a critical biomarker of cholinergic dysregulation accompanying lentiviral encephalopathy. These results imply that insufficiently prompt initiation of antiretroviral therapy in lentiviral infection may lead to neurostructurally unremarkable but neurochemically prominent, irreversible brain damage. PMID:22157616

The effect of aniracetam on cerebral glucose metabolism in rats after lesioning of the basal forebrain measured by PET.

PubMed

Ouchi, Y; Kakiuchi, T; Okada, H; Nishiyama, S; Tsukada, H

1999-03-15

To evaluate the effect of aniracetam, a potent modulator of the glutamatergic and cholinergic systems, on the altered cerebral glucose metabolism after lesioning of the basal forebrain, we measured the cerebral metabolic rate of glucose (CMRGlc) with positron emission tomography and the choline acetyltransferase (ChAT) activity in the frontal cortex of the lesioned rats after treating them with aniracetam. Continuous administration of aniracetam for 7 days after the surgery prevented CMRGlc reduction in the frontal cortex ipsilateral to the lesion while the lesioned rats without aniracetam showed significant CMRGlc reduction in the frontal cortex. The level of CMRGlc in the lesion-side basal forebrain was lower in all rats regardless of the aniracetam treatment. Biochemical studies showed that aniracetam did not alter the reduction in the frontal ChAT activity. These results showed that aniracetam prevents glucose metabolic reduction in the cholinergically denervated frontal cortex with little effect on the cortical cholinergic system. The present study suggested that a neurotransmitter system other than the cholinergic system, e.g. the glutamatergic system, plays a central role in the cortical metabolic recovery after lesioning of the basal forebrain.

NCAM deficiency in the mouse forebrain impairs innate and learned avoidance behaviours.

PubMed

Brandewiede, J; Stork, O; Schachner, M

2014-06-01

The neural cell adhesion molecule (NCAM) has been implicated in the development and plasticity of neural circuits and the control of hippocampus- and amygdala-dependent learning and behaviour. Previous studies in constitutive NCAM null mutants identified emotional behaviour deficits related to disturbances of hippocampal and amygdala functions. Here, we studied these behaviours in mice conditionally deficient in NCAM in the postmigratory forebrain neurons. We report deficits in both innate and learned avoidance behaviours, as observed in elevated plus maze and passive avoidance tasks. In contrast, general locomotor activity, trait anxiety or neophobia were unaffected by the mutation. Altered avoidance behaviour of the conditional NCAM mutants was associated with a deficit in serotonergic signalling, as indicated by their reduced responsiveness to (±)-8-hydroxy-2-(dipropylamino)-tetralin-induced hypothermia. Another serotonin-dependent behaviour, namely intermale aggression that is massively increased in constitutively NCAM-deficient mice, was not affected in the forebrain-specific mutants. Our data suggest that genetically or environmentally induced changes of NCAM expression in the late postnatal and mature forebrain determine avoidance behaviour and serotonin (5-HT)1A receptor signalling. © 2014 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

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

PubMed Central

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

2015-01-01

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

Effects of short-term hormonal replacement on learning and on basal forebrain ChAT and TrkA content in ovariectomized rats.

PubMed

Espinosa-Raya, Judith; Plata-Cruz, Noemí; Neri-Gómez, Teresa; Camacho-Arroyo, Ignacio; Picazo, Ofir

2011-02-23

It has been proposed that sex steroid hormones improve performance in some cognitive tasks by regulating the basal forebrain cholinergic function. However, the molecular basis of such influence still remains unknown. Current study analyzed the performance of ovariectomized rats in an autoshaping learning task after a short-term treatment with 17β-estradiol (E2: 4 and 40μg/kg) and/or progesterone (P4: 4mg/kg). These results were correlated with basal forebrain choline acetyltransferase (ChAT) and TrkA protein content. The high dose of E2 enhanced both acquisition in the autoshaping task and the content of ChAT and TrkA. P4 treatment increased ChAT and TrkA content without affecting performance of rats in the autoshaping learning task. Interestingly, the continuous and simultaneous administration of E2 plus P4 did not significantly modify behavioral and biochemical evaluated parameters. These results address the influence of both E2 and P4 on cholinergic and TrkA activity and suggest that the effects of ovarian hormones on cognitive performance involve basal forebrain cholinergic neurons. Copyright © 2010 Elsevier B.V. All rights reserved.

Deformation behavior and mechanical analysis of vertically aligned carbon nanotube (VACNT) bundles

NASA Astrophysics Data System (ADS)

Hutchens, Shelby B.

Vertically aligned carbon nanotubes (VACNTs) serve as integral components in a variety of applications including MEMS devices, energy absorbing materials, dry adhesives, light absorbing coatings, and electron emitters, all of which require structural robustness. It is only through an understanding of VACNT's structural mechanical response and local constitutive stress-strain relationship that future advancements through rational design may take place. Even for applications in which the structural response is not central to device performance, VACNTs must be sufficiently robust and therefore knowledge of their microstructure-property relationship is essential. This thesis first describes the results of in situ uniaxial compression experiments of 50 micron diameter cylindrical bundles of these complex, hierarchical materials as they undergo unusual deformation behavior. Most notably they deform via a series of localized folding events, originating near the bundle base, which propagate laterally and collapse sequentially from bottom to top. This deformation mechanism accompanies an overall foam-like stress-strain response having elastic, plateau, and densification regimes with the addition of undulations in the stress throughout the plateau regime that correspond to the sequential folding events. Microstructural observations indicate the presence of a strength gradient, due to a gradient in both tube density and alignment along the bundle height, which is found to play a key role in both the sequential deformation process and the overall stress-strain response. Using the complicated structural response as both motivation and confirmation, a finite element model based on a viscoplastic solid is proposed. This model is characterized by a flow stress relation that contains an initial peak followed by strong softening and successive hardening. Analysis of this constitutive relation results in capture of the sequential buckling phenomenon and a strength gradient effect. This combination of experimental and modeling approaches motivates discussion of the particular microstructural mechanisms and local material behavior that govern the non-trivial energy absorption via sequential, localized buckle formation in the VACNT bundles.

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

PubMed Central

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

2015-01-01

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

Temporal variations in early developmental decisions: an engine of forebrain evolution.

PubMed

Bielen, H; Pal, S; Tole, S; Houart, C

2017-02-01

Tight control of developmental timing is pivotal to many major processes in developmental biology, such as patterning, fate specification, cell cycle dynamics, cell migration and connectivity. Temporal change in these ontogenetic sequences is known as heterochrony, a major force in the evolution of body plans and organogenesis. In the last 5 years, studies in fish and rodents indicate that heterochrony in signaling during early development generates diversity in forebrain size and complexity. Here, we summarize these findings and propose that, additionally to spatio-temporal tuning of neurogenesis, temporal and quantitative modulation of signaling events drive pivotal changes in shape, size and complexity of the forebrain across evolution, participating to the generation of diversity in animal behavior and emergence of cognition. Copyright © 2017 Elsevier Ltd. All rights reserved.

Circuit Architecture of VTA Dopamine Neurons Revealed by Systematic Input-Output Mapping.

PubMed

Beier, Kevin T; Steinberg, Elizabeth E; DeLoach, Katherine E; Xie, Stanley; Miyamichi, Kazunari; Schwarz, Lindsay; Gao, Xiaojing J; Kremer, Eric J; Malenka, Robert C; Luo, Liqun

2015-07-30

Dopamine (DA) neurons in the midbrain ventral tegmental area (VTA) integrate complex inputs to encode multiple signals that influence motivated behaviors via diverse projections. Here, we combine axon-initiated viral transduction with rabies-mediated trans-synaptic tracing and Cre-based cell-type-specific targeting to systematically map input-output relationships of VTA-DA neurons. We found that VTA-DA (and VTA-GABA) neurons receive excitatory, inhibitory, and modulatory input from diverse sources. VTA-DA neurons projecting to different forebrain regions exhibit specific biases in their input selection. VTA-DA neurons projecting to lateral and medial nucleus accumbens innervate largely non-overlapping striatal targets, with the latter also sending extensive extra-striatal axon collaterals. Using electrophysiology and behavior, we validated new circuits identified in our tracing studies, including a previously unappreciated top-down reinforcing circuit from anterior cortex to lateral nucleus accumbens via VTA-DA neurons. This study highlights the utility of our viral-genetic tracing strategies to elucidate the complex neural substrates that underlie motivated behaviors. Copyright © 2015 Elsevier Inc. All rights reserved.

Single microfilaments mediate the early steps of microtubule bundling during preprophase band formation in onion cotyledon epidermal cells

PubMed Central

Takeuchi, Miyuki; Karahara, Ichirou; Kajimura, Naoko; Takaoka, Akio; Murata, Kazuyoshi; Misaki, Kazuyo; Yonemura, Shigenobu; Staehelin, L. Andrew; Mineyuki, Yoshinobu

2016-01-01

The preprophase band (PPB) is a cytokinetic apparatus that determines the site of cell division in plants. It originates as a broad band of microtubules (MTs) in G2 and narrows to demarcate the future division site during late prophase. Studies with fluorescent probes have shown that PPBs contain F-actin during early stages of their development but become actin depleted in late prophase. Although this suggests that actins contribute to the early stages of PPB formation, how actins contribute to PPB-MT organization remains unsolved. To address this question, we used electron tomography to investigate the spatial relationship between microfilaments (MFs) and MTs at different stages of PPB assembly in onion cotyledon epidermal cells. We demonstrate that the PPB actins observed by fluorescence microscopy correspond to short, single MFs. A majority of the MFs are bound to MTs, with a subset forming MT-MF-MT bridging structures. During the later stages of PPB assembly, the MF-mediated links between MTs are displaced by MT-MT linkers as the PPB MT arrays mature into tightly packed MT bundles. On the basis of these observations, we propose that the primary function of actins during PPB formation is to mediate the initial bundling of the PPB MTs. PMID:27053663

A Biophysical Model for the Staircase Geometry of Stereocilia

PubMed Central

Orly, Gilad; Manor, Uri; Gov, Nir S.

2015-01-01

Cochlear hair cell bundles, made up of 10s to 100s of individual stereocilia, are essential for hearing, and even relatively minor structural changes, due to mutations or injuries, can result in total deafness. Consistent with its specialized role, the staircase geometry (SCG) of hair cell bundles presents one of the most striking, intricate, and precise organizations of actin-based cellular shapes. Composed of rows of actin-filled stereocilia with increasing lengths, the hair cell’s staircase-shaped bundle is formed from a progenitor field of smaller, thinner, and uniformly spaced microvilli with relatively invariant lengths. While recent genetic studies have provided a significant increase in information on the multitude of stereocilia protein components, there is currently no model that integrates the basic physical forces and biochemical processes necessary to explain the emergence of the SCG. We propose such a model derived from the biophysical and biochemical characteristics of actin-based protrusions. We demonstrate that polarization of the cell’s apical surface, due to the lateral polarization of the entire epithelial layer, plays a key role in promoting SCG formation. Furthermore, our model explains many distinct features of the manifestations of SCG in different species and in the presence of various deafness-associated mutations. PMID:26207893

Piezo- and Flexoelectric Membrane Materials Underlie Fast Biological Motors in the Ear

PubMed Central

Breneman, Kathryn D.; Rabbitt, Richard D.

2010-01-01

The mammalian inner ear is remarkably sensitive to quiet sounds, exhibits over 100dB dynamic range, and has the exquisite ability to discriminate closely spaced tones even in the presence of noise. This performance is achieved, in part, through active mechanical amplification of vibrations by sensory hair cells within the inner ear. All hair cells are endowed with a bundle of motile microvilli, stereocilia, located at the apical end of the cell, and the more specialized outer hair cells (OHC’s) are also endowed with somatic electromotility responsible for changes in cell length in response to perturbations in membrane potential. Both hair bundle and somatic motors are known to feed energy into the mechanical vibrations in the inner ear. The biophysical origin and relative significance of the motors remains a subject of intense research. Several biological motors have been identified in hair cells that might underlie the motor(s), including a cousin of the classical ATP driven actin-myosin motor found in skeletal muscle. Hydrolysis of ATP, however, is much too slow to be viable at audio frequencies on a cycle-by-cycle basis. Heuristically, the OHC somatic motor behaves as if the OHC lateral wall membrane were a piezoelectric material and the hair bundle motor behaves as if the plasma membrane were a flexoelectric material. We propose these observations from a continuum materials perspective are literally true. To examine this idea, we formulated mathematical models of the OHC lateral wall “piezoelectric” motor and the more ubiquitous “flexoelectric” hair bundle motor. Plausible biophysical mechanisms underlying piezo- and flexoelectricity were established. Model predictions were compared extensively to the available data. The models were then applied to study the power conversion efficiency of the motors. Results show that the material properties of the complex membranes in hair cells provide them with the ability to convert electrical power available in the inner ear cochlea into useful mechanical amplification of sound induced vibrations at auditory frequencies. We also examined how hair cell amplification might be controlled by the brain through efferent synaptic contacts on hair cells and found a simple mechanism to tune hearing to signals of interest to the listener by electrical control of these motors. PMID:21188296

Analysis of gene expression profiles for cell wall modifying proteins and ACC synthases in soybean cyst nematode colonized roots, adventitious rooting hypocotyls, root tips, flooded roots, and IBA and ACC treatment roots

USDA-ARS?s Scientific Manuscript database

We hypothesized that soybean cyst nematode (SCN) co-opts a part or all of one or more innate developmental process in soybean to establish its feeding structure, syncytium, in soybean roots. The syncytium in soybean roots is formed in a predominantly lateral direction within the vascular bundle by ...

Low Level Chlorpyrifos Exposure Increases Anandamide Accumulation in Juvenile Rat Brain in the Absence of Brain Cholinesterase Inhibition

PubMed Central

Carr, Russell L.; Graves, Casey A.; Mangum, Lee C.; Nail, Carole A.; Ross, Matthew K.

2014-01-01

The prevailing dogma is that chlorpyrifos (CPF) mediates its toxicity through inhibition of cholinesterase (ChE). However, in recent years, the toxicological effects of developmental CPF exposure have been attributed to an unknown non-cholinergic mechanism of action. We hypothesize that the endocannabinoid system may be an important target because of its vital role in nervous system development. We have previously reported that repeated exposure to CPF results in greater inhibition of fatty acid amide hydrolase (FAAH), the enzyme that metabolizes the endocannabinoid anandamide (AEA), than inhibition of either forebrain ChE or monoacylglycerol lipase (MAGL), the enzyme that metabolizes the endocannabinoid 2-arachidonylglycerol (2-AG). This exposure resulted in the accumulation of 2-AG and AEA in the forebrain of juvenile rats; however, even at the lowest dosage level used (1.0 mg/kg), forebrain ChE inhibition was still present. Thus, it is not clear if FAAH activity would be inhibited at dosage levels that do not inhibit ChE. To determine this, 10 day old rat pups were exposed daily for 7 days to either corn oil or 0.5 mg/kg CPF by oral gavage. At 4 and 12 h post-exposure on the last day of administration, the activities of serum ChE and carboxylesterase (CES) and forebrain ChE, MAGL, and FAAH were determined as well as the forebrain AEA and 2-AG levels. Significant inhibition of serum ChE and CES was present at both 4 and 12 h. There was no significant inhibition of the activities of forebrain ChE or MAGL and no significant change in the amount of 2-AG at either time point. On the other hand, while no statistically significant effects were observed at 4 h, FAAH activity was significantly inhibited at 12 h resulting in a significant accumulation of AEA. Although it is not clear if this level of accumulation impacts brain maturation, this study demonstrates that developmental CPF exposure at a level that does not inhibit brain ChE can alter components of endocannabinoid signaling. PMID:24373905

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

PubMed

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

2015-12-09

In the ventral tegmental area (VTA), a subpopulation of dopamine neurons express vesicular glutamate transporter 2 and make glutamatergic connections to nucleus accumbens (NAc) and olfactory tubercle (OT) neurons. However, their glutamatergic connections across the forebrain have not been explored systematically. To visualize dopamine neuron forebrain projections and to enable photostimulation of their axons independent of transmitter status, we virally transfected VTA neurons with channelrhodopsin-2 fused to enhanced yellow fluorescent protein (ChR2-EYFP) and used DAT(IREScre) mice to restrict expression to dopamine neurons. ChR2-EYFP-expressing neurons almost invariably stained for tyrosine hydroxylase, identifying them as dopaminergic. Dopamine neuron axons visualized by ChR2-EYFP fluorescence projected most densely to the striatum, moderately to the amygdala and entorhinal cortex (ERC), sparsely to prefrontal and cingulate cortices, and rarely to the hippocampus. Guided by ChR2-EYFP fluorescence, we recorded systematically from putative principal neurons in target areas and determined the incidence and strength of glutamatergic connections by activating all dopamine neuron terminals impinging on recorded neurons with wide-field photostimulation. This revealed strong glutamatergic connections in the NAc, OT, and ERC; moderate strength connections in the central amygdala; and weak connections in the cingulate cortex. No glutamatergic connections were found in the dorsal striatum, hippocampus, basolateral amygdala, or prefrontal cortex. These results indicate that VTA dopamine neurons elicit widespread, but regionally distinct, glutamatergic signals in the forebrain and begin to define the dopamine neuron excitatory functional connectome. Dopamine neurons are important for the control of motivated behavior and are involved in the pathophysiology of several major neuropsychiatric disorders. Recent studies have shown that some ventral midbrain dopamine neurons are capable of glutamate cotransmission. With conditional expression of channelrhodopsin in dopamine neurons, we systematically explored dopamine neuron connections in the forebrain and identified regionally specific dopamine neuron excitatory connections. Establishing that only a subset of forebrain regions receive excitatory connections from dopamine neurons will help to determine the function of dopamine neuron glutamate cotransmission, which likely involves transmission of precise temporal signals and enhancement of the dynamic range of dopamine neuron signals. Copyright © 2015 the authors 0270-6474/15/3516259-13$15.00/0.

Dynamic changes in murine forebrain miR-211 expression associate with cholinergic imbalances and epileptiform activity

PubMed Central

Mishra, Nibha; Milikovsky, Dan Z.; Hanin, Geula; Zelig, Daniel; Sheintuch, Liron; Berson, Amit; Greenberg, David S.; Friedman, Alon

2017-01-01

Epilepsy is a common neurological disease, manifested in unprovoked recurrent seizures. Epileptogenesis may develop due to genetic or pharmacological origins or following injury, but it remains unclear how the unaffected brain escapes this susceptibility to seizures. Here, we report that dynamic changes in forebrain microRNA (miR)-211 in the mouse brain shift the threshold for spontaneous and pharmacologically induced seizures alongside changes in the cholinergic pathway genes, implicating this miR in the avoidance of seizures. We identified miR-211 as a putative attenuator of cholinergic-mediated seizures by intersecting forebrain miR profiles that were Argonaute precipitated, synaptic vesicle target enriched, or differentially expressed under pilocarpine-induced seizures, and validated TGFBR2 and the nicotinic antiinflammatory acetylcholine receptor nAChRa7 as murine and human miR-211 targets, respectively. To explore the link between miR-211 and epilepsy, we engineered dTg-211 mice with doxycycline-suppressible forebrain overexpression of miR-211. These mice reacted to doxycycline exposure by spontaneous electrocorticography-documented nonconvulsive seizures, accompanied by forebrain accumulation of the convulsive seizures mediating miR-134. RNA sequencing demonstrated in doxycycline-treated dTg-211 cortices overrepresentation of synaptic activity, Ca2+ transmembrane transport, TGFBR2 signaling, and cholinergic synapse pathways. Additionally, a cholinergic dysregulated mouse model overexpressing a miR refractory acetylcholinesterase-R splice variant showed a parallel propensity for convulsions, miR-211 decreases, and miR-134 elevation. Our findings demonstrate that in mice, dynamic miR-211 decreases induce hypersynchronization and nonconvulsive and convulsive seizures, accompanied by expression changes in cholinergic and TGFBR2 pathways as well as in miR-134. Realizing the importance of miR-211 dynamics opens new venues for translational diagnosis of and interference with epilepsy. PMID:28584127

Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration.

PubMed

Hambright, William Sealy; Fonseca, Rene Solano; Chen, Liuji; Na, Ren; Ran, Qitao

2017-08-01

Synaptic loss and neuron death are the underlying cause of neurodegenerative diseases such as Alzheimer's disease (AD); however, the modalities of cell death in those diseases remain unclear. Ferroptosis, a newly identified oxidative cell death mechanism triggered by massive lipid peroxidation, is implicated in the degeneration of neurons populations such as spinal motor neurons and midbrain neurons. Here, we investigated whether neurons in forebrain regions (cerebral cortex and hippocampus) that are severely afflicted in AD patients might be vulnerable to ferroptosis. To this end, we generated Gpx4BIKO mouse, a mouse model with conditional deletion in forebrain neurons of glutathione peroxidase 4 (Gpx4), a key regulator of ferroptosis, and showed that treatment with tamoxifen led to deletion of Gpx4 primarily in forebrain neurons of adult Gpx4BIKO mice. Starting at 12 weeks after tamoxifen treatment, Gpx4BIKO mice exhibited significant deficits in spatial learning and memory function versus Control mice as determined by the Morris water maze task. Further examinations revealed that the cognitively impaired Gpx4BIKO mice exhibited hippocampal neurodegeneration. Notably, markers associated with ferroptosis, such as elevated lipid peroxidation, ERK activation and augmented neuroinflammation, were observed in Gpx4BIKO mice. We also showed that Gpx4BIKO mice fed a diet deficient in vitamin E, a lipid soluble antioxidant with anti-ferroptosis activity, had an expedited rate of hippocampal neurodegeneration and behavior dysfunction, and that treatment with a small-molecule ferroptosis inhibitor ameliorated neurodegeneration in those mice. Taken together, our results indicate that forebrain neurons are susceptible to ferroptosis, suggesting that ferroptosis may be an important neurodegenerative mechanism in diseases such as AD. Copyright © 2017. Published by Elsevier B.V.

Oxidative stress and Na,K-ATPase activity differential regulation in brainstem and forebrain of Wistar Audiogenic rats may lead to increased seizure susceptibility.

PubMed

Parreira, Gabriela Machado; Resende, Maria Daniela Aparecida; Garcia, Israel José Pereira; Sartori, Daniela Bueno; Umeoka, Eduardo Henrique de Lima; Godoy, Lívea Dornela; Garcia-Cairasco, Norberto; Barbosa, Leandro Augusto; Santos, Hérica de Lima; Tilelli, Cristiane Queixa

2018-01-15

The Wistar Audiogenic Rat (WAR) is a well-characterized seizure-prone, inbred rodent strain that, when acutely stimulated with high-intensity sounds, develops brainstem-dependent tonic-clonic seizures that can evolve to limbic-like, myoclonic (forebrain) seizures when the acoustic stimuli are presented chronically (audiogenic kindling). In order to investigate possible mechanisms underlying WAR susceptibility to seizures, we evaluated Na,K-ATPase activity, Ca-ATPase activity, Mg-ATPase activity, lipid membrane composition and oxidative stress markers in whole forebrain and whole brainstem samples of naïve WAR, as compared to samples from control Wistar rats. We also evaluated the expression levels of α1 and α3 isoforms of Na,K-ATPase in forebrain samples. We observed increased Na,K-ATPase activity in forebrain samples and increased oxidative stress markers (lipid peroxidation, glutathione peroxidase and superoxide dismutase) in brainstem samples of WAR. The Ca-ATPase activity, Mg-ATPase activity, lipid membrane composition and expression levels of α1 and α3 isoforms of Na,K-ATPase were unaltered. In view of previous data showing that the membrane potentials from naïve WAR's neurons are less negative than that from neurons from Wistar rats, we suggest that Na,K-ATPase increased activity might be involved in a compensatory mechanism necessary to maintain WAR's brains normal activity. Additionally, ongoing oxidative stress in the brainstem could bring Na,K-ATPase activity back to normal levels, which may explain why WAR's present increased susceptibility to seizures triggered by high-intensity sound stimulation. Copyright © 2017 Elsevier B.V. All rights reserved.

Dynamic changes in murine forebrain miR-211 expression associate with cholinergic imbalances and epileptiform activity.

PubMed

Bekenstein, Uriya; Mishra, Nibha; Milikovsky, Dan Z; Hanin, Geula; Zelig, Daniel; Sheintuch, Liron; Berson, Amit; Greenberg, David S; Friedman, Alon; Soreq, Hermona

2017-06-20

Epilepsy is a common neurological disease, manifested in unprovoked recurrent seizures. Epileptogenesis may develop due to genetic or pharmacological origins or following injury, but it remains unclear how the unaffected brain escapes this susceptibility to seizures. Here, we report that dynamic changes in forebrain microRNA (miR)-211 in the mouse brain shift the threshold for spontaneous and pharmacologically induced seizures alongside changes in the cholinergic pathway genes, implicating this miR in the avoidance of seizures. We identified miR-211 as a putative attenuator of cholinergic-mediated seizures by intersecting forebrain miR profiles that were Argonaute precipitated, synaptic vesicle target enriched, or differentially expressed under pilocarpine-induced seizures, and validated TGFBR2 and the nicotinic antiinflammatory acetylcholine receptor nAChRa7 as murine and human miR-211 targets, respectively. To explore the link between miR-211 and epilepsy, we engineered dTg-211 mice with doxycycline-suppressible forebrain overexpression of miR-211. These mice reacted to doxycycline exposure by spontaneous electrocorticography-documented nonconvulsive seizures, accompanied by forebrain accumulation of the convulsive seizures mediating miR-134. RNA sequencing demonstrated in doxycycline-treated dTg-211 cortices overrepresentation of synaptic activity, Ca 2+ transmembrane transport, TGFBR2 signaling, and cholinergic synapse pathways. Additionally, a cholinergic dysregulated mouse model overexpressing a miR refractory acetylcholinesterase-R splice variant showed a parallel propensity for convulsions, miR-211 decreases, and miR-134 elevation. Our findings demonstrate that in mice, dynamic miR-211 decreases induce hypersynchronization and nonconvulsive and convulsive seizures, accompanied by expression changes in cholinergic and TGFBR2 pathways as well as in miR-134. Realizing the importance of miR-211 dynamics opens new venues for translational diagnosis of and interference with epilepsy.

Forebrain neurogenesis: From embryo to adult.

PubMed

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

2016-01-01

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

Engrailed-2 (En2) deletion produces multiple neurodevelopmental defects in monoamine systems, forebrain structures and neurogenesis and behavior

PubMed Central

Genestine, Matthieu; Lin, Lulu; Durens, Madel; Yan, Yan; Jiang, Yiqin; Prem, Smrithi; Bailoor, Kunal; Kelly, Brian; Sonsalla, Patricia K.; Matteson, Paul G.; Silverman, Jill; Crawley, Jacqueline N.; Millonig, James H.; DiCicco-Bloom, Emanuel

2015-01-01

Many genes involved in brain development have been associated with human neurodevelopmental disorders, but underlying pathophysiological mechanisms remain undefined. Human genetic and mouse behavioral analyses suggest that ENGRAILED-2 (EN2) contributes to neurodevelopmental disorders, especially autism spectrum disorder. In mouse, En2 exhibits dynamic spatiotemporal expression in embryonic mid-hindbrain regions where monoamine neurons emerge. Considering their importance in neuropsychiatric disorders, we characterized monoamine systems in relation to forebrain neurogenesis in En2-knockout (En2-KO) mice. Transmitter levels of serotonin, dopamine and norepinephrine (NE) were dysregulated from Postnatal day 7 (P7) to P21 in En2-KO, though NE exhibited the greatest abnormalities. While NE levels were reduced ∼35% in forebrain, they were increased 40–75% in hindbrain and cerebellum, and these patterns paralleled changes in locus coeruleus (LC) fiber innervation, respectively. Although En2 promoter was active in Embryonic day 14.5–15.5 LC neurons, expression diminished thereafter and gene deletion did not alter brainstem NE neuron numbers. Significantly, in parallel with reduced NE levels, En2-KO forebrain regions exhibited reduced growth, particularly hippocampus, where P21 dentate gyrus granule neurons were decreased 16%, suggesting abnormal neurogenesis. Indeed, hippocampal neurogenic regions showed increased cell death (+77%) and unexpectedly, increased proliferation. Excess proliferation was restricted to early Sox2/Tbr2 progenitors whereas increased apoptosis occurred in differentiating (Dcx) neuroblasts, accompanied by reduced newborn neuron survival. Abnormal neurogenesis may reflect NE deficits because intra-hippocampal injections of β-adrenergic agonists reversed cell death. These studies suggest that disruption of hindbrain patterning genes can alter monoamine system development and thereby produce forebrain defects that are relevant to human neurodevelopmental disorders. PMID:26220976

Lentiviral infection of rhesus macaques causes long-term injury to cortical and hippocampal projections of prostaglandin-expressing cholinergic basal forebrain neurons.

PubMed

Depboylu, Candan; Weihe, Eberhard; Eiden, Lee E

2012-01-01

The simian immunodeficiency virus (SIV) macaque model resembles human immunodeficiency virus-acquired immunodeficiency syndrome (AIDS) and associated brain dysfunction. Altered expression of synaptic markers and transmitters in neuro-AIDS has been reported, but limited data exist for the cholinergic system and lipid mediators such as prostaglandins. Here, we analyzed cholinergic basal forebrain neurons with their telencephalic projections and the rate-limiting enzymes for prostaglandin synthesis, cyclooxygenase isotypes 1 and 2 (COX1 and COX2) in the brains of SIV-infected macaques with or without encephalitis and antiretroviral therapy and uninfected controls.Cyclooxygenase isotype 1, but not COX2, was coexpressed with markers of cholinergic phenotype, that is, choline acetyltransferase and vesicular acetylcholine transporter (VAChT), in basal forebrain neurons of monkey, as well as human, brain. Cyclooxygenase isotype 1 was decreased in basal forebrain neurons in macaques with AIDS versus uninfected and asymptomatic SIV-infected macaques. The VAChT-positive fiber density was reduced in frontal, parietal, and hippocampal-entorhinal cortex. Although brain SIV burden and associated COX1- and COX2-positive mononuclear and endothelial inflammatory reactions were mostly reversed in AIDS-diseased macaques that received 6-chloro-2',3'-dideoxyguanosine treatment, decreased VAChT-positive terminal density and reduced cholinergic COX1 expression were not. Thus, COX1 expression is a feature of primate cholinergic basal forebrain neurons; it may be functionally important and a critical biomarker of cholinergic dysregulation accompanying lentiviral encephalopathy. These results further imply that insufficiently prompt initiation of antiretroviral therapy in lentiviral infection may lead to neurostructurally unremarkable but neurochemically prominent irreversible brain damage.

Glutamic acid decarboxylase isoform distribution in transgenic mouse septum: an anti-GFP immunofluorescence study.

PubMed

Verimli, Ural; Sehirli, Umit S

2016-09-01

The septum is a basal forebrain region located between the lateral ventricles in rodents. It consists of lateral and medial divisions. Medial septal projections regulate hippocampal theta rhythm whereas lateral septal projections are involved in processes such as affective functions, memory formation, and behavioral responses. Gamma-aminobutyric acidergic neurons of the septal region possess the 65 and 67 isoforms of the enzyme glutamic acid decarboxylase. Although data on the glutamic acid decarboxylase isoform distribution in the septal region generally appears to indicate glutamic acid decarboxylase 67 dominance, different studies have given inconsistent results in this regard. The aim of this study was therefore to obtain information on the distributions of both of these glutamic acid decarboxylase isoforms in the septal region in transgenic mice. Two animal groups of glutamic acid decarboxylase-green fluorescent protein knock-in transgenic mice were utilized in the experiment. Brain sections from the region were taken for anti-green fluorescent protein immunohistochemistry in order to obtain estimated quantitative data on the number of gamma-aminobutyric acidergic neurons. Following the immunohistochemical procedures, the mean numbers of labeled cells in the lateral and medial septal nuclei were obtained for the two isoform groups. Statistical analysis yielded significant results which indicated that the 65 isoform of glutamic acid decarboxylase predominates in both lateral and medial septal nuclei (unpaired two-tailed t-test p < 0.0001 for LS, p < 0.01 for MS). This study is the first to reveal the dominance of glutamic acid decarboxylase isoform 65 in the septal region in glutamic acid decarboxylase-green fluorescent protein transgenic mice.

Embryology of Maldives clownfish, Amphiprion nigripes (Amphiprioninae)

NASA Astrophysics Data System (ADS)

Ghosh, Swagat; Kumar, Thipramalai Thankappanpillai Ajith; Balasubramanian, Thangavel

2012-06-01

This study investigated the embryonic development of Maldives clownfish Amphiprion nigripes under natural conditions (28-30°C) at a lagoon of Agatti Island, Lakshadweep, India. The newly deposited fish egg was capsule-shaped and orange-red, with a (0.73 ± 0.04) mm3 yolk containing 5-10 fat globules. The embryonic development of fertilized eggs was divided into 26 stages and the time elapsing for each stage was recorded. Results showed that the cleavage was rapid, with the first division observed 1 h 20 min after fertilization. Blastulation occurred 4 h later, followed by gastrulation 12 h after fertilization, with a yolk volume of (0.61 ± 0.06) mm3. The organogenesis process started 22 h after fertilization when the blastopores closed and notochord formation began. The embryonic stage was recorded 24 h later, with the appearance of forebrain, midbrain, hindbrain, melanophores on yolk-sac and 22 somites, and a decreased yolk volume of (0.54 ± 0.08) mm3. Other organs developed well 31 h after fertilization, whereas the heart started beating and blood circulation began 78 h later. Red pigmentation (erytrophores) appeared 96 h after fertilization, with a small yolk volume of (0.22 ± 0.02) mm3. Mouth developed well and eyes were noticeable 120 h later, with head, pectoral fin and tail frequently moving 144 h after fertilization. The embryo reached the pre-hatching stage 168 h later and started to hatch after 170-180 h incubation. This study first detailed the embryonic development and yolk absorption of A. nigripes under natural conditions.

The course and the anatomo-functional relationships of the optic radiation: a combined study with ‘post mortem’ dissections and ‘in vivo’ direct electrical mapping

PubMed Central

Sarubbo, Silvio; De Benedictis, Alessandro; Milani, Paola; Paradiso, Beatrice; Barbareschi, Mattia; Rozzanigo, Umbero; Colarusso, Enzo; Tugnoli, Valeria; Farneti, Marco; Granieri, Enrico; Duffau, Hugues; Chioffi, Franco

2015-01-01

Even if different dissection, tractographic and connectivity studies provided pure anatomical evidences about the optic radiations (ORs), descriptions of both the anatomical structure and the anatomo-functional relationships of the ORs with the adjacent bundles were not reported. We propose a detailed anatomical and functional study with ‘post mortem’ dissections and ‘in vivo’ direct electrical stimulation (DES) of the OR, demonstrating also the relationships with the adjacent eloquent bundles in a neurosurgical ‘connectomic’ perspective. Six human hemispheres (three left, three right) were dissected after a modified Klingler's preparation. The anatomy of the white matter was analysed according to systematic and topographical surgical perspectives. The anatomical results were correlated to the functional responses collected during three resections of tumours guided by cortico-subcortical DES during awake procedures. We identified two groups of fibres forming the OR. The superior component runs along the lateral wall of the occipital horn, the trigone and the supero-medial wall of the temporal horn. The inferior component covers inferiorly the occipital horn and the trigone, the lateral wall of the temporal horn and arches antero-medially to form the Meyer's Loop. The inferior fronto-occipital fascicle (IFOF) covers completely the superior OR along its entire course, as confirmed by the subcortical DES. The inferior longitudinal fascicle runs in a postero-anterior and inferior direction, covering the superior OR posteriorly and the inferior OR anteriorly. The IFOF identification allows the preservation of the superior OR in the anterior temporal resection, avoiding post-operative complete hemianopia. The identification of the superior OR during the posterior temporal, inferior parietal and occipital resections leads to the preservation of the IFOF and of the eloquent functions it subserves. The accurate knowledge of the OR course and the relationships with the adjacent bundles is crucial to optimize quality of resection and functional outcome. PMID:25402811

Patients with left bundle branch block and left axis deviation show a specific left ventricular asynchrony pattern: Implications for left ventricular lead placement during CRT implantation.

PubMed

Sciarra, Luigi; Golia, Paolo; Palamà, Zefferino; Scarà, Antonio; De Ruvo, Ermenegildo; Borrelli, Alessio; Martino, Anna Maria; Minati, Monia; Fagagnini, Alessandro; Tota, Claudia; De Luca, Lucia; Grieco, Domenico; Delise, Pietro; Calò, Leonardo

Left bundle branch block (LBBB) and left axis deviation (LAD) patients may have poor response to resynchronization therapy (CRT). We sought to assess if LBBB and LAD patients show a specific pattern of mechanical asynchrony. CRT candidates with non-ischemic cardiomyopathy and LBBB were categorized as having normal QRS axis (within -30° and +90°) or LAD (within -30° and -90°). Patients underwent tissue Doppler imaging (TDI) to measure time interval between onset of QRS complex and peak systolic velocity in ejection period (Q-peak) at basal segments of septal, inferior, lateral and anterior walls, as expression of local timing of mechanical activation. Thirty patients (mean age 70.6years; 19 males) were included. Mean left ventricular ejection fraction was 0.28±0.06. Mean QRS duration was 172.5±13.9ms. Fifteen patients showed LBBB with LAD (QRS duration 173±14; EF 0.27±0.06). The other 15 patients had LBBB with a normal QRS axis (QRS duration 172±14; EF 0.29±0.05). Among patients with LAD, Q-peak interval was significantly longer at the anterior wall in comparison to each other walls (septal 201±46ms, inferior 242±58ms, lateral 267±45ms, anterior 302±50ms; p<0.0001). Conversely, in patients without LAD Q-peak interval was longer at lateral wall, when compared to each other (septal 228±65ms, inferior 250±64ms, lateral 328±98ms, anterior 291±86ms; p<0.0001). Patients with heart failure, presenting LBBB and LAD, show a specific pattern of ventricular asynchrony, with latest activation at anterior wall. This finding could affect target vessel selection during CRT procedures in these patients. Copyright © 2017 Elsevier Inc. All rights reserved.

Lack of effect of dopaminergic denervation on caudate-putamen hyperthermia or hypothermia induced by drugs and mild stressors.

PubMed

Marcangione, Caterina; Constantin, Annie; Clarke, Paul B S

2010-07-01

A number of drugs and psychological stressors induce brain hyperthermia and increase extracellular dopamine in the caudate-putamen. The present study tested whether caudate-putamen hyperthermia produced by such stimuli is dependent on dopaminergic transmission. Rats were infused with 6-hydroxydopamine unilaterally into the medial forebrain bundle, and after a two-week recovery period, removable thermocouples were used to monitor temperature in the depleted and intact caudate-putamen in freely-moving animals. The indirect dopamine agonist d-amphetamine (1 and 2mg/kg s.c.) increased caudate-putamen temperature, whereas a low dose of the direct agonist apomorphine (0.1mg/kg s.c.) reduced it. Gamma-butyrolactone, which strongly inhibits dopamine release at the dose administered (700mg/kg i.p.), initially reduced and then increased caudate-putamen temperature. Brief (5-10min) presentation of mild stressors, including tail pinch, produced a rapid and transient caudate-putamen hyperthermia. Quantitative (125)I-RTI-55 autoradiography in post-mortem tissue revealed a 97-100% loss of binding to dopamine transporters in the lesioned caudate-putamen. Despite this near-total dopamine denervation, neither basal caudate-putamen temperature, nor any of the observed temperature responses to drugs or mild stressors, was altered. We conclude that in the caudate-putamen, endogenous dopamine is unlikely to modulate temperature significantly at a local level. Copyright 2010 Elsevier Inc. All rights reserved.

Edaravone protects neurons in the rat substantia nigra against 6-hydroxydopamine-induced oxidative stress damage.

PubMed

Liu, Xiqi; Shao, Rushing; Li, Meng; Yang, Guofeng

2014-11-01

To investigate the mechanism of the neuroprotective effect of edaravone in substantia nigra (SN) of the 6-OHDA-induced rat model of Parkinson's disease. Animal model of Parkinson's disease was induced in male Sprague-Dawley rats by injecting 6-OHDA into the left medial forebrain bundle. Subsequently, rats were intraperitoneally injected with 0.3, 1, or 3 mg/kg of edaravone for 14 days or with 3 mg/kg edaravone for 14 days followed by 14 days of no treatment. We evaluated the effect of edaravone on the rotational and normal behavior of the rats, and on the number of tyrosine hydroxylase (TH)-positive cells, the amount of Nissl bodies, and the levels of glutathione (GSH), and malondialdehyde (MDA) in the SN. Edaravone treatment at 3 mg/kg significantly reduced apomorphine-induced rotational behavior (P < 0.01), improved the spontaneous behavior, prevented the decrease in the levels of TH-positive cells, Nissl bodies and GSH, and inhibited the increase in the levels of MDA (P < 0.05) in SN of rats with 6-OHDA-induced PD. Edaravone exerted a long-term neuroprotective effects in 6-OHDA-induced PD animal model by attenuating changes in the levels of GSH and MDA in SN, caused by oxidative stress. Edaravone prevented 6-OHDA-induced behavioral changes and de-pigmentation of SN that results from the loss of dopaminergic neurons.

Evaluation of chronic omega-3 fatty acids supplementation on behavioral and neurochemical alterations in 6-hydroxydopamine-lesion model of Parkinson's disease.

PubMed

Delattre, Ana Marcia; Kiss, Agata; Szawka, Raphael E; Anselmo-Franci, Janete A; Bagatini, Pamela Brambilla; Xavier, Léder Leal; Rigon, Paula; Achaval, Matilde; Iagher, Fabíola; de David, Cíntia; Marroni, Norma A P; Ferraz, Anete Curte

2010-03-01

Omega-3 polyunsaturated fatty acids (omega-3 PUFAs) have been widely associated to beneficial effects over different neuropathologies, but only a few studies associate them to Parkinson's disease (PD). Rats were submitted to chronic supplementation (21-90 days of life) with fish oil, rich in omega-3 PUFAs, and were uni- or bilaterally lesioned with 4microg of the neurotoxin 6-hydroxydopamine (6-OHDA) in the medial forebrain bundle. Although lipid incorporation was evidenced in neuronal membranes, it was not sufficient to compensate motor deficits induced by 6-OHDA. In contrast, omega-3 PUFAs were capable of reducing rotational behavior induced by apomorphine, suggesting neuroprotection over dyskinesia. The beneficial effects of omega-3 PUFAs were also evident in the maintenance of thiobarbituric acid reactive substances index from animals lesioned with 6-OHDA similar to levels from SHAM and intact animals. Although omega-3 PUFAs did not modify the tyrosine hydroxylase immunoreactivity in the substantia nigra pars compacta and in the ventral tegmental area, nor the depletion of dopamine (DA) and its metabolites in the striatum, DA turnover was increased after omega-3 PUFAs chronic supplementation. Therefore, it is proposed that omega-3 PUFAs action characterizes the adaptation of remaining neurons activity, altering striatal DA turnover without modifying the estimated neuronal population.

Operant conditioning of rat navigation using electrical stimulation for directional cues and rewards.

PubMed

Lee, Maan-Gee; Jun, Gayoung; Choi, Hyo-Soon; Jang, Hwan Soo; Bae, Yong Chul; Suk, Kyoungho; Jang, Il-Sung; Choi, Byung-Ju

2010-07-01

Operant conditioning is often used to train a desired behavior in an animal. The contingency between a specific behavior and a reward is required for successful training. Here, we compared the effectiveness of two different mazes for training turning behaviors in response to directional cues in Sprague-Dawley rats. Forty-three rats were implanted with electrodes into the medial forebrain bundle and the left and right somatosensory cortices for reward and cues. Among them, thirteen rats discriminated between the left and right somatosensory stimulations to obtain rewards. They were trained to learn ipsilateral turning response to the stimulation of the left or right somatosensory cortex in either the T-maze (Group T) or the E| maze (Group W). Performance was measured by the navigation speed in the mazes. Performances of rats in Group T were enhanced faster than those in Group W. A significant correlation between performances during training and performance in final testing was observed in Group T starting with the fifth training session while such a correlation was not observed in Group W until the tenth training session. The training mazes did not however affect the performances in the final test. These results suggest that a simple maze is better than a complicated maze for training animals to learn directions and direct cortical stimulation can be used as a cue for direction training. Copyright (c) 2010 Elsevier B.V. All rights reserved.

The Serotonin 2C Receptor Agonist Lorcaserin Attenuates Intracranial Self-Stimulation and Blocks the Reward-Enhancing Effects of Nicotine.

PubMed

Zeeb, Fiona D; Higgins, Guy A; Fletcher, Paul J

2015-07-15

Lorcaserin, a serotonin (5-hydroxytryptamine, 5-HT) 2C receptor agonist, was recently approved for the treatment of obesity. We previously suggested that 5-HT2C receptor agonists affect reward processes and reduce the rewarding effects of drugs of abuse. Here, we determined whether lorcaserin (1) decreases responding for brain stimulation reward (BSR) and (2) prevents nicotine from enhancing the efficacy of BSR. Rats were trained on the intracranial self-stimulation (ICSS) paradigm to nosepoke for BSR of either the dorsal raphé nucleus or left medial forebrain bundle. In Experiment 1, lorcaserin (0.3-1.0 mg/kg) dose-dependently reduced the efficacy of BSR. This effect was blocked by prior administration of the 5-HT2C receptor antagonist SB242084. In Experiment 2, separate groups of rats received saline or nicotine (0.4 mg/kg) for eight sessions prior to testing. Although thresholds were unaltered in saline-treated rats, nicotine reduced reward thresholds. An injection of lorcaserin (0.3 mg/kg) prior to nicotine prevented the reward-enhancing effect of nicotine across multiple test sessions. These results demonstrated that lorcaserin reduces the rewarding value of BSR and also prevents nicotine from facilitating ICSS. Hence, lorcaserin may be effective in treating psychiatric disorders, including obesity and nicotine addiction, by reducing the value of food or drug rewards.

Nigrostriatal proteasome inhibition impairs dopamine neurotransmission and motor function in minipigs.

PubMed

Lillethorup, Thea P; Glud, Andreas N; Alstrup, Aage K O; Mikkelsen, Trine W; Nielsen, Erik H; Zaer, Hamed; Doudet, Doris J; Brooks, David J; Sørensen, Jens Christian H; Orlowski, Dariusz; Landau, Anne M

2018-05-01

Parkinson's disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra leading to slowness and stiffness of limb movement with rest tremor. Using ubiquitin proteasome system inhibitors, rodent models have shown nigrostriatal degeneration and motor impairment. We translated this model to the Göttingen minipig by administering lactacystin into the medial forebrain bundle (MFB). Minipigs underwent positron emission tomography (PET) imaging with (+)-α-[ 11 C]dihydrotetrabenazine ([ 11 C]DTBZ), a marker of vesicular monoamine transporter 2 availability, at baseline and three weeks after the unilateral administration of 100 μg lactacystin into the MFB. Compared to their baseline values, minipigs injected with lactacystin showed on average a 36% decrease in ipsilateral striatal binding potential corresponding to impaired presynaptic dopamine terminals. Behaviourally, minipigs displayed asymmetrical motor disability with spontaneous rotations in one of the animals. Immunoreactivity for tyrosine hydroxylase (TH) and HLA-DR-positive microglia confirmed asymmetrical reduction in nigral TH-positive neurons with an inflammatory response in the lactacystin-injected minipigs. In conclusion, direct injection of lactacystin into the MFB of minipigs provides a model of PD with reduced dopamine neurotransmission, TH-positive neuron reduction, microglial activation and behavioural deficits. This large animal model could be useful in studies of symptomatic and neuroprotective therapies with translatability to human PD. Copyright © 2018 Elsevier Inc. All rights reserved.

Effects of the hook of Uncaria rhynchophylla on neurotoxicity in the 6-hydroxydopamine model of Parkinson's disease.

PubMed

Shim, Jin Sup; Kim, Hyo Geun; Ju, Mi Sun; Choi, Jin Gyu; Jeong, Seo Young; Oh, Myung Sook

2009-11-12

While the hook of Uncaria rhynchophylla (URH) is a traditional herb used in northeast Asia for the treatment of Parkinson's disease (PD)-like symptoms such as tremor, it has not been experimentally evaluated in a PD model. We investigated the effects of URH on 6-hydroxydapamine (6-OHDA)-induced neurotoxicity in in vitro and in vivo models of PD. The cell viability, anti-oxidative activity, and anti-apoptotic activity of a water extract of URH (URE) were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide, reactive oxygen species (ROS), total glutathione (GSH), and caspase-3 assays in PC12 cells stressed by 6-OHDA. We also investigated the behavioral recovery and dopaminergic neuron protection of URE using an apomorphine-induced rotation test and tyrosine hydroxylase immunohistochemistry in the hemi-parkinsonian rat model of the unilateral 6-OHDA lesion of the medial forebrain bundle. In PC12 cells, URE significantly reduced cell death and the generation of ROS, increased GSH levels, and inhibited caspase-3 activity induced by 6-OHDA. In 6-OHDA-lesioned rats, posttreatment with URE (5 mg/kg/day for 14 days) significantly reduced apomorphine-induced rotation, and it lowered dopaminergic neuronal loss in substantia nigra pars compacta. URE possesses neuroprotective activity against 6-OHDA-induced toxicity through anti-oxidative and anti-apoptotic activities in PD models.

Endoplasmic Reticulum Stress as a Mediator of Neurotoxin-Induced Dopamine Neuron Death

DTIC Science & Technology

2006-07-01

reversible reduction in choline acetyl- transferase concentration in rat hypoglossal nucleus after hypoglossal nerve transection. Nature 275, 324–325...cally, analogs were evaluated for their ability to enhance choline acetyltransferase (ChAT) activity in embryonic rat spinal cord and basal forebrain...of ibotenate, CEP1347 protected basal forebrain cholinergic neurons.102 In a model of apoptosis induced in auditory hair cells by noise trauma, CEP1347

Development and characterization of NEX- Pten, a novel forebrain excitatory neuron-specific knockout mouse.

PubMed

Kazdoba, Tatiana M; Sunnen, C Nicole; Crowell, Beth; Lee, Gum Hwa; Anderson, Anne E; D'Arcangelo, Gabriella

2012-01-01

The phosphatase and tensin homolog located on chromosome 10 (PTEN) suppresses the activity of the phosphoinositide-3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway, a signaling cascade critically involved in the regulation of cell proliferation and growth. Human patients carrying germ line PTEN mutations have an increased predisposition to tumors, and also display a variety of neurological symptoms and increased risk of epilepsy and autism, implicating PTEN in neuronal development and function. Consistently, loss of Pten in mouse neural cells results in ataxia, seizures, cognitive abnormalities, increased soma size and synaptic abnormalities. To better understand how Pten regulates the excitability of principal forebrain neurons, a factor that is likely to be altered in cognitive disorders, epilepsy and autism, we generated a novel conditional knockout mouse line (NEX-Pten) in which Cre, under the control of the NEX promoter, drives the deletion of Pten specifically in early postmitotic, excitatory neurons of the developing forebrain. Homozygous mutant mice exhibited a massive enlargement of the forebrain, and died shortly after birth due to excessive mTOR activation. Analysis of the neonatal cerebral cortex further identified molecular defects resulting from Pten deletion that likely affect several aspects of neuronal development and excitability. Copyright © 2012 S. Karger AG, Basel.

Drinking by amphibious fish: convergent evolution of thirst mechanisms during vertebrate terrestrialization.

PubMed

Katayama, Yukitoshi; Sakamoto, Tatsuya; Saito, Kazuhiro; Tsuchimochi, Hirotsugu; Kaiya, Hiroyuki; Watanabe, Taro; Pearson, James T; Takei, Yoshio

2018-01-12

Thirst aroused in the forebrain by angiotensin II (AngII) or buccal drying motivates terrestrial vertebrates to search for water, whereas aquatic fish can drink surrounding water only by reflex swallowing generated in the hindbrain. Indeed, AngII induces drinking through the hindbrain even after removal of the whole forebrain in aquatic fish. Here we show that AngII induces thirst also in the amphibious mudskipper goby without direct action on the forebrain, but through buccal drying. Intracerebroventricular injection of AngII motivated mudskippers to move into water and drink as with tetrapods. However, AngII primarily increased immunoreactive c-Fos at the hindbrain swallowing center where AngII receptors were expressed, as in other ray-finned fish, and such direct action on the forebrain was not found. Behavioural analyses showed that loss of buccal water on land by AngII-induced swallowing, by piercing holes in the opercula, or by water-absorptive gel placed in the cavity motivated mudskippers to move to water for refilling. Since sensory detection of water at the bucco-pharyngeal cavity like 'dry mouth' has recently been noted to regulate thirst in mammals, similar mechanisms seem to have evolved in distantly related species in order to solve osmoregulatory problems during terrestrialization.

Disconnection of the Ascending Arousal System in Traumatic Coma

PubMed Central

Edlow, Brian L.; Haynes, Robin L.; Takahashi, Emi; Klein, Joshua P.; Cummings, Peter; Benner, Thomas; Greer, David M.; Greenberg, Steven M.; Wu, Ona; Kinney, Hannah C.; Folkerth, Rebecca D.

2013-01-01

Traumatic coma is associated with disruption of axonal pathways throughout the brain but the specific pathways involved in humans are incompletely understood. In this study, we used high angular resolution diffusion imaging (HARDI) to map the connectivity of axonal pathways that mediate the 2 critical components of consciousness – arousal and awareness – in the postmortem brain of a 62-year-old woman with acute traumatic coma and in 2 control brains. HARDI tractography guided tissue sampling in the neuropathological analysis. HARDI tractography demonstrated complete disruption of white matter pathways connecting brainstem arousal nuclei to the basal forebrain and thalamic intralaminar and reticular nuclei. In contrast, hemispheric arousal pathways connecting the thalamus and basal forebrain to the cerebral cortex were only partially disrupted, as were the cortical “awareness pathways.” Neuropathologic examination, which utilized β-amyloid precursor protein and fractin immunomarkers, revealed axonal injury in the white matter of the brainstem and cerebral hemispheres that corresponded to sites of HARDI tract disruption. Axonal injury was also present within the grey matter of the hypothalamus, thalamus, basal forebrain, and cerebral cortex. We propose that traumatic coma may be a subcortical disconnection syndrome related to the disconnection of specific brainstem arousal nuclei from the thalamus and basal forebrain. PMID:23656993

Trigeminal and telencephalic projections to jaw and other upper vocal tract premotor neurons in songbirds: sensorimotor circuitry for beak movements during singing.

PubMed

Wild, J M; Krützfeldt, N E O

2012-02-15

During singing in songbirds, the extent of beak opening, like the extent of mouth opening in human singers, is partially correlated with the fundamental frequency of the sounds emitted. Since song in songbirds is under the control of "the song system" (a collection of interconnected forebrain nuclei dedicated to the learning and production of song), it might be expected that beak movements during singing would also be controlled by this system. However, direct neural connections between the telencephalic output of the song system and beak muscle motor neurons in the brainstem are conspicuous by their absence, leaving unresolved the question of how beak movements are affected during singing. By using standard tract tracing methods, we sought to answer this question by defining beak premotor neurons and examining their afferent projections. In the caudal medulla, jaw premotor cell bodies were located adjacent to the terminal field of the output of the song system, into which many premotor neurons extended their dendrites. The premotor neurons also received a novel input from the trigeminal ganglion and an overlapping input from a lateral arcopallial component of a trigeminal sensorimotor circuit that traverses the forebrain. The ganglionic input in songbirds, which is not present in doves and pigeons that vocalize with a closed beak, may modulate the activity of beak premotor neurons in concert with the output of the song system. These inputs to jaw premotor neurons could, together, affect beak movements as a means of modulating filter properties of the upper vocal tract during singing. Copyright © 2011 Wiley-Liss, Inc.

Distribution of androgen receptor mRNA expression in vocal, auditory, and neuroendocrine circuits in a teleost fish.

PubMed

Forlano, Paul M; Marchaterre, Margaret; Deitcher, David L; Bass, Andrew H

2010-02-15

Across all major vertebrate groups, androgen receptors (ARs) have been identified in neural circuits that shape reproductive-related behaviors, including vocalization. The vocal control network of teleost fishes presents an archetypal example of how a vertebrate nervous system produces social, context-dependent sounds. We cloned a partial cDNA of AR that was used to generate specific probes to localize AR expression throughout the central nervous system of the vocal plainfin midshipman fish (Porichthys notatus). In the forebrain, AR mRNA is abundant in proposed homologs of the mammalian striatum and amygdala, and in anterior and posterior parvocellular and magnocellular nuclei of the preoptic area, nucleus preglomerulosus, and posterior, ventral and anterior tuberal nuclei of the hypothalamus. Many of these nuclei are part of the known vocal and auditory circuitry in midshipman. The midbrain periaqueductal gray, an essential link between forebrain and hindbrain vocal circuitry, and the lateral line recipient nucleus medialis in the rostral hindbrain also express abundant AR mRNA. In the caudal hindbrain-spinal vocal circuit, high AR mRNA is found in the vocal prepacemaker nucleus and along the dorsal periphery of the vocal motor nucleus congruent with the known pattern of expression of aromatase-containing glial cells. Additionally, abundant AR mRNA expression is shown for the first time in the inner ear of a vertebrate. The distribution of AR mRNA strongly supports the role of androgens as modulators of behaviorally defined vocal, auditory, and neuroendocrine circuits in teleost fish and vertebrates in general. 2009 Wiley-Liss, Inc.

An Avian Basal Ganglia-Forebrain Circuit Contributes Differentially to Syllable Versus Sequence Variability of Adult Bengalese Finch Song

PubMed Central

Hampton, Cara M.; Sakata, Jon T.; Brainard, Michael S.

2009-01-01

Behavioral variability is important for motor skill learning but continues to be present and actively regulated even in well-learned behaviors. In adult songbirds, two types of song variability can persist and are modulated by social context: variability in syllable structure and variability in syllable sequencing. The degree to which the control of both types of adult variability is shared or distinct remains unknown. The output of a basal ganglia-forebrain circuit, LMAN (the lateral magnocellular nucleus of the anterior nidopallium), has been implicated in song variability. For example, in adult zebra finches, neurons in LMAN actively control the variability of syllable structure. It is unclear, however, whether LMAN contributes to variability in adult syllable sequencing because sequence variability in adult zebra finch song is minimal. In contrast, Bengalese finches retain variability in both syllable structure and syllable sequencing into adulthood. We analyzed the effects of LMAN lesions on the variability of syllable structure and sequencing and on the social modulation of these forms of variability in adult Bengalese finches. We found that lesions of LMAN significantly reduced the variability of syllable structure but not of syllable sequencing. We also found that LMAN lesions eliminated the social modulation of the variability of syllable structure but did not detect significant effects on the modulation of sequence variability. These results show that LMAN contributes differentially to syllable versus sequence variability of adult song and suggest that these forms of variability are regulated by distinct neural pathways. PMID:19357331

Excessive disgust caused by brain lesions or temporary inactivations: Mapping hotspots of nucleus accumbens and ventral pallidum

PubMed Central

Ho, Chao-Yi; Berridge, Kent C.

2014-01-01

Disgust is a prototypical type of negative affect. In animal models of excessive disgust, only a few brain sites are known in which localized dysfunction (lesions or neural inactivations) can induce intense ‘disgust reactions’ (e.g., gapes) to a normally pleasant sensation such as sweetness. Here we aimed to map forebrain candidates more precisely to identify where either local neuronal damage (excitotoxin lesions) or local pharmacological inactivation (muscimol-baclofen microinjections) caused rats to emit excessive sensory disgust reactions to sucrose. Our study compared subregions of nucleus accumbens shell, ventral pallidum, lateral hypothalamus and adjacent extended amygdala. Results indicated the posterior half of ventral pallidum to be the only forebrain site where intense sensory disgust gapes to sucrose were induced by both lesions and temporary inactivations (this site was previously identified as a hedonic hotspot for enhancements of sweetness ‘liking’). By comparison, for the nucleus accumbens, temporary GABA inactivations in the caudal half of the medial shell also generated sensory disgust but lesions never did at any site. Further, even inactivations failed to induce disgust in the rostral half of accumbens shell (which also contains a hedonic hotspot). In other structures, neither lesions nor inactivations induced disgust as long as the posterior ventral pallidum remained spared. We conclude that the posterior ventral pallidum is an especially crucial hotspot for producing excessive sensory disgust by local pharmacological/lesion dysfunction. By comparison, the nucleus accumbens appears to segregate sites for pharmacological disgust induction and hedonic enhancement into separate posterior versus rostral halves of medial shell. PMID:25229197

Traumatic brain injury causes an FK506-sensitive loss and an overgrowth of dendritic spines in rat forebrain.

PubMed

Campbell, John N; Register, David; Churn, Severn B

2012-01-20

Traumatic brain injury (TBI) causes both an acute loss of tissue and a progressive injury through reactive processes such as excitotoxicity and inflammation. These processes may worsen neural dysfunction by altering neuronal circuitry beyond the focally-damaged tissue. One means of circuit alteration may involve dendritic spines, micron-sized protuberances of dendritic membrane that support most of the excitatory synapses in the brain. This study used a modified Golgi-Cox technique to track changes in spine density on the proximal dendrites of principal cells in rat forebrain regions. Spine density was assessed at 1 h, 24 h, and 1 week after a lateral fluid percussion TBI of moderate severity. At 1 h after TBI, no changes in spine density were observed in any of the brain regions examined. By 24 h after TBI, however, spine density had decreased in ipsilateral neocortex in layer II and III and dorsal dentate gyrus (dDG). This apparent loss of spines was prevented by a single, post-injury administration of the calcineurin inhibitor FK506. These results, together with those of a companion study, indicate an FK506-sensitive mechanism of dendritic spine loss in the TBI model. Furthermore, by 1 week after TBI, spine density had increased substantially above control levels, bilaterally in CA1 and CA3 and ipsilaterally in dDG. The apparent overgrowth of spines in CA1 is of particular interest, as it may explain previous reports of abnormal and potentially epileptogenic activity in this brain region.

Trigeminal and Telencephalic Projections to Jaw and Other Upper Vocal Tract Premotor Neurons in Songbirds: Sensorimotor Circuitry for Beak Movements During Singing

PubMed Central

Wild, J.M.; Krützfeldt, N.E.O.

2014-01-01

During singing in songbirds, the extent of beak opening, like the extent of mouth opening in human singers, is partially correlated with the fundamental frequency of the sounds emitted. Since song in songbirds is under the control of “the song system” (a collection of interconnected forebrain nuclei dedicated to the learning and production of song), it might be expected that beak movements during singing would also be controlled by this system. However, direct neural connections between the telencephalic output of the song system and beak muscle motor neurons in the brainstem are conspicuous by their absence, leaving unresolved the question of how beak movements are affected during singing. By using standard tract tracing methods, we sought to answer this question by defining beak premotor neurons and examining their afferent projections. In the caudal medulla, jaw premotor cell bodies were located adjacent to the terminal field of the output of the song system, into which many premotor neurons extended their dendrites. The premotor neurons also received a novel input from the trigeminal ganglion and an overlapping input from a lateral arcopallial component of a trigeminal sensorimotor circuit that traverses the forebrain. The ganglionic input in songbirds, which is not present in doves and pigeons that vocalize with a closed beak, may modulate the activity of beak premotor neurons in concert with the output of the song system. These inputs to jaw premotor neurons could, together, affect beak movements as a means of modulating filter properties of the upper vocal tract during singing. PMID:21858818

Exercise and sleep in aging: emphasis on serotonin.

PubMed

Melancon, M O; Lorrain, D; Dionne, I J

2014-10-01

Reductions in central serotonin activity with aging might be involved in sleep-related disorders in later life. Although the beneficial effects of aerobic exercise on sleep are not new, sleep represents a complex recurring state of unconsciousness involving many lines of transmitters which remains only partly clear despite intense ongoing research. It is known that serotonin released into diencephalon and cerebrum might play a key inhibitory role to help promote sleep, likely through an active inhibition of supraspinal neural networks. Several lines of evidence support the stimulatory effects of exercise on higher serotonergic pathways. Hence, exercise has proved to elicit acute elevations in forebrain serotonin concentrations, an effect that waned upon cessation of exercise. While adequate exercise training might lead to adaptations in higher serotonergic networks (desensitization of forebrain receptors), excessive training has been linked to serious brain serotonergic maladaptations accompanied by insomnia. Dietary supplementation of tryptophan (the only serotonin precursor) is known to stimulate serotonergic activity and promote sleep, whereas acute tryptophan depletion causes deleterious effects on sleep. Regarding sleep-wake regulation, exercise has proved to accelerate resynchronization of the biological clock to new light-dark cycles following imposition of phase shifts in laboratory animals. Noteworthy, the effect of increased serotonergic transmission on wake state appears to be biphasic, i.e. promote wake and thereafter drowsiness. Therefore, it might be possible that acute aerobic exercise would act on sleep by increasing activity of ascending brain serotonergic projections, though additional work is warranted to better understand the implication of serotonin in the exercise-sleep axis. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Specific Connectivity and Unique Molecular Identity of MET Receptor Tyrosine Kinase Expressing Serotonergic Neurons in the Caudal Dorsal Raphe Nuclei.

PubMed

Kast, Ryan J; Wu, Hsiao-Huei; Williams, Piper; Gaspar, Patricia; Levitt, Pat

2017-05-17

Molecular characterization of neurons across brain regions has revealed new taxonomies for understanding functional diversity even among classically defined neuronal populations. Neuronal diversity has become evident within the brain serotonin (5-HT) system, which is far more complex than previously appreciated. However, until now it has been difficult to define subpopulations of 5-HT neurons based on molecular phenotypes. We demonstrate that the MET receptor tyrosine kinase (MET) is specifically expressed in a subset of 5-HT neurons within the caudal part of the dorsal raphe nuclei (DRC) that is encompassed by the classic B6 serotonin cell group. Mapping from embryonic day 16 through adulthood reveals that MET is expressed almost exclusively in the DRC as a condensed, paired nucleus, with an additional sparse set of MET+ neurons scattered within the median raphe. Retrograde tracing experiments reveal that MET-expressing 5-HT neurons provide substantial serotonergic input to the ventricular/subventricular region that contains forebrain stem cells, but do not innervate the dorsal hippocampus or entorhinal cortex. Conditional anterograde tracing experiments show that 5-HT neurons in the DRC/B6 target additional forebrain structures such as the medial and lateral septum and the ventral hippocampus. Molecular neuroanatomical analysis identifies 14 genes that are enriched in DRC neurons, including 4 neurotransmitter/neuropeptide receptors and 2 potassium channels. These analyses will lead to future studies determining the specific roles that 5-HT MET+ neurons contribute to the broader set of functions regulated by the serotonergic system.

Alleviation of response suppression to conditioned aversive stimuli by lesions of the dorsal noradrenergic bundle.

PubMed

Tsaltas, E; Gray, J A; Fillenz, M

1984-08-01

Rats with neurotoxic lesions of the dorsal ascending noradrenergic bundle (DB) were compared with sham-operated (SH) controls on the acquisition, steady state and extinction of response suppression maintained by a classical (conditioned suppression) or an instrumental (discriminated punishment) contingency. DB lesions interfered neither with the acquisition of the reference response of sucrose-rewarded barpressing nor with unconditioned responding to the overhead flashing light subsequently used as a signal of shock. The acquisition of discriminated response suppression was also unaffected by the lesion under both types of contingency. However, once discriminated suppression had stabilized, both the conditioned and the discriminative stimulus used were significantly less effective in maintaining suppression in DB animals than in SH controls provided that low intensity footshock (0.2 mA) was used as the unconditioned stimulus (UCS). Upon increase of UCS intensity (to 0.5 mA) normal suppression was observed in the DB group under both contingencies. Extinction of the classical contingency reinstated the difference between DB and SH performance: DB lesion resulted in significantly faster extinction of fear. In contrast, extinction of the discriminated punishment contingency was unaffected by the lesion, although generalized response suppression dissipated faster in the DB than in the SH animals trained under this condition. Our results offer no support for the reinforcement hypothesis of DB function (normal acquisition of barpressing and of discriminated suppression of barpressing); mixed support (greater initial generalization of suppression in DB animals) and contradiction (more rapid extinction of conditioned suppression in DB animals) for the attentional hypothesis; and weak support (reduced suppression and more rapid extinction of suppression in DB animals, but only within limited experimental parameters) for the anxiety hypothesis of DB function. Hence none of the extant theories of DB function offer a ready explanation of the pattern of results presented here. A simple interpretation which conforms with the sparsity of positive behavioural findings in the literature on DB lesions is that forebrain noradrenaline contributes to the detection and utilization of conditioned stimuli; but that this contribution is critical only for the detection of stimuli with low associative strength.

Ultrastructural study and ontogenesis of the appendages and related musculature of Paraspadella (Chaetognatha).

PubMed

Casanova, J-P; Duvert, M; Goto, T

2003-10-01

A lineage of benthic chaetognaths has developed limb-like appendages on the caudal part of the body, resulting from a local modification of the lateral fins, which are folds of the epidermis and have a role in balance when swimming. The most complex are those of Paraspadella gotoi which are used as props with the tip of the tail, allowing an elaborated mating behaviour comprising different movements: complete erection of the body, swings and jumps, astonishing for so simple-bodied animals. In the tail, the epidermis and the connective tissue, together with the longitudinal musculature, are involved in this innovation. All the components of the fins, i.e. connective tissue, fin rays and multilayered epidermic cells are conserved, but their function has changed. The movements of appendages are adjusted by one pair of small appendicular muscles localised in the body wall, while posture movements of the body are allowed by four longitudinal bundles of raising muscle. These two new muscles have successively appeared in the evolutive series previously described in Paraspadella. They have definitely arisen from the secondary muscle: the two lateral bundles for the former, and the two dorsal and two ventral ones for the latter. All are supercontracting muscles, a muscle kind also observed in the other benthic genus Spadella, but unknown in planktonic and benthoplanktonic chaetognaths.

Numerical determination of lateral loss coefficients for subchannel analysis in nuclear fuel bundles

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

Sin Kim; Goon-Cherl Park

1995-09-01

An accurate prediction of cross-flow based on detailed knowledge of the velocity field in subchannels of a nuclear fuel assembly is of importance in nuclear fuel performance analysis. In this study, the low-Reynolds number {kappa}-{epsilon} turbulence model has been adopted in two adjacent subchannels with cross-flow. The secondary flow is estimated accurately by the anisotropic algebraic Reynolds stress model. This model was numerically calculated by the finite element method and has been verified successfully through comparison with existing experimental data. Finally, with the numerical analysis of the velocity field in such subchannel domain, an analytical correlation of the lateral lossmore » coefficient is obtained to predict the cross-flow rate in subchannel analysis codes. The correlation is expressed as a function of the ratio of the lateral flow velocity to the donor subchannel axial velocity, recipient channel Reynolds number and pitch-to-diameter.« less

Lateral Structure Formation in Polyelectrolyte Brushes Induced by Multivalent Ions

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

Brettmann, Blair; Pincus, Philip; Tirrell, Matthew

2017-01-13

We provide a theoretical model for the collapse of polyelectrolyte brushes in the presence of multivalent ions, focusing on the formation of lateral inhomogeneties in the collapsed state. Polyelectrolyte brushes are important in a variety of applications, including stabilizing colloidal particles and lubricating surfaces. Many uses rely on the extension of the densely grafted polymer chains from the surface in the extended brush morphology. In the presence Extended Brush of multivalent ions, brushes are significantly shorter than in monovalent ionic solutions, which greatly affects their properties. We base our theoretical analysis on an analogous collapse of polyelectrolyte brushes in amore » poor solvent, providing an energy balance representation for pinned micelles and cylindrical bundles. The equilibrium brush heights predicted for these structures are of a similar magnitude to those measured experimentally. The formation of lateral structures can open new avenues for stimuli-responsive applications that rely on nanoscale pattern formation on surfaces.« less

Effects of an Isolated Complete Right Bundle Branch Block on Mechanical Ventricular Function.

PubMed

Zhang, Qin; Xue, Minghua; Li, Zhan; Wang, Haiyan; Zhu, Lei; Liu, Xinling; Meng, Haiyan; Hou, Yinglong

2015-12-01

The purpose of this study was to investigate the effects of an isolated complete right bundle branch block on mechanical ventricular function. Two groups of participants were enrolled in this study: a block group, consisting of 98 patients with isolated complete right bundle branch blocks without structural heart disease, and a control group, consisting of 92 healthy adults. The diameter, end-diastolic area, end-systolic area, and right ventricular (RV) fractional area change were obtained to evaluate morphologic and systolic function by 2-dimensional sonographic technology. Systolic and diastolic velocities and time interval parameters were measured to assess mechanical ventricular performance using pulsed wave tissue Doppler imaging. Although there was no significant difference in the RV fractional area change between the patients with blocks and controls, the diameter, end-diastolic area, and end-systolic area of the RV were significantly larger in the patients with blocks (P < .05). In the patients with blocks, the peak velocities during systole and early diastole and the ratio of the peak velocities during early and late diastole decreased. The block group had a prolonged pre-ejection period, electromechanical delay time, and isovolumic relaxation time, a decreased ejection time, and an increased pre-ejection period/ejection time ratio, and the myocardial performance index (Tei index) at the basal RV lateral wall was significantly increased. There were no significant differences in any echocardiographic parameters at different sites of the left ventricle. In patients with isolated complete right bundle branch blocks, systolic and diastolic functions are impaired in the RV, and follow-up is needed. © 2015 by the American Institute of Ultrasound in Medicine.

Robot-assisted laparoscopic radical prostatectomy with early retrograde release of the neurovascular bundle and endopelvic fascia sparing

PubMed Central

de Albuquerque, George Augusto Monteiro Lins; Guglielmetti, Giuliano Betoni; Cordeiro, Maurício Dener; Nahas, William Carlos; Coelho, Rafael Ferreira

2017-01-01

ABSTRACT Introduction Robotic-assisted radical prostatectomy (RAP) is the dominant minimally invasive surgical treatment for patients with localized prostate cancer. The introduction of robotic assistance has the potential to improve surgical outcomes and reduce the steep learning curve associated with conventional laparoscopic radical prostatectomy. The purpose of this video is to demonstrate the early retrograde release of the neurovascular bundle without open the endopelvic fascia during RAP. Materials and Methods A 51-year old male, presenting histological diagnosis of prostate adenocarcinoma, Gleason 6 (3+3), in 4 cores of 12, with an initial PSA=3.41ng/dl and the digital rectal examination demonstrating a prostate with hardened nodule in the right lobe of the prostate base (clinical stage T2a). Surgical treatment with the robot-assisted technique was offered as initial therapeutic option and the critical technical point was the early retrograde release of the neurovascular bundle with endopelvic fascia preservation, during radical prostatectomy. Results The operative time was of 89 minutes, blood loss was 100ml. No drain was left in the peritoneal cavity. The patient was discharged within 24 hours. There were no intraoperative or immediate postoperative complications. The pathological evaluation revealed prostate adenocarcinoma, Gleason 6, with free surgical margins and seminal vesicles free of neoplastic involvement (pathologic stage T2a). At 3-month-follow-up, the patient lies with undetectable PSA, continent and potent. Conclusion This is a feasible technique combining the benefits of retrograde release of the neurovascular bundle, the preservation of the pubo-prostatic collar and the preservation of the antero-lateral cavernous nerves. PMID:27802002

Flat midsubstance of the anterior cruciate ligament with tibial "C"-shaped insertion site.

PubMed

Siebold, Rainer; Schuhmacher, Peter; Fernandez, Francis; Śmigielski, Robert; Fink, Christian; Brehmer, Axel; Kirsch, Joachim

2015-11-01

This anatomical cadaver study was performed to investigate the flat appearance of the midsubstance shape of the anterior cruciate ligament (ACL) and its tibial "C"-shaped insertion site. The ACL midsubstance and the tibial ACL insertion were dissected in 20 cadaveric knees (n = 6 fresh frozen and n = 14 paraffined). Magnifying spectacles were used for all dissections. Morphometric measurements were performed using callipers and on digital photographs. In all specimens, the midsubstance of the ACL was flat with a mean width of 9.9 mm, thickness of 3.9 mm and cross-sectional area of 38.7 mm(2). The "direct" "C"-shaped tibial insertion runs from along the medial tibial spine to the anterior aspect of the lateral meniscus. The mean width (length) of the "C" was 12.6 mm, its thickness 3.3 mm and area 31.4 mm(2). The centre of the "C" was the bony insertion of the anterior root of the lateral meniscus overlayed by fat and crossed by the ACL. No posterolateral (PL) inserting ACL fibres were found. Together with the larger "indirect" part (area 79.6 mm(2)), the "direct" one formed a "duck-foot"-shaped footprint. The tibial ACL midsubstance and tibial "C"-shaped insertion are flat and are resembling a "ribbon". The centre of the "C" is the bony insertion of the anterior root of the lateral meniscus. There are no central or PL inserting ACL fibres. Anatomical ACL reconstruction may therefore require a flat graft and a "C"-shaped tibial footprint reconstruction with an anteromedial bone tunnel for single bundle and an additional posteromedial bone tunnel for double bundle.

Aligning Arrays of Lenses and Single-Mode Optical Fibers

NASA Technical Reports Server (NTRS)

Liu, Duncan

2004-01-01

A procedure now under development is intended to enable the precise alignment of sheet arrays of microscopic lenses with the end faces of a coherent bundle of as many as 1,000 single-mode optical fibers packed closely in a regular array (see Figure 1). In the original application that prompted this development, the precise assembly of lenses and optical fibers serves as a single-mode spatial filter for a visible-light nulling interferometer. The precision of alignment must be sufficient to limit any remaining wavefront error to a root-mean-square value of less than 1/10 of a wavelength of light. This wavefront-error limit translates to requirements to (1) ensure uniformity of both the lens and fiber arrays, (2) ensure that the lateral distance from the central axis of each lens and the corresponding optical fiber is no more than a fraction of a micron, (3) angularly align the lens-sheet planes and the fiber-bundle end faces to within a few arc seconds, and (4) axially align the lenses and the fiber-bundle end faces to within tens of microns of the focal distance. Figure 2 depicts the apparatus used in the alignment procedure. The beam of light from a Zygo (or equivalent) interferometer is first compressed by a ratio of 20:1 so that upon its return to the interferometer, the beam will be magnified enough to enable measurement of wavefront quality. The apparatus includes relay lenses that enable imaging of the arrays of microscopic lenses in a charge-coupled-device (CCD) camera that is part of the interferometer. One of the arrays of microscopic lenses is mounted on a 6-axis stage, in proximity to the front face of the bundle of optical fibers. The bundle is mounted on a separate stage. A mirror is attached to the back face of the bundle of optical fibers for retroreflection of light. When a microscopic lens and a fiber are aligned with each other, the affected portion of the light is reflected back by the mirror, recollimated by the microscopic lens, transmitted through the relay lenses and the beam compressor/expander, then split so that half goes to a detector and half to the interferometer. The output of the detector is used as a feedback control signal for the six-axis stage to effect alignment.

Morphogenetic interaction of presumptive neural and mesodermal cells mixed in different ratios.

PubMed

Toivonen, S; Saxen, L

1968-02-02

Cells of the presumptive forebrain region and axial mesoderm of Triturus neurulae were disaggregated and combined in different ratios. The differentiation of the central nervous systen in these explants was dependent on the relative amount of mesodermal cells present: an increase of mesodermal cells resulted in a corresponding increase in the frequency with which caudal structures of the central nervous system developed and a gradual loss of the forebrain formations.

Developmentally defined forebrain circuits regulate appetitive and aversive olfactory learning.

PubMed

Muthusamy, Nagendran; Zhang, Xuying; Johnson, Caroline A; Yadav, Prem N; Ghashghaei, H Troy

2017-01-01

Postnatal and adult neurogenesis are region- and modality-specific, but the significance of developmentally distinct neuronal populations remains unclear. We demonstrate that chemogenetic inactivation of a subset of forebrain and olfactory neurons generated at birth disrupts responses to an aversive odor. In contrast, novel appetitive odor learning is sensitive to inactivation of adult-born neurons, revealing that developmentally defined sets of neurons may differentially participate in hedonic aspects of sensory learning.

Ludwig Edinger: the vertebrate series and comparative neuroanatomy.

PubMed

Patton, Paul

2015-01-01

At the end of the nineteenth century, Ludwig Edinger completed the first comparative survey of the microscopic anatomy of vertebrate brains. He is regarded as the founder of the field of comparative neuroanatomy. Modern commentators have misunderstood him to have espoused an anti-Darwinian linear view of brain evolution, harkening to the metaphysics of the scala naturae. This understanding arises, in part, from an increasingly contested view of nineteenth-century morphology in Germany. Edinger did espouse a progressionist, though not strictly linear, view of forebrain evolution, but his work also provided carefully documented evidence that brain stem structures vary in complexity independently from one another and across species in a manner that is not compatible with linear progress. This led Edinger to reject progressionism for all brain structures other than the forebrain roof, based on reasoning not too dissimilar from those his successors used to dismiss it for the forebrain roof.

A subcortical inhibitory signal for behavioral arrest in the thalamus

PubMed Central

Dugué, Guillaume P.; Bokor, Hajnalka; Rousseau, Charly V.; Maglóczky, Zsófia; Havas, László; Hangya, Balázs; Wildner, Hendrik; Zeilhofer, Hanns Ulrich; Dieudonné, Stéphane; Acsády, László

2016-01-01

Organization of behavior requires rapid coordination of brainstem and forebrain activity. The exact mechanisms of effective communication between these regions are presently unclear. The intralaminar thalamus (IL) probably serves as a central hub in this circuit by connecting the critical brainstem and forebrain areas. Here we found that GABAergic/glycinergic fibers ascending from the pontine reticular formation (PRF) of the brainstem evoke fast and reliable inhibition in the IL thalamus via large, multisynaptic terminals. This inhibition was fine-tuned through heterogeneous GABAergic/glycinergic receptor ratios expressed at individual synapses. Optogenetic activation of PRF axons in the IL of freely moving mice led to behavioral arrest and transient interruption of awake cortical activity. An afferent system with comparable morphological features was also found in the human IL. These data reveal an evolutionarily conserved ascending system which gates forebrain activity through fast and powerful synaptic inhibition of the IL thalamus. PMID:25706472

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

PubMed

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

2015-01-01

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

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

PubMed Central

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

2015-01-01

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

Trastuzumab (Herceptin)-associated cardiomyopathy presented as new onset of complete left bundle-branch block mimicking acute coronary syndrome: a case report and literature review.

PubMed

Tu, Chung-Ming; Chu, Kai-Ming; Yang, Shin-Ping; Cheng, Shu-Mung; Wang, Wen-Been

2009-09-01

Trastuzumab (Herceptin) is well documented in reducing suffering and mortality from breast cancer. The clinically most important side effect of Herceptin is cardiotoxicity, which is reported in 2.6% to 4.5% of patients receiving trastuzumab alone and in as many as 27% of patients when trastuzumab is combined with an anthracycline in metastatic disease. We reported the case of a 50-year-old woman who presented to our emergency department (ED) because of chest pain and shortness of breath. On physical examination, holosystolic murmur over apex could be heard. Pulmonary and abdominal examinations were unremarkable. Twelve-lead electrocardiography showed sinus tachycardia and new onset of complete left bundle-branch block. Emergent transthoracic echocardiography revealed generalized hypokinesia of left ventricle and akinesia over interventricular septum and apex. She subsequently underwent immediate coronary angiography that revealed normal coronary angiography, and left ventriculogram revealed generalized hypokinesia with severe left ventricle dysfunction with ejection fraction of 33%. During right heart catheterization and endomyocardial biopsy, cardiac tamponade developed and was successfully relieved by pericardial window. She was discharged event-free 3 weeks later with conservative treatment. Although new onset of complete left bundle-branch block in a patient with chest pain may be acute coronary syndrome, careful review of medicine history is mandatory to avoid unnecessary procedure and complications.

Fast optically sectioned fluorescence HiLo endomicroscopy

PubMed Central

Lim, Daryl; Mertz, Jerome

2012-01-01

Abstract. We describe a nonscanning, fiber bundle endomicroscope that performs optically sectioned fluorescence imaging with fast frame rates and real-time processing. Our sectioning technique is based on HiLo imaging, wherein two widefield images are acquired under uniform and structured illumination and numerically processed to reject out-of-focus background. This work is an improvement upon an earlier demonstration of widefield optical sectioning through a flexible fiber bundle. The improved device features lateral and axial resolutions of 2.6 and 17 μm, respectively, a net frame rate of 9.5 Hz obtained by real-time image processing with a graphics processing unit (GPU) and significantly reduced motion artifacts obtained by the use of a double-shutter camera. We demonstrate the performance of our system with optically sectioned images and videos of a fluorescently labeled chorioallantoic membrane (CAM) in the developing G. gallus embryo. HiLo endomicroscopy is a candidate technique for low-cost, high-speed clinical optical biopsies. PMID:22463023

Contraction and stress-dependent growth shape the forebrain of the early chicken embryo.

PubMed

Garcia, Kara E; Okamoto, Ruth J; Bayly, Philip V; Taber, Larry A

2017-01-01

During early vertebrate development, local constrictions, or sulci, form to divide the forebrain into the diencephalon, telencephalon, and optic vesicles. These partitions are maintained and exaggerated as the brain tube inflates, grows, and bends. Combining quantitative experiments on chick embryos with computational modeling, we investigated the biophysical mechanisms that drive these changes in brain shape. Chemical perturbations of contractility indicated that actomyosin contraction plays a major role in the creation of initial constrictions (Hamburger-Hamilton stages HH11-12), and fluorescent staining revealed that F-actin is circumferentially aligned at all constrictions. A finite element model based on these findings shows that the observed shape changes are consistent with circumferential contraction in these regions. To explain why sulci continue to deepen as the forebrain expands (HH12-20), we speculate that growth depends on wall stress. This idea was examined by including stress-dependent growth in a model with cerebrospinal fluid pressure and bending (cephalic flexure). The results given by the model agree with observed morphological changes that occur in the brain tube under normal and reduced eCSF pressure, quantitative measurements of relative sulcal depth versus time, and previously published patterns of cell proliferation. Taken together, our results support a biphasic mechanism for forebrain morphogenesis consisting of differential contractility (early) and stress-dependent growth (late). Copyright © 2016 Elsevier Ltd. All rights reserved.

Rapid Effects of Hearing Song on Catecholaminergic Activity in the Songbird Auditory Pathway

PubMed Central

Matragrano, Lisa L.; Beaulieu, Michaël; Phillip, Jessica O.; Rae, Ali I.; Sanford, Sara E.; Sockman, Keith W.; Maney, Donna L.

2012-01-01

Catecholaminergic (CA) neurons innervate sensory areas and affect the processing of sensory signals. For example, in birds, CA fibers innervate the auditory pathway at each level, including the midbrain, thalamus, and forebrain. We have shown previously that in female European starlings, CA activity in the auditory forebrain can be enhanced by exposure to attractive male song for one week. It is not known, however, whether hearing song can initiate that activity more rapidly. Here, we exposed estrogen-primed, female white-throated sparrows to conspecific male song and looked for evidence of rapid synthesis of catecholamines in auditory areas. In one hemisphere of the brain, we used immunohistochemistry to detect the phosphorylation of tyrosine hydroxylase (TH), a rate-limiting enzyme in the CA synthetic pathway. We found that immunoreactivity for TH phosphorylated at serine 40 increased dramatically in the auditory forebrain, but not the auditory thalamus and midbrain, after 15 min of song exposure. In the other hemisphere, we used high pressure liquid chromatography to measure catecholamines and their metabolites. We found that two dopamine metabolites, dihydroxyphenylacetic acid and homovanillic acid, increased in the auditory forebrain but not the auditory midbrain after 30 min of exposure to conspecific song. Our results are consistent with the hypothesis that exposure to a behaviorally relevant auditory stimulus rapidly induces CA activity, which may play a role in auditory responses. PMID:22724011

Mast cells in the sheep, hedgehog and rat forebrain

PubMed Central

MICHALOUDI, HELEN C.; PAPADOPOULOS, GEORGIOS C.

1999-01-01

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

Neuroprotection and aging of the cholinergic system: a role for the ergoline derivative nicergoline (Sermion).

PubMed

Giardino, L; Giuliani, A; Battaglia, A; Carfagna, N; Aloe, L; Calza', L

2002-01-01

The aging brain is characterized by selective neurochemical changes involving several neural populations. A deficit in the cholinergic system of the basal forebrain is thought to contribute to the development of cognitive symptoms of dementia. Attempts to prevent age-associated cholinergic vulnerability and deterioration therefore represent a crucial point for pharmacotherapy in the elderly. In this paper we provide evidence for the protective effect of nicergoline (Sermion) on the degeneration of cholinergic neurons induced by nerve growth factor deprivation. Nerve growth factor deprivation was induced by colchicine administration in rats 13 and 18 months old. Colchicine induces a rapid and substantial down-regulation of choline acetyltransferase messenger RNA level in the basal forebrain in untreated adult, middle-aged and old rats. Colchicine failed to cause these effects in old rats treated for 120 days with nicergoline 10 mg/kg/day, orally. Moreover, a concomitant increase of both nerve growth factor and brain-derived neurotrophic factor content was measured in the basal forebrain of old, nicergoline-treated rats. Additionally, the level of messenger RNA for the brain isoform of nitric oxide synthase in neurons of the basal forebrain was also increased in these animals. Based on the present findings, nicergoline proved to be an effective drug for preventing neuronal vulnerability due to experimentally induced nerve growth factor deprivation.

Optimization of ITER Nb3Sn CICCs for coupling loss, transverse electromagnetic load and axial thermal contraction

NASA Astrophysics Data System (ADS)

Nijhuis, A.; van Lanen, E. P. A.; Rolando, G.

2012-01-01

The ITER cable-in-conduit conductors (CICCs) are built up from sub-cable bundles, wound in different stages, which are twisted to counter coupling loss caused by time-changing external magnet fields. The selection of the twist pitch lengths has major implications for the performance of the cable in the case of strain-sensitive superconductors, i.e. Nb3Sn, as the electromagnetic and thermal contraction loads are large but also for the heat load from the AC coupling loss. At present, this is a great challenge for the ITER central solenoid (CS) CICCs and the solution presented here could be a breakthrough for not only the ITER CS but also for CICC applications in general. After proposing longer twist pitches in 2006 and successful confirmation by short sample tests later on, the ITER toroidal field (TF) conductor cable pattern was improved accordingly. As the restrictions for coupling loss are more demanding for the CS conductors than for the TF conductors, it was believed that longer pitches would not be applicable for the conductors in the CS coils. In this paper we explain how, with the use of the TEMLOP model and the newly developed models JackPot-ACDC and CORD, the design of a CICC can be improved appreciably, particularly for the CS conductor layout. For the first time a large improvement is predicted not only providing very low sensitivity to electromagnetic load and thermal axial cable stress variations but at the same time much lower AC coupling loss. Reduction of the transverse load and warm-up-cool-down degradation can be reached by applying longer twist pitches in a particular sequence for the sub-stages, offering a large cable transverse stiffness, adequate axial flexibility and maximum allowed lateral strand support. Analysis of short sample (TF conductor) data reveals that increasing the twist pitch can lead to a gain of the effective axial compressive strain of more than 0.3% with practically no degradation from bending. This is probably explained by the distinct difference in mechanical response of the cable during axial contraction for short and long pitches. For short pitches periodic bending in different directions with relatively short wavelength is imposed because of a lack of sufficient lateral restraint of radial pressure. This can lead to high bending strain and eventually buckling. Whereas for cables with long twist pitches, the strands are only able to react as coherent bundles, being tightly supported by the surrounding strands, providing sufficient lateral restraint of radial pressure in combination with enough slippage to avoid single strand bending along detrimental short wavelengths. Experimental evidence of good performance was already provided with the test of the long pitch TFPRO2-OST2, which is still until today, the best ITER-type cable to strand performance ever without any cyclic load (electromagnetic and thermal contraction) degradation. For reduction of the coupling loss, specific choices of the cabling twist sequence are needed to minimize the area of linked strands and bundles that are coupled and form loops with the applied changing magnetic field, instead of simply avoiding longer pitches. In addition we recommend increasing the wrap coverage of the CS conductor from 50% to at least 70%. A larger wrap coverage fraction enhances the overall strand bundle lateral restraint. The long pitch design seems the best solution to optimize the ITER CS conductor within the given restrictions of the present coil design envelope, only allowing marginal changes. The models predict significant improvement against strain sensitivity and substantial decrease of the AC coupling loss in Nb3Sn CICCs, but also for NbTi CICCs minimization of the coupling loss can obviously be achieved. Although the success of long pitches to transverse load degradation was already demonstrated, the prediction of the elegant innovative combination with low coupling loss needs to be validated by a short sample test.

On the properties of a bundle of flexible actin filaments in an optical trap.

PubMed

Perilli, Alessia; Pierleoni, Carlo; Ciccotti, Giovanni; Ryckaert, Jean-Paul

2016-06-28

We establish the statistical mechanics framework for a bundle of Nf living and uncrosslinked actin filaments in a supercritical solution of free monomers pressing against a mobile wall. The filaments are anchored normally to a fixed planar surface at one of their ends and, because of their limited flexibility, they grow almost parallel to each other. Their growing ends hit a moving obstacle, depicted as a second planar wall, parallel to the previous one and subjected to a harmonic compressive force. The force constant is denoted as the trap strength while the distance between the two walls as the trap length to make contact with the experimental optical trap apparatus. For an ideal solution of reactive filaments and free monomers at fixed free monomer chemical potential μ1, we obtain the general expression for the grand potential from which we derive averages and distributions of relevant physical quantities, namely, the obstacle position, the bundle polymerization force, and the number of filaments in direct contact with the wall. The grafted living filaments are modeled as discrete Wormlike chains, with F-actin persistence length ℓp, subject to discrete contour length variations ±d (the monomer size) to model single monomer (de)polymerization steps. Rigid filaments (ℓp = ∞), either isolated or in bundles, all provide average values of the stalling force in agreement with Hill's predictions Fs (H)=NfkBTln(ρ1/ρ1c)/d, independent of the average trap length. Here ρ1 is the density of free monomers in the solution and ρ1c its critical value at which the filament does not grow nor shrink in the absence of external forces. Flexible filaments (ℓp < ∞) instead, for values of the trap strength suitable to prevent their lateral escape, provide an average bundle force and an average trap length slightly larger than the corresponding rigid cases (few percents). Still the stalling force remains nearly independent on the average trap length, but results from the product of two strongly L-dependent contributions: the fraction of touching filaments ∝〈L〉(O.T.) (2) and the single filament buckling force ∝〈L〉(O.T.) (-2).

Zebrafish aussicht mutant embryos exhibit widespread overexpression of ace (fgf8) and coincident defects in CNS development.

PubMed

Heisenberg, C P; Brennan, C; Wilson, S W

1999-05-01

During the development of the zebrafish nervous system both noi, a zebrafish pax2 homolog, and ace, a zebrafish fgf8 homolog, are required for development of the midbrain and cerebellum. Here we describe a dominant mutation, aussicht (aus), in which the expression of noi and ace is upregulated. In aus mutant embryos, ace is upregulated at many sites in the embryo, while noi expression is only upregulated in regions of the forebrain and midbrain which also express ace. Subsequent to the alterations in noi and ace expression, aus mutants exhibit defects in the differentiation of the forebrain, midbrain and eyes. Within the forebrain, the formation of the anterior and postoptic commissures is delayed and the expression of markers within the pretectal area is reduced. Within the midbrain, En and wnt1 expression is expanded. In heterozygous aus embryos, there is ectopic outgrowth of neural retina in the temporal half of the eyes, whereas in putative homozygous aus embryos, the ventral retina is reduced and the pigmented retinal epithelium is expanded towards the midline. The observation that aus mutant embryos exhibit widespread upregulation of ace raised the possibility that aus might represent an allele of the ace gene itself. However, by crossing carriers for both aus and ace, we were able to generate homozygous ace mutant embryos that also exhibited the aus phenotype. This indicated that aus is not tightly linked to ace and is unlikely to be a mutation directly affecting the ace locus. However, increased Ace activity may underly many aspects of the aus phenotype and we show that the upregulation of noi in the forebrain of aus mutants is partially dependent upon functional Ace activity. Conversely, increased ace expression in the forebrain of aus mutants is not dependent upon functional Noi activity. We conclude that aus represents a mutation involving a locus normally required for the regulation of ace expression during embryogenesis.

Song exposure regulates known and novel microRNAs in the zebra finch auditory forebrain

PubMed Central

2011-01-01

Background In an important model for neuroscience, songbirds learn to discriminate songs they hear during tape-recorded playbacks, as demonstrated by song-specific habituation of both behavioral and neurogenomic responses in the auditory forebrain. We hypothesized that microRNAs (miRNAs or miRs) may participate in the changing pattern of gene expression induced by song exposure. To test this, we used massively parallel Illumina sequencing to analyse small RNAs from auditory forebrain of adult zebra finches exposed to tape-recorded birdsong or silence. Results In the auditory forebrain, we identified 121 known miRNAs conserved in other vertebrates. We also identified 34 novel miRNAs that do not align to human or chicken genomes. Five conserved miRNAs showed significant and consistent changes in copy number after song exposure across three biological replications of the song-silence comparison, with two increasing (tgu-miR-25, tgu-miR-192) and three decreasing (tgu-miR-92, tgu-miR-124, tgu-miR-129-5p). We also detected a locus on the Z sex chromosome that produces three different novel miRNAs, with supporting evidence from Northern blot and TaqMan qPCR assays for differential expression in males and females and in response to song playbacks. One of these, tgu-miR-2954-3p, is predicted (by TargetScan) to regulate eight song-responsive mRNAs that all have functions in cellular proliferation and neuronal differentiation. Conclusions The experience of hearing another bird singing alters the profile of miRNAs in the auditory forebrain of zebra finches. The response involves both known conserved miRNAs and novel miRNAs described so far only in the zebra finch, including a novel sex-linked, song-responsive miRNA. These results indicate that miRNAs are likely to contribute to the unique behavioural biology of learned song communication in songbirds. PMID:21627805

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

PubMed

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

2015-04-01

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

A lateralized functional auditory network is involved in anuran sexual selection.

PubMed

Xue, Fei; Fang, Guangzhan; Yue, Xizi; Zhao, Ermi; Brauth, Steven E; Tang, Yezhong

2016-12-01

Right ear advantage (REA) exists in many land vertebrates in which the right ear and left hemisphere preferentially process conspecific acoustic stimuli such as those related to sexual selection. Although ecological and neural mechanisms for sexual selection have been widely studied, the brain networks involved are still poorly understood. In this study we used multi-channel electroencephalographic data in combination with Granger causal connectivity analysis to demonstrate, for the first time, that auditory neural network interconnecting the left and right midbrain and forebrain function asymmetrically in the Emei music frog (Babina daunchina), an anuran species which exhibits REA. The results showed the network was lateralized. Ascending connections between the mesencephalon and telencephalon were stronger in the left side while descending ones were stronger in the right, which matched with the REA in this species and implied that inhibition from the forebrainmay induce REA partly. Connections from the telencephalon to ipsilateral mesencephalon in response to white noise were the highest in the non-reproductive stage while those to advertisement calls were the highest in reproductive stage, implying the attention resources and living strategy shift when entered the reproductive season. Finally, these connection changes were sexually dimorphic, revealing sex differences in reproductive roles.

Cerebral correlates of depressed behavior in rats, visualized using /sup 14/C-2-deoxyglucose autoradiography

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

Caldecott-Hazard, S.; Mazziotta, J.; Phelps, M.

1988-06-01

/sup 14/C-2-Deoxyglucose (2DG) was used to investigate changes in the rate of cerebral metabolism in 3 rat models of depressed behavior. The models had already been established in the literature and were induced by injections of alpha-methyl-para-tyrosine, withdrawal from chronic amphetamine, or stress. We verified that exploratory behaviors were depressed in each model and that an antidepressant drug, tranylcypromine, prevented the depressed behavior in each model. 2DG studies revealed that the rate of regional glucose metabolism was elevated bilaterally in the lateral habenula of each of the 3 models. Regional metabolic rates were reduced in each model in the dorsalmore » medial prefrontal cortex, anterior ventral nucleus of the thalamus, and inferior colliculus. Forebrain global metabolic rates were also reduced in each of the models. Tranylcypromine prevented the elevated rate of lateral habenula metabolism seen in each of the models alone but did not significantly affect the rates of global metabolism. Our findings of identical metabolic changes in each of the models indicate that these changes are not idiosyncratic to a particular model; rather, they correlate with a generalizable state of depressed exploratory behavior in rats.« less

Mechanisms of dendritic spine remodeling in a rat model of traumatic brain injury.

PubMed

Campbell, John N; Low, Brian; Kurz, Jonathan E; Patel, Sagar S; Young, Matt T; Churn, Severn B

2012-01-20

Traumatic brain injury (TBI), a leading cause of death and disability in the United States, causes potentially preventable damage in part through the dysregulation of neural calcium levels. Calcium dysregulation could affect the activity of the calcium-sensitive phosphatase calcineurin (CaN), with serious implications for neural function. The present study used both an in vitro enzymatic assay and Western blot analyses to characterize the effects of lateral fluid percussion injury on CaN activity and CaN-dependent signaling in the rat forebrain. TBI resulted in an acute alteration of CaN phosphatase activity and long-lasting alterations of its downstream effector, cofilin, an actin-depolymerizing protein. These changes occurred bilaterally in the neocortex and hippocampus, appeared to persist for hours after injury, and coincided with synapse degeneration, as suggested by a loss of the excitatory post-synaptic protein PSD-95. Interestingly, the effect of TBI on cofilin in some brain regions was blocked by a single bolus of the CaN inhibitor FK506, given 1 h post-TBI. Overall, these findings suggest a loss of synapse stability in both hemispheres of the laterally-injured brain, and offer evidence for region-specific, CaN-dependent mechanisms.

Mechanisms of Dendritic Spine Remodeling in a Rat Model of Traumatic Brain Injury

PubMed Central

Campbell, John N.; Low, Brian; Kurz, Jonathan E.; Patel, Sagar S.; Young, Matt T.

2012-01-01

Abstract Traumatic brain injury (TBI), a leading cause of death and disability in the United States, causes potentially preventable damage in part through the dysregulation of neural calcium levels. Calcium dysregulation could affect the activity of the calcium-sensitive phosphatase calcineurin (CaN), with serious implications for neural function. The present study used both an in vitro enzymatic assay and Western blot analyses to characterize the effects of lateral fluid percussion injury on CaN activity and CaN-dependent signaling in the rat forebrain. TBI resulted in an acute alteration of CaN phosphatase activity and long-lasting alterations of its downstream effector, cofilin, an actin-depolymerizing protein. These changes occurred bilaterally in the neocortex and hippocampus, appeared to persist for hours after injury, and coincided with synapse degeneration, as suggested by a loss of the excitatory post-synaptic protein PSD-95. Interestingly, the effect of TBI on cofilin in some brain regions was blocked by a single bolus of the CaN inhibitor FK506, given 1 h post-TBI. Overall, these findings suggest a loss of synapse stability in both hemispheres of the laterally-injured brain, and offer evidence for region-specific, CaN-dependent mechanisms. PMID:21838518

[Neural Mechanisms Underlying the Processing of Temporal Information in Episodic Memory and Its Disturbance].

PubMed

Iwata, Saeko; Tsukiura, Takashi

2017-11-01

Episodic memory is defined as memory for personally experienced events, and includes memory content and contextual information of time and space. Previous neuroimaging and neuropsychological studies have demonstrated three possible roles of the temporal context in episodic memory. First, temporal information contributes to the arrangement of temporal order for sequential events in episodic memory, and this process is involved in the lateral prefrontal cortex. The second possible role of temporal information in episodic memory is the segregation between memories of multiple events, which are segregated by cues of different time information. The role of segregation is associated with the orbitofrontal regions including the orbitofrontal cortex and basal forebrain region. Third, temporal information in episodic memory plays an important role in the integration of multiple components into a coherent episodic memory, in which episodic components in the different modalities are combined by temporal information as an index. The role of integration is mediated by the medial temporal lobe including the hippocampus and parahippocampal gyrus. Thus, temporal information in episodic memory could be represented in multiple stages, which are involved in a network of the lateral prefrontal, orbitofrontal, and medial temporal lobe regions.

Estradiol increases choline acetyltransferase activity in specific basal forebrain nuclei and projection areas of female rats.

PubMed

Luine, V N

1985-08-01

Administration of estradiol to gonadectomized female, but not male rats, is associated with increased activity of choline acetyltransferase in the medial aspect of the horizontal diagonal band nucleus, the frontal cortex, and CA1 of the dorsal hippocampus. Four other basal forebrain cholinergic nuclei did not show changes in choline acetyltransferase activity after estradiol. These data have implications for possible benefits of estradiol administration to patients with senile dementia of the Alzheimer's type.

Recognition of white matter bundles using local and global streamline-based registration and clustering.

PubMed

Garyfallidis, Eleftherios; Côté, Marc-Alexandre; Rheault, Francois; Sidhu, Jasmeen; Hau, Janice; Petit, Laurent; Fortin, David; Cunanne, Stephen; Descoteaux, Maxime

2018-04-15

Virtual dissection of diffusion MRI tractograms is cumbersome and needs extensive knowledge of white matter anatomy. This virtual dissection often requires several inclusion and exclusion regions-of-interest that make it a process that is very hard to reproduce across experts. Having automated tools that can extract white matter bundles for tract-based studies of large numbers of people is of great interest for neuroscience and neurosurgical planning. The purpose of our proposed method, named RecoBundles, is to segment white matter bundles and make virtual dissection easier to perform. This can help explore large tractograms from multiple persons directly in their native space. RecoBundles leverages latest state-of-the-art streamline-based registration and clustering to recognize and extract bundles using prior bundle models. RecoBundles uses bundle models as shape priors for detecting similar streamlines and bundles in tractograms. RecoBundles is 100% streamline-based, is efficient to work with millions of streamlines and, most importantly, is robust and adaptive to incomplete data and bundles with missing components. It is also robust to pathological brains with tumors and deformations. We evaluated our results using multiple bundles and showed that RecoBundles is in good agreement with the neuroanatomical experts and generally produced more dense bundles. Across all the different experiments reported in this paper, RecoBundles was able to identify the core parts of the bundles, independently from tractography type (deterministic or probabilistic) or size. Thus, RecoBundles can be a valuable method for exploring tractograms and facilitating tractometry studies. Copyright © 2017 Elsevier Inc. All rights reserved.

On the concept of a filtered bundle

NASA Astrophysics Data System (ADS)

Bruce, Andrew James; Grabowska, Katarzyna; Grabowski, Janusz

We present the notion of a filtered bundle as a generalization of a graded bundle. In particular, we weaken the necessity of the transformation laws for local coordinates to exactly respect the weight of the coordinates by allowing more general polynomial transformation laws. The key examples of such bundles include affine bundles and various jet bundles, both of which play fundamental roles in geometric mechanics and classical field theory. We also present the notion of double filtered bundles which provide natural generalizations of double vector bundles and double affine bundles. Furthermore, we show that the linearization of a filtered bundle — which can be seen as a partial polarization of the admissible changes of local coordinates — is well defined.

Left-Right Asymmetry of Maturation Rates in Human Embryonic Neural Development.

PubMed

de Kovel, Carolien G F; Lisgo, Steven; Karlebach, Guy; Ju, Jia; Cheng, Gang; Fisher, Simon E; Francks, Clyde

2017-08-01

Left-right asymmetry is a fundamental organizing feature of the human brain, and neuropsychiatric disorders such as schizophrenia sometimes involve alterations of brain asymmetry. As early as 8 weeks postconception, the majority of human fetuses move their right arms more than their left arms, but because nerve fiber tracts are still descending from the forebrain at this stage, spinal-muscular asymmetries are likely to play an important developmental role. We used RNA sequencing to measure gene expression levels in the left and right spinal cords, and the left and right hindbrains, of 18 postmortem human embryos aged 4 to 8 weeks postconception. Genes showing embryonic lateralization were tested for an enrichment of signals in genome-wide association data for schizophrenia. The left side of the embryonic spinal cord was found to mature faster than the right side. Both sides transitioned from transcriptional profiles associated with cell division and proliferation at earlier stages to neuronal differentiation and function at later stages, but the two sides were not in synchrony (p = 2.2 E-161). The hindbrain showed a left-right mirrored pattern compared with the spinal cord, consistent with the well-known crossing over of function between these two structures. Genes that showed lateralization in the embryonic spinal cord were enriched for association signals with schizophrenia (p = 4.3 E-05). These are the earliest stage left-right differences of human neural development ever reported. Disruption of the lateralized developmental program may play a role in the genetic susceptibility to schizophrenia. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Surgical anatomy of medial open-wedge high tibial osteotomy: crucial steps and pitfalls.

PubMed

Madry, Henning; Goebel, Lars; Hoffmann, Alexander; Dück, Klaus; Gerich, Torsten; Seil, Romain; Tschernig, Thomas; Pape, Dietrich

2017-12-01

To give an overview of the basic knowledge of the functional surgical anatomy of the proximal lower leg and the popliteal region relevant to medial high tibial osteotomy (HTO) as key anatomical structures in spatial relation to the popliteal region and the proximal tibiofibular joint are usually not directly visible and thus escape a direct inspection. The surgical anatomy of the human proximal lower leg and its relevance for HTO are illustrated with a special emphasis on the individual steps of the operation involving creation of the osteotomy planes and plate fixation. The posteriorly located popliteal neurovascular bundle, but also lateral structures such as the peroneal nerve, the head of the fibula and the lateral collateral ligament must be protected from the instruments used for osteotomy. Neither positioning the knee joint in flexion, nor the posterior thin muscle layer of the popliteal muscle offers adequate protection of the popliteal neurovascular bundle when performing the osteotomy. Tactile feedback through a loss-of-resistance when the opposite cortex is perforated is only possible when sawing and drilling is performed in a pounding fashion. Kirschner wires with a proximal thread, therefore, always need to be introduced under fluoroscopic control. Due to anatomy of the tibial head, the tibial slope may increase inadvertently. Enhanced surgical knowledge of anatomical structures that are at a potential risk during the different steps of osteotomy or plate fixation will help to avoid possible injuries. Expert opinion, Level V.

Targeted sections in either XY or XZ plane with dual-axes confocal endomicroscope (Conference Presentation)

NASA Astrophysics Data System (ADS)

Li, Gaoming; Li, Haijun; Duan, Xiyu; Zhou, Quan; Zhou, Juan; Oldham, Kenn R.; Wang, Thomas D.

2017-02-01

We demonstrate a dual axes confocal architecture, which can be used to collect horizontal(XY-plane) or vertical cross-sectional(XZ-plane) images for tissue. This scanner head is 5.5mm in outer diameter(OD), and integrates a 3D MEMS scanner with a compact chip size of 3.2×2.9mm2. To realize the miniaturization, there are some obstacles of the small size of 3D MEMS scanner, MEMS wire bundle, the air pressure effect for MEMS motion, the processing of parabolic mirror, and optical alignment to come over. In our probe, separation mechanical structure for optical alignment was adopted and a step shape MEMS holder was designed to deal with the difficult of MEMS wire bundle. Peptides have been demonstrated tremendous potential for in vivo use to detect colonic dysplasia. This class of in vivo molecular probe can be labeled with near-infrared (NIR) dyes for visualizing the full depth of the epithelium in small animals. To confirm our probe performance, we take use of USAF 1951 resolution target to test its lateral and axial resolution. It has lateral and axial resolution of 2.49um and 4.98um, respectively. When we collect the fluorescence imaging of colon, it shows that the field of view are 1000um×1000um (horizontal) and 1000um×430um (vertical). The horizontal and vertical cross-sectional images of fresh mouse colonic mucosa demonstrate imaging performance with this miniature instrument.

Seasonal neuronal plasticity in song-control and auditory forebrain areas in subtropical nonmigratory and palearctic-indian migratory male songbirds.

PubMed

Surbhi; Rastogi, Ashutosh; Malik, Shalie; Rani, Sangeeta; Kumar, Vinod

2016-10-01

This study examines whether differences in annual life-history states (LHSs) among the inhabitants of two latitudes would have an impact on the neuronal plasticity of the song-control system in songbirds. At the times of equinoxes and solstices during the year (n = 4 per year) corresponding to different LHSs, we measured the volumetric changes and expression of doublecortin (DCX; an endogenous marker of the neuronal recruitment) in the song-control nuclei and higher order auditory forebrain regions of the subtropical resident Indian weaverbirds (Ploceus philippinus) and Palearctic-Indian migratory redheaded buntings (Emberiza bruniceps). Area X in basal ganglia, lateral magnocellular nucleus of the anterior nidopallium (LMAN), HVC (proper name), and robust nucleus of the arcopallium (RA) were enlarged during the breeding LHS. Both round and fusiform DCX-immunoreactive (DCX-ir) cells were found in area X and HVC but not in LMAN or RA, with a significant seasonal difference. Also, as shown by increase in volume and by dense, round DCX-ir cells, the neuronal incorporation was increased in HVC alone during the breeding LHS. This suggests differences in the response of song-control nuclei to photoperiod-induced changes in LHSs. Furthermore, DCX immunoreactivity indicated participation of the cortical caudomedial nidopallium and caudomedial mesopallium in the song-control system, albeit with differences between the weaverbirds and the buntings. Overall, these results show seasonal neuronal plasticity in the song-control system closely associated with annual reproductive LHS in both of the songbirds. Differences between species probably account for the differences in the photoperiod-response system between the relative refractory weaverbirds and absolute refractory redheaded buntings. J. Comp. Neurol. 524:2914-2929, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Abnormal Positioning of Diencephalic Cell Types in Neocortical Tissue in the Dorsal Telencephalon of Mice Lacking Functional Gli3

PubMed Central

Fotaki, Vassiliki; Yu, Tian; Zaki, Paulette A.; Mason, John O.; Price, David J.

2008-01-01

The transcription factor Gli3 (glioma-associated oncogene homolog) is essential for normal development of the mammalian forebrain. One extreme requirement for Gli3 is at the dorsomedial telencephalon, which does not form in Gli3Xt/Xt mutant mice lacking functional Gli3. In this study, we analyzed expression of Gli3 in the wild-type telencephalon and observed a highdorsal-to-lowventral gradient of Gli3 expression and predominance of the cleaved form of the Gli3 protein dorsally. This graded expression correlates with the severedorsal-to-mildventral telencephalic phenotype observed in Gli3Xt/Xt mice. We characterized the abnormal joining of the telencephalon to the diencephalon and defined the medial limit of the dorsal telencephalon in Gli3Xt/Xt mice early in corticogenesis. Based on this analysis, we concluded that some of the abnormal expression of ventral telencephalic markers previously described as being in the dorsal telencephalon is, in fact, expression in adjacent diencephalic tissue, which expresses many of the same genes that mark the ventral telencephalon. We observed occasional cells with diencephalic character in the Foxg1 (forkhead box)-expressing Gli3Xt/Xt telencephalon at embryonic day 10.5, a day after the anatomical subdivision of the forebrain vesicle. Large clusters of such cells appear in the Gli3Xt/Xt neocortical region at later ages, when the neocortex becomes highly disorganized, forming rosettes comprising mainly neural progenitors. We propose that Gli3 is indispensable for formation of an intact telencephalic-diencephalic boundary and for preventing the abnormal positioning of diencephalic cells in the dorsal telencephalon. PMID:16957084

Forebrain networks and the control of feeding by environmental learned cues

PubMed Central

Petrovich, Gorica D.

2013-01-01

The motivation to eat is driven by a complex sum of physiological and non-physiological influences computed by the brain. Physiological signals that inform the brain about energy and nutrient needs are the primary drivers, but environmental signals unrelated to energy balance also control appetite and eating. The two components could act in concert to support the homeostatic regulation of food intake. Often, however, environmental influences rival physiological control and stimulate eating irrespective of satiety, or inhibit eating irrespective of hunger. If persistent, such maladaptive challenges to the physiological system could lead to dysregulated eating and ultimately to eating disorders. Nevertheless, the brain mechanisms underlying environmental contribution in the control of food intake are poorly understood. This paper provides an overview in recent advances in deciphering the critical brain systems using rodent models for environmental control by learned cues. These models use associative learning to compete with the physiological control, and in one preparation food cues stimulate a meal despite satiety, while in another preparation fear cues stop a meal despite hunger. Thus far, four forebrain regions have been identified as part of the essential cue induced feeding circuitry. These are telencephalic areas critical for associative learning, memory encoding, and decision making, the amygdala, hippocampus and prefrontal cortex and the lateral hypothalamus, which functions to integrate feeding, reward, and motivation. This circuitry also engages two orexigenic peptides, ghrelin and orexin. A parallel amygdalar circuitry supports fear cue cessation of feeding. These findings illuminate the brain mechanisms underlying environmental control of food intake and might be also relevant to aspects of human appetite and maladaptive overeating and undereating. PMID:23562305

Neural connectivity of the anterior body of the fornix in the human brain: diffusion tensor imaging study.

PubMed

Jang, Sung Ho; Kwon, Hyeok Gyu

2014-01-24

A few studies have reported on the neural connectivity of the fornix in the human brain, however, little is known about the neural connectivity of the anterior body of the fornix. In this study, we used diffusion tensor imaging in investigation of the neural connectivity of the anterior body of the fornix in normal subjects. Forty healthy subjects were recruited for this study. A seed region of interest was placed on the anterior body of the fornix using the FMRIB Software Library. Connectivity was defined as the incidence of connection between the anterior body of the fornix and any neural structure of the brain at the threshold of 5, 25, and 50 streamlines. In all subjects, the anterior body of the fornix showed 100% connectivity to the anterior commissure and hypothalamus at thresholds of 5, 25, and 50. On the other hand, regarding the thresholds of 5, 25, and 50, the anterior body of the fornix showed connectivity to the septal forebrain region (53.8, 23.8, and 15.0%), frontal lobe via anterior commissure (41.3,12.5, and 10.0%), medial temporal lobe (85.0,66.3, and 62.5%), lateral temporal lobe (75.0, 56.3, and 35.0%), occipital lobe (21.3, 5.0, and 1.3%), frontal lobe via septum pellucidum (28.8, 13.8, and 8.8%), tegmentum of midbrain (7.5, 5.0, and 0%), tectum of midbrain (2.5,0, and 0%), and tegmentum of pons (5.0,0, and 0%). The anterior body of the fornix showed high connectivity with the anterior commissure and hypothalamus, and brain areas relevant to cholinergic nuclei (the septal forebrain region and brainstem) and memory function (the medial temporal lobe). Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

FoxA4 favours notochord formation by inhibiting contiguous mesodermal fates and restricts anterior neural development in Xenopus embryos.

PubMed

Murgan, Sabrina; Castro Colabianchi, Aitana Manuela; Monti, Renato José; Boyadjián López, Laura Elena; Aguirre, Cecilia E; Stivala, Ernesto González; Carrasco, Andrés E; López, Silvia L

2014-01-01

In vertebrates, the embryonic dorsal midline is a crucial signalling centre that patterns the surrounding tissues during development. Members of the FoxA subfamily of transcription factors are expressed in the structures that compose this centre. Foxa2 is essential for dorsal midline development in mammals, since knock-out mouse embryos lack a definitive node, notochord and floor plate. The related gene foxA4 is only present in amphibians. Expression begins in the blastula -chordin and -noggin expressing centre (BCNE) and is later restricted to the dorsal midline derivatives of the Spemann's organiser. It was suggested that the early functions of mammalian foxa2 are carried out by foxA4 in frogs, but functional experiments were needed to test this hypothesis. Here, we show that some important dorsal midline functions of mammalian foxa2 are exerted by foxA4 in Xenopus. We provide new evidence that the latter prevents the respecification of dorsal midline precursors towards contiguous fates, inhibiting prechordal and paraxial mesoderm development in favour of the notochord. In addition, we show that foxA4 is required for the correct regionalisation and maintenance of the central nervous system. FoxA4 participates in constraining the prospective rostral forebrain territory during neural specification and is necessary for the correct segregation of the most anterior ectodermal derivatives, such as the cement gland and the pituitary anlagen. Moreover, the early expression of foxA4 in the BCNE (which contains precursors of the whole forebrain and most of the midbrain and hindbrain) is directly required to restrict anterior neural development.

Excessive disgust caused by brain lesions or temporary inactivations: mapping hotspots of the nucleus accumbens and ventral pallidum.

PubMed

Ho, Chao-Yi; Berridge, Kent C

2014-11-01

Disgust is a prototypical type of negative affect. In animal models of excessive disgust, only a few brain sites are known in which localized dysfunction (lesions or neural inactivations) can induce intense 'disgust reactions' (e.g. gapes) to a normally pleasant sensation such as sweetness. Here, we aimed to map forebrain candidates more precisely, to identify where either local neuronal damage (excitotoxin lesions) or local pharmacological inactivation (muscimol/baclofen microinjections) caused rats to show excessive sensory disgust reactions to sucrose. Our study compared subregions of the nucleus accumbens shell, ventral pallidum, lateral hypothalamus, and adjacent extended amygdala. The results indicated that the posterior half of the ventral pallidum was the only forebrain site where intense sensory disgust gapes in response to sucrose were induced by both lesions and temporary inactivations (this site was previously identified as a hedonic hotspot for enhancements of sweetness 'liking'). By comparison, for the nucleus accumbens, temporary GABA inactivations in the caudal half of the medial shell also generated sensory disgust, but lesions never did at any site. Furthermore, even inactivations failed to induce disgust in the rostral half of the accumbens shell (which also contains a hedonic hotspot). In other structures, neither lesions nor inactivations induced disgust as long as the posterior ventral pallidum remained spared. We conclude that the posterior ventral pallidum is an especially crucial hotspot for producing excessive sensory disgust by local pharmacological/lesion dysfunction. By comparison, the nucleus accumbens appears to segregate sites for pharmacological disgust induction and hedonic enhancement into separate posterior and rostral halves of the medial shell. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Central oxytocin receptor stimulation attenuates the orexigenic effects of butorphanol tartrate.

PubMed

Olszewski, Pawel K; Klockars, Oscar A; Klockars, Anica; Levine, Allen S

2016-09-28

Butorphanol tartrate (BT), a mixed µ/κ/δ opioid receptor agonist, is one of the most potent orexigens known to date. The central mechanisms through which BT causes hyperphagia are largely unknown. Interestingly, BT suppresses meal-end activation of neurons synthesizing anorexigenic neuropeptide, oxytocin (OT), which suggests that BT promotes hyperphagia by silencing OT-derived satiety signaling. As OT terminates consumption by acting by distinct hindbrain and forebrain circuits, we investigated whether stimulation of the OT receptor in the forebrain or the hindbrain [through lateral ventricular (LV) and fourth ventricular (4V) OT injections] leads to termination of food intake induced by BT. We established effective doses of BT on chow intake in ad-libitum-fed and overnight-deprived rats as well as effective doses of LV and 4V OT in deprived animals. Then, we determined doses of LV and 4V OT that reduce hyperphagia produced by BT in sated and deprived rats. Finally, we assessed whether OT's effects on BT-induced feeding can be suppressed by an OT receptor antagonist. 4 mg/kg BT increased intake in ad-libitum-fed and overnight-deprived rats, whereas LV and 4V OT at 1 μg caused a decrease in deprived rats. BT-induced chow intake in hungry and sated animals was suppressed by a very low, 0.1 μg dose of 4V OT, whereas 1 μg OT was effective LV. The effect of OT was attenuated by OT receptor antagonist, L-368 899. Reduced activity of the OT circuit, especially its hindbrain component, is a critical factor in shaping the magnitude of consumption in response to BT treatment.

Substantia Nigra Volume Loss Before Basal Forebrain Degeneration in Early Parkinson Disease

PubMed Central

Ziegler, David A.; Wonderlick, Julien S.; Ashourian, Paymon; Hansen, Leslie A.; Young, Jeremy C.; Murphy, Alex J.; Koppuzha, Cecily K.; Growdon, John H.; Corkin, Suzanne

2017-01-01

Objective To test the hypothesis that degeneration of the substantia nigra pars compacta (SNc) precedes that of the cholinergic basal forebrain (BF) in Parkinson disease (PD) using new multispectral structural magnetic resonance (MR) imaging tools to measure the volumes of the SNc and BF. Design Matched case-control study. Setting The Athinoula A. Martinos Imaging Center at the McGovern Institute for Brain Research, Massachusetts Institute of Technology (MIT), and the Massachusetts General Hospital/MIT Morris Udall Center of Excellence in Parkinson Disease Research. Patients Participants included 29 patients with PD (Hoehn and Yahr [H&Y] stages 1–3) and 27 matched healthy control subjects. Main Outcome Measures We acquired multiecho T1-weighted, multiecho proton density, T2-weighted, and T2-weighted fluid-attenuated inversion recovery (FLAIR) sequences from each participant. For the SNc, we created a weighted mean of the multiple echoes, yielding a single volume with a high ratio of contrast to noise. We visualized the BF using T2-weighted FLAIR images. For each participant, we manually labeled the 2 structures and calculated their volumes. Results Relative to the controls, 13 patients with H&Y stage 1 PD had significantly decreased SNc volumes. Sixteen patients with H&Y stage 2 or 3 PD showed little additional volume loss. In contrast, the BF volume loss occurred later in the disease, with a significant decrease apparent in patients having H&Y stage 2 or 3 PD compared with the controls and the patients having H&Y stage 1 PD. The latter group did not differ significantly from the controls. Conclusion Our results support the proposed neuropathological trajectory in PD and establish novel multispectral methods as MR imaging biomarkers for tracking the degeneration of the SNc and BF. PMID:23183921

Aldosterone acting through the central nervous system sensitizes angiotensin II-induced hypertension.

PubMed

Xue, Baojian; Zhang, Zhongming; Roncari, Camila F; Guo, Fang; Johnson, Alan Kim

2012-10-01

Previous studies have shown that preconditioning rats with a nonpressor dose of angiotensin II (Ang II) sensitizes the pressor response produced by later treatment with a higher dose of Ang II and that Ang II and aldosterone (Aldo) can modulate each other's pressor effects through actions involving the central nervous system. The current studies tested whether Aldo can cross-sensitize the pressor actions of Ang II to enhance hypertension by employing an induction-delay-expression experimental design. Male rats were implanted for telemetered blood pressure recording. During induction, subpressor doses of either subcutaneous or intracerebroventricular Aldo were delivered for 1 week. Rats were then rested for 1 week (delay) to assure that any exogenous Aldo was metabolized. After this, Ang II was given subcutaneously for 2 weeks (expression). During induction and delay, Aldo had no sustained effect on blood pressure. However, during expression, Ang II-induced hypertension was greater in the groups receiving subcutaneous or intracerebroventricular Aldo during induction in comparison with those groups receiving vehicle. Central administration of mineralocorticoid receptor antagonist blocked sensitization. Brain tissue collected at the end of delay and expression showed increased mRNA expression of several renin-angiotensin-aldosterone system components in cardiovascular-related forebrain regions of cross-sensitized rats. Cultured subfornical organ neurons preincubated with Aldo displayed greater increases in [Ca2+]i after Ang II treatment, and there was a greater Fra-like immunoreactivity present at the end of expression in cardiovascular-related forebrain structures. Taken together, these results indicate that Aldo pretreatment cross-sensitizes the development of Ang II-induced hypertension probably by mechanisms that involve the central nervous system.

Motivational Modulation of Rhythms of the Expression of the Clock Protein PER2 in the Limbic Forebrain.

PubMed

Amir, Shimon; Stewart, Jane

2009-05-15

Key molecular components of the mammalian circadian clock are expressed rhythmically in many brain areas and peripheral tissues in mammals. Here we review findings from our work on rhythms of expression of the clock protein Period2 (PER2) in four regions of the limbic forebrain known to be important in the regulation of motivational and emotional states. These regions include the oval nucleus of the bed nucleus of the stria terminalis (BNSTov), the central nucleus of the amygdala (CEA), the basolateral amygdala (BLA), and the dentate gyrus (DG). Daily rhythms in the expression of PER2 in these regions are controlled by the master circadian pacemaker, the suprachiasmatic nucleus (SCN), but, importantly, they are also sensitive to homeostatic perturbations and to hormonal states that directly influence motivated behavior. Thus, circadian information from the SCN and homeostatic signals are integrated in these regions of the limbic forebrain to affect the temporal organization of motivational and emotional processes.

Oxidant and enzymatic antioxidant status (gene expression and activity) in the brain of chickens with cold-induced pulmonary hypertension

NASA Astrophysics Data System (ADS)

Hassanpour, Hossein; Khalaji-Pirbalouty, Valiallah; Nasiri, Leila; Mohebbi, Abdonnaser; Bahadoran, Shahab

2015-11-01

To evaluate oxidant and antioxidant status of the brain (hindbrain, midbrain, and forebrain) in chickens with cold-induced pulmonary hypertension, the measurements of lipid peroxidation, protein oxidation, antioxidant capacity, enzymatic activity, and gene expression (for catalase, glutathione peroxidase, and superoxide dismutases) were done. There were high lipid peroxidation/protein oxidation and low antioxidant capacity in the hindbrain of cold-induced pulmonary hypertensive chickens compared to control ( P < 0.05). In the hypertensive chickens, superoxide dismutase activity was decreased (forebrain, midbrain, and hindbrain), while catalase activity was increased (forebrain and midbrain) ( P < 0.05). Glutathione peroxidase activity did not change. Relative gene expression of catalase and superoxide dismutases (1 and 2) was downregulated, while glutathione peroxidase was upregulated in the brain of the cold-induced pulmonary hypertensive chickens. Probably, these situations in the oxidant and antioxidant status of the brain especially hindbrain may change its function at cardiovascular center and sympathetic nervous system to exacerbate pulmonary hypertension.

Transcriptional regulation of intermediate progenitor cell generation during hippocampal development

PubMed Central

Harris, Lachlan; Zalucki, Oressia; Gobius, Ilan; McDonald, Hannah; Osinki, Jason; Harvey, Tracey J.; Essebier, Alexandra; Vidovic, Diana; Gladwyn-Ng, Ivan; Burne, Thomas H.; Heng, Julian I.; Richards, Linda J.; Gronostajski, Richard M.

2016-01-01

During forebrain development, radial glia generate neurons through the production of intermediate progenitor cells (IPCs). The production of IPCs is a central tenet underlying the generation of the appropriate number of cortical neurons, but the transcriptional logic underpinning this process remains poorly defined. Here, we examined IPC production using mice lacking the transcription factor nuclear factor I/X (Nfix). We show that Nfix deficiency delays IPC production and prolongs the neurogenic window, resulting in an increased number of neurons in the postnatal forebrain. Loss of additional Nfi alleles (Nfib) resulted in a severe delay in IPC generation while, conversely, overexpression of NFIX led to precocious IPC generation. Mechanistically, analyses of microarray and ChIP-seq datasets, coupled with the investigation of spindle orientation during radial glial cell division, revealed that NFIX promotes the generation of IPCs via the transcriptional upregulation of inscuteable (Insc). These data thereby provide novel insights into the mechanisms controlling the timely transition of radial glia into IPCs during forebrain development. PMID:27965439

ZIC2 in Holoprosencephaly.

PubMed

Barratt, Kristen S; Arkell, Ruth M

2018-01-01

The ZIC2 transcription factor is one of the most commonly mutated genes in Holoprosencephaly (HPE) probands. HPE is a severe congenital defect of forebrain development which occurs when the cerebral hemispheres fail to separate during the early stages of organogenesis and is typically associated with mispatterning of the embryonic midline. Recent study of genotype-phenotype correlations in HPE cases has defined distinctive features of ZIC2-associated HPE presentation and genetics, revealing that ZIC2 mutation does not produce the craniofacial abnormalities generally thought to characterise HPE but leads to a range of non-forebrain phenotypes. Furthermore, the studies confirm the extent of ZIC2 allelic heterogeneity and that pathogenic variants of ZIC2 are associated with both classic and middle interhemispheric variant (MIHV) HPE which arise from defective ventral and dorsal forebrain patterning, respectively. An allelic series of mouse mutants has helped to delineate the cellular and molecular mechanisms by which one gene leads to defects in these related but distinct embryological processes.

Selective immunotoxic lesions of basal forebrain cholinergic cells: effects on learning and memory in rats.

PubMed

Baxter, Mark G; Bucci, David J; Gorman, Linda K; Wiley, Ronald G; Gallagher, Michela

2013-10-01

Male Long-Evans rats were given injections of either 192 IgG-saporin, an apparently selective toxin for basal forebrain cholinergic neurons (LES), or vehicle (CON) into either the medial septum and vertical limb of the diagonal band (MS/VDB) or bilaterally into the nucleus basalis magnocellularis and substantia innominata (nBM/SI). Place discrimination in the Morris water maze assessed spatial learning, and a trial-unique matching-to-place task in the water maze assessed memory for place information over varying delays. MS/VDB-LES and nBM/SI-LES rats were not impaired relative to CON rats in acquisition of the place discrimination, but were mildly impaired relative to CON rats in performance of the memory task even at the shortest delay, suggesting a nonmnemonic deficit. These results contrast with effects of less selective lesions, which have been taken to support a role for basal forebrain cholinergic neurons in learning and memory. 2013 APA, all rights reserved

The cholinergic forebrain arousal system acts directly on the circadian pacemaker

PubMed Central

Yamakawa, Glenn R.; Basu, Priyoneel; Cortese, Filomeno; MacDonnell, Johanna; Whalley, Danica; Smith, Victoria M.

2016-01-01

Sleep and wake states are regulated by a variety of mechanisms. One such important system is the circadian clock, which provides temporal structure to sleep and wake. Conversely, changes in behavioral state, such as sleep deprivation (SD) or arousal, can phase shift the circadian clock. Here we demonstrate that the level of wakefulness is critical for this arousal resetting of the circadian clock. Specifically, drowsy animals with significant power in the 7- to 9-Hz band of their EEGs do not exhibit phase shifts in response to a mild SD procedure. We then show that treatments that both produce arousal and reset the phase of circadian clock activate (i.e., induce Fos expression in) the basal forebrain. Many of the activated cells are cholinergic. Using retrograde tract tracing, we demonstrate that cholinergic cells activated by these arousal procedures project to the circadian clock in the suprachiasmatic nuclei (SCN). We then demonstrate that arousal-induced phase shifts are blocked when animals are pretreated with atropine injections to the SCN, demonstrating that cholinergic activity at the SCN is necessary for arousal-induced phase shifting. Finally, we demonstrate that electrical stimulation of the substantia innominata of the basal forebrain phase shifts the circadian clock in a manner similar to that of our arousal procedures and that these shifts are also blocked by infusions of atropine to the SCN. These results establish a functional link between the major forebrain arousal center and the circadian system. PMID:27821764

Estrogen alters behavior and forebrain c-fos expression in ovariectomized rats subjected to the forced swim test

PubMed Central

Rachman, Ilya M.; Unnerstall, James R.; Pfaff, Donald W.; Cohen, Rochelle S.

1998-01-01

Estrogen has been implicated in brain functions related to affective state, including hormone-related affective disorders in women. Although some reports suggest that estrogen appears to decrease vulnerability to affective disorders in certain cases, the mechanisms involved are unknown. We used the forced swim test (FST), a paradigm used to test the efficacy of antidepressants, and addressed the hypotheses that estrogen alters behavior of ovariectomized rats in the FST and the FST-induced expression of c-fos, a marker for neuronal activity, in the rat forebrain. The behaviors displayed included struggling, swimming, and immobility. One hour after the beginning of the test on day 2, the animals were perfused, and the brains were processed for c-fos immunocytochemistry. On day 1, the estradiol benzoate-treated animals spent significantly less time struggling and virtually no time in immobility and spent most of the time swimming. Control rats spent significantly more time struggling or being immobile during a comparable period. On day 2, similar behavioral patterns with still more pronounced differences were observed between estradiol benzoate and ovariectomized control groups in struggling, immobility, and swimming. Analysis of the mean number of c-fos immunoreactive cell nuclei showed a significant reduction in the estradiol benzoate versus control groups in areas of the forebrain relating to sensory, contextual, and integrative processing. Our results suggest that estrogen-induced neurochemical changes in forebrain neurons may translate into an altered behavioral output in the affective domain. PMID:9811905

Evolution of the vertebrate neurocranium: problems of the premandibular domain and the origin of the trabecula.

PubMed

Kuratani, Shigeru; Ahlberg, Per E

2018-01-01

The subdivision of the gnathostome neurocranium into an anterior neural crest-derived moiety and a posterior mesodermal moiety has attracted the interest of researchers for nearly two centuries. We present a synthetic scenario for the evolution of this structure, uniting developmental data from living cyclostomes and gnathostomes with morphological data from fossil stem gnathostomes in a common phylogenetic framework. Ancestrally, vertebrates had an anteroposteriorly short forebrain, and the neurocranium was essentially mesodermal; skeletal structures derived from premandibular ectomesenchyme were mostly anterior to the brain and formed part of the visceral arch skeleton. The evolution of a one-piece neurocranial 'head shield' in jawless stem gnathostomes, such as galeaspids and osteostracans, caused this mesenchyme to become incorporated into the neurocranium, but its position relative to the brain and nasohypophyseal duct remained unchanged. Basically similar distribution of the premandibular ectomesenchyme is inferred, even in placoderms, the earliest jawed vertebrates, in which the separation of hypophyseal and nasal placodes obliterated the nasohypophyseal duct, leading to redeployment of this ectomesenchyme between the separate placodes and permitting differentiation of the crown gnathostome trabecula that floored the forebrain. Initially this region was very short, and the bulk of the premandibular cranial part projected anteroventral to the nasal capsule, as in jawless stem gnathostomes. Due to the lengthening of the forebrain, the anteriorly projecting 'upper lip' was lost, resulting in the modern gnathostome neurocranium with a long forebrain cavity floored by the trabeculae.

Competing signals drive telencephalon diversity.

PubMed

Sylvester, J B; Rich, C A; Yi, C; Peres, J N; Houart, C; Streelman, J T

2013-01-01

The telencephalon is the most complex brain region, controlling communication, emotion, movement and memory. Its adult derivatives develop from the dorsal pallium and ventral subpallium. Despite knowledge of genes required in these territories, we do not understand how evolution has shaped telencephalon diversity. Here, using rock- and sand-dwelling cichlid fishes from Lake Malawi, we demonstrate that differences in strength and timing of opposing Hedgehog and Wingless signals establish evolutionary divergence in dorsal-ventral telencephalon patterning. Rock dwellers exhibit early, extensive Hedgehog activity in the ventral forebrain resulting in expression of foxg1 before dorsal Wingless signals, and a larger subpallium. Sand dwellers show rapid deployment of Wingless, later foxg1 expression and a larger pallium. Manipulation of the Hedgehog and Wingless pathways in cichlid and zebrafish embryos is sufficient to mimic differences between rock- versus sand-dweller brains. Our data suggest that competing ventral Hedgehog and dorsal Wingless signals mediate evolutionary diversification of the telencephalon.

Fgfr3 regulates development of the caudal telencephalon.

PubMed

Moldrich, Randal X; Mezzera, Cecilia; Holmes, William M; Goda, Sailaja; Brookfield, Sam J; Rankin, Alastair J; Barr, Emily; Kurniawan, Nyoman; Dewar, Deborah; Richards, Linda J; López-Bendito, Guillermina; Iwata, Tomoko

2011-06-01

The fibroblast growth factor receptor 3 (Fgfr3) is expressed in a rostral(low) to caudal(high) gradient in the developing cerebral cortex. Therefore, we hypothesized that Fgfr3 contributes to the correct morphology and connectivity of the caudal cortex. Overall, the forebrain structures appeared normal in Fgfr3(-/-) mice. However, cortical and hippocampal volumes were reduced by 26.7% and 16.3%, respectively. Hypoplasia was particularly evident in the caudo-ventral region of the telencephalon where proliferation was mildly decreased at embryonic day 18.5. Dysplasia of GABAergic neurons in the amygdala and piriform cortex was seen following GAD67 immunohistochemistry. Dye-tracing studies and diffusion magnetic resonance imaging and tractography detected a subtle thalamocortical tract deficit, and significant decreases in the stria terminalis and lateral arms of the anterior commissure. These results indicate the subtle role of Fgfr3 in formation of caudal regions of the telencephalon affecting some brain projections. Copyright © 2011 Wiley-Liss, Inc.

Decreased subcortical cholinergic arousal in focal seizures

PubMed Central

Motelow, Joshua E.; Li, Wei; Zhan, Qiong; Mishra, Asht M.; Sachdev, Robert N. S.; Liu, Geoffrey; Gummadavelli, Abhijeet; Zayyad, Zaina; Lee, Hyun Seung; Chu, Victoria; Andrews, John P.; Englot, Dario J.; Herman, Peter; Sanganahalli, Basavaraju G.; Hyder, Fahmeed; Blumenfeld, Hal

2015-01-01

SUMMARY Impaired consciousness in temporal lobe seizures has a major negative impact on quality of life. The prevailing view holds that this disorder impairs consciousness by seizure spread to the bilateral temporal lobes. We propose instead that seizures invade subcortical regions and depress arousal, causing impairment through decreases rather than through increases in activity. Using functional magnetic resonance imaging in a rodent model, we found increased activity in regions known to depress cortical function including lateral septum and anterior hypothalamus. Importantly, we found suppression of intralaminar thalamic and brainstem arousal systems and suppression of the cortex. At a cellular level, we found reduced firing of identified cholinergic neurons in the brainstem pedunculopontine tegmental nucleus and basal forebrain. Finally, we used enzyme-based amperometry to demonstrate reduced cholinergic neurotransmission in both cortex and thalamus. Decreased subcortical arousal is a novel mechanism for loss of consciousness in focal temporal lobe seizures. PMID:25654258

Thyroid hormone modulates the development of cholinergic terminal fields in the rat forebrain: relation to nerve growth factor receptor.

PubMed

Oh, J D; Butcher, L L; Woolf, N J

1991-04-24

Hyperthyroidism, induced in rat pups by the daily intraperitoneal administration of 1 microgram/g body weight triiodothyronine, facilitated the development of ChAT fiber plexuses in brain regions innervated by basal forebrain cholinergic neurons, leading to an earlier and increased expression of cholinergic markers in those fibers in the cortex, hippocampus and amygdala. A similar enhancement was seen in the caudate-putamen complex. This histochemical profile was correlated with an accelerated appearance of ChAT-positive telencephalic puncta, as well as with a larger total number of cholinergic terminals expressed, which persisted throughout the eight postnatal week, the longest time examined in the present study. Hypothyroidism was produced in rat pups by adding 0.5% propylthiouracil to the dams' diet beginning the day after birth. This dietary manipulation resulted in the diminished expression of ChAT in forebrain fibers and terminals. Hypothyroid treatment also reduced the quantity of ChAT puncta present during postnatal weeks 2 and 3, and, from week 4 and continuing through week 6, the number of ChAT-positive terminals in the telencephalic regions examined was actually less than the amount extant during the former developmental epoch. Immunostaining for nerve growth factor receptor (NGF-R), which is associated almost exclusively with ChAT-positive somata and fibers in the basal forebrain, demonstrated a different time course of postnatal development. Forebrain fibers and terminals demonstrating NGF-R were maximally visualized 1 week postnatally, a time at which these same neuronal elements evinced minimal ChAT-like immunopositivity. Thereafter and correlated with increased immunoreactivity for ChAT, fine details of NGF-R stained fibers were observed less frequently. Although propylthiouracil administration decreased NGF-R immunodensity, no alteration in the development of that receptor was observed as a function of triiodothyronine treatment. Cholinergic terminals in the ventrobasal thalamus, which derive from ChAT-positive neurons in the pedunculopontine and laterodorsal tegmental nucleus, were unaffected by either hyperthyroid or hypothyroid conditions. These cells also do not demonstrate NGF-R. We conclude from these experiments (1) that cholinergic fiber plexuses eventually exhibiting ChAT positivity in the telencephalon demonstrate NGF-R prior to the cholinergic synthetic enzyme, (2) that susceptibility to thyroid hormone manipulations may involve sensitivity to NGF, at least in some forebrain cholinergic systems and (3) that the effects of thyroid hormone imbalances on brain cholinergic neurons are regionally selective.

Miniaturized fiber-coupled confocal fluorescence microscope with an electrowetting variable focus lens using no moving parts

PubMed Central

Ozbay, Baris N.; Losacco, Justin T.; Cormack, Robert; Weir, Richard; Bright, Victor M.; Gopinath, Juliet T.; Restrepo, Diego; Gibson, Emily A.

2015-01-01

We report a miniature, lightweight fiber-coupled confocal fluorescence microscope that incorporates an electrowetting variable focus lens to provide axial scanning for full three-dimensional (3D) imaging. Lateral scanning is accomplished by coupling our device to a laser-scanning confocal microscope through a coherent imaging fiber-bundle. The optical components of the device are combined in a custom 3D-printed adapter with an assembled weight of <2 g that can be mounted onto the head of a mouse. Confocal sectioning provides an axial resolution of ~12 µm and an axial scan range of ~80 µm. The lateral field-of-view is 300 µm, and the lateral resolution is 1.8 µm. We determined these parameters by imaging fixed sections of mouse neuronal tissue labeled with green fluorescent protein (GFP) and fluorescent bead samples in agarose gel. To demonstrate viability for imaging intact tissue, we resolved multiple optical sections of ex vivo mouse olfactory nerve fibers expressing yellow fluorescent protein (YFP). PMID:26030555

Effects of acute and repeated dosing of the synthetic cannabinoid CP55,940 on intracranial self-stimulation in mice*

PubMed Central

Grim, Travis W.; Wiebelhaus, Jason M.; Negus, S. Stevens; Lichtman, Aron H.

2015-01-01

Background Synthetic cannabinoids have emerged as a significant public health concern. To increase the knowledge of how these molecules interact on brain reward processes, we investigated the effects of CP55,940, a high efficacy synthetic CB1 receptor agonist, in a frequency-rate intracranial self-stimulation (ICSS) procedure. Methods The impact of acute and repeated administration (seven days) of CP55,940 on operant responding for electrical brain stimulation of the medial forebrain bundle was investigated in C57BL/6J mice. Results CP55,940 attenuated ICSS in a dose-related fashion (ED50 (95% C.L.) = 0.15 (0.12–0.18) mg/kg). This effect was blocked by the CB1 receptor antagonist rimonabant. Tolerance developed quickly, though not completely, to the rate-decreasing effects of CP55,940 (0.3 mg/kg). Abrupt discontinuation of drug did not alter baseline responding for up to seven days. Moreover, rimonabant (10 mg/kg) challenge did not alter ICSS responding in mice treated repeatedly with CP55,940. Conclusions The finding that CP55,940 reduced ICSS in mice with no evidence of facilitation at any dose is consistent with synthetic cannabinoid effects on ICSS in rats. CP55,940-induced ICSS depression was mediated through a CB1 receptor mechanism. Additionally, tolerance and dependence following repeated CP55,940 administration were dissociable. Thus, CP55,940 does not produce reward-like effects in ICSS under these conditions. PMID:25772438

Pharmacological modulation of neuropathic pain-related depression of behavior: Effects of morphine, ketoprofen, bupropion and Δ9-tetrahydrocannabinol on formalin-induced depression of intracranial self-stimulation (ICSS) in rats

PubMed Central

Leitl, Michael D.; Negus, Stevens

2015-01-01

Neuropathic pain is often associated with behavioral depression. Intraplantar formalin produces sustained, neuropathy-associated depression of intracranial self-stimulation (ICSS) in rats. This study evaluated pharmacological modulation of formalin-induced ICSS depression. Rats with intracranial electrodes targeting the medial forebrain bundle responded for electrical brain stimulation in an ICSS procedure. Bilateral intraplantar formalin administration depressed ICSS for 14 days. Morphine (0.32–3.2 mg/kg), ketoprofen (0.1–10 mg/kg), bupropion (3.2–32 mg/kg), and Δ9-tetrahydrocannabinol (THC; 0.32–3.2 mg/kg) were evaluated for their effectiveness to reverse formalin-induced depression of ICSS. Drug effects on formalin-induced mechanical allodynia were evaluated for comparison. Morphine and bupropion reversed both formalin-induced ICSS depression and mechanical allodynia, and effects on ICSS were sustained during repeated treatment. Ketoprofen failed to reverse either formalin effect. THC blocked mechanical allodynia, but decreased ICSS in control rats and exacerbated formalin-induced depression of ICSS. The failure of ketoprofen to alter formalin effects suggests that formalin effects result from neuropathy rather than inflammation. The effectiveness of morphine and bupropion to reverse formalin effects agrees with other evidence that these drugs block pain-depressed behavior in rats and relieve neuropathic pain in humans. The effects of THC suggest general behavioral suppression and do not support the use of THC to treat neuropathic pain. PMID:26588213

Naringin protects the nigrostriatal dopaminergic projection through induction of GDNF in a neurotoxin model of Parkinson's disease.

PubMed

Leem, Eunju; Nam, Jin Han; Jeon, Min-Tae; Shin, Won-Ho; Won, So-Yoon; Park, Sang-Joon; Choi, Myung-Sook; Jin, Byung Kwan; Jung, Un Ju; Kim, Sang Ryong

2014-07-01

This study investigated the effect of naringin, a major flavonoid in grapefruit and citrus fruits, on the degeneration of the nigrostriatal dopaminergic (DA) projection in a neurotoxin model of Parkinson's disease (PD) in vivo and the potential underlying mechanisms focusing on the induction of glia-derived neurotrophic factor (GDNF), well known as an important neurotrophic factor involved in the survival of adult DA neurons. 1-Methyl-4-phenylpyridinium (MPP(+)) was unilaterally injected into the medial forebrain bundle of rat brains for a neurotoxin model of PD in the presence or absence of naringin by daily intraperitoneal injection. To ascertain whether naringin-induced GDNF contributes to neuroprotection, we further investigated the effects of intranigral injection of neutralizing antibodies against GDNF in the MPP(+) rat model of PD. Our observations demonstrate that naringin could increase the level of GDNF in DA neurons, contributing to neuroprotection in the MPP(+) rat model of PD, with activation of mammalian target of rapamycin complex 1. Moreover, naringin could attenuate the level of tumor necrosis factor-α in microglia increased by MPP(+)-induced neurotoxicity in the substantia nigra. These results indicate that naringin could impart to DA neurons the important ability to produce GDNF as a therapeutic agent against PD with anti-inflammatory effects, suggesting that naringin is a beneficial natural product for the prevention of DA degeneration in the adult brain. Copyright © 2014 Elsevier Inc. All rights reserved.

Motivational effects of methamphetamine as measured by the runway method using priming stimulation of intracranial self-stimulation behavior.

PubMed

Sagara, Hidenori; Kitamura, Yoshihisa; Sendo, Toshiaki; Araki, Hiroaki; Gomita, Yutaka

2008-04-01

Priming stimulation is known to promote the motivational effects of intracranial self-stimulation (ICSS) behavior. The runway method using priming stimulation can experimentally distinguish the reward and motivational effects of ICSS behavior. In this study, we examined the motivational effect of a drug as determined by the runway method using priming stimulation of ICSS behavior. Electrodes were implanted chronically into the medial forebrain bundle (MFB) of the rats. A lever for stimulation of the MFB was set on the opposite side of the start box in the apparatus. The rats were trained to obtain a reward stimulation (50-200 muA, 0.2 ms, 60 Hz) of the MFB by pressing the goal lever, and then priming stimulation of the MFB was applied. After priming stimulation, rats were placed in the start box of the runway apparatus and the time taken by the rat to press the lever was recorded. Priming stimulation frequency was significantly correlated with running speed (r=0.897, p<0.05). Methamphetamine (1, 3 mg/kg) induced an increase in running speed (F(3, 20)=16.257, p<0.01), and was further increased with increase in priming stimulation frequency. In addition, methamphetamine significantly enhanced the motivational effect. These results suggest that the runway method using priming stimulation of ICSS behavior may be an effective way to evaluate the enhancing effect of a drug on motivation.

Flow and Temperature Distribution Evaluation on Sodium Heated Large-sized Straight Double-wall-tube Steam Generator

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

Kisohara, Naoyuki; Moribe, Takeshi; Sakai, Takaaki

2006-07-01

The sodium heated steam generator (SG) being designed in the feasibility study on commercialized fast reactor cycle systems is a straight double-wall-tube type. The SG is large sized to reduce its manufacturing cost by economics of scale. This paper addresses the temperature and flow multi-dimensional distributions at steady state to obtain the prospect of the SG. Large-sized heat exchanger components are prone to have non-uniform flow and temperature distributions. These phenomena might lead to tube buckling or tube to tube-sheet junction failure in straight tube type SGs, owing to tubes thermal expansion difference. The flow adjustment devices installed in themore » SG are optimized to prevent these issues, and the temperature distribution properties are uncovered by analysis methods. The analysis model of the SG consists of two parts, a sodium inlet distribution plenum (the plenum) and a heat transfer tubes bundle region (the bundle). The flow and temperature distributions in the plenum and the bundle are evaluated by the three-dimensional code 'FLUENT' and the two dimensional thermal-hydraulic code 'MSG', respectively. The MSG code is particularly developed for sodium heated SGs in JAEA. These codes have revealed that the sodium flow is distributed uniformly by the flow adjustment devices, and that the lateral tube temperature distributions remain within the allowable temperature range for the structural integrity of the tubes and the tube to tube-sheet junctions. (authors)« less

Intrafascial nerve-sparing endoscopic extraperitoneal radical prostatectomy.

PubMed

Stolzenburg, Jens-Uwe; Rabenalt, Robert; Do, Minh; Schwalenberg, Thilo; Winkler, Mathias; Dietel, Anja; Liatsikos, Evangelos

2008-05-01

Based on our recently published anatomic studies, we present the most recent refinement of the endoscopic extraperitoneal radical prostatectomy (EERPE), the intrafascial nerve-sparing EERPE (nsEERPE). As part of the intrafascial technique, the dissection plane is directly on the prostatic capsule, freeing the prostate laterally from its thin surrounding fascia that contains small vessels and nerves. The technique enables puboprostatic ligament preservation, leaving intact endopelvic fascia, periprostatic fascia, and neurovascular bundles. The operation was performed in 150 patients with indications for nerve-sparing procedure. The mean operative time was 131 min (range: 50-210 min) and the mean catheterization time was 5.9 d (range: 4-20 d). Twelve months postoperatively, 94.3% of the patients were continent (no need for pads), 4.6% had minimal stress incontinence, and one patient required >2 pads/d. At the 12-mo follow-up, the potency rates (erections sufficient for intercourse with or without the use of phosphodiesterase 5 [PDE5] inhibitors) of the patients who underwent bilateral intrafascial nsEERPE were 89.7% (age: 44-55 yr), 81.1% (age: 56-65 yr), and 61.9% (age: >65 yr). Positive surgical margins in pT2 and pT3 tumors were 4.5% and 29.4%, respectively. The intrafascial nsEERPE enables the dissection of the prostate with limited trauma to the surrounding fascias and the enclosed neurovascular bundles. We propose that the preserved neurovascular bundles with intrafascial nsEERPE are more viable. The results advocate this proposition.

Arthroscopic and 3D CT Scan Evaluation of Femoral Footprint of the Anterior Cruciate Ligament in Chronic ACL Deficient Knees.

PubMed

Das, Anupam; Yadav, C S; Gamanagatti, Shivanand; Pandey, R M; Mittal, Ravi

2018-06-13

The outcome of single-bundle anterior cruciate ligament (ACL) reconstruction depends largely on the anatomic placement of bone tunnel. The lateral intercondylar ridge (LIR) and bifurcate ridge (BR) are useful bony landmarks for femoral tunnel placement. The purpose of our study was to compare the bony landmarks of ACL footprint on femur by three-dimensional computed tomography (3D CT) scan and arthroscopy in chronic ACL-deficient knees. Fifty patients above 18 years of age who were diagnosed of having ACL tear were selected for the study. All the cases were more than 6 months old since the injury. Preoperative 3D CT scan of the affected knee was obtained for each of them. They underwent single-bundle anatomic ACL reconstruction. Measurements were done on the preoperative 3D CT and arthroscopy to quantify the position of the LIR and BR. The proximodistal distance of lateral femoral condyle was 21.41+/-2.5 mm on CT scan and 22.02+/-2.02 mm on arthroscopy. On preoperative 3D CT scan, the midpoint of the LIR was found to be located at a mean distance of 11.17±2.11 mm from the proximal margin of the lateral femoral condyle. On arthroscopy, it was at 10.18+/-1.52 mm from the proximal margin the lateral femoral condyle. The "bifurcate ridge"(BR) was not visible in any of the cases during arthroscopy or CT scan. We concluded that LIR is an easily identifiable bony landmark on arthroscopy in all cases. It can also be identified on CT scans. BR is not identified both on arthroscopy and CT scans in chronic ACL tears. The arthroscopic measurements of bony landmarks are quite close to those of CT scan. Midpoint of LIR is at 52.185% of the proximodistal distance on CT scan evaluation and it is at 46.21% on arthroscopic evaluation. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Verification of the FBR fuel bundle-duct interaction analysis code BAMBOO by the out-of-pile bundle compression test with large diameter pins

NASA Astrophysics Data System (ADS)

Uwaba, Tomoyuki; Ito, Masahiro; Nemoto, Junichi; Ichikawa, Shoichi; Katsuyama, Kozo

2014-09-01

The BAMBOO computer code was verified by results for the out-of-pile bundle compression test with large diameter pin bundle deformation under the bundle-duct interaction (BDI) condition. The pin diameters of the examined test bundles were 8.5 mm and 10.4 mm, which are targeted as preliminary fuel pin diameters for the upgraded core of the prototype fast breeder reactor (FBR) and for demonstration and commercial FBRs studied in the FaCT project. In the bundle compression test, bundle cross-sectional views were obtained from X-ray computer tomography (CT) images and local parameters of bundle deformation such as pin-to-duct and pin-to-pin clearances were measured by CT image analyses. In the verification, calculation results of bundle deformation obtained by the BAMBOO code analyses were compared with the experimental results from the CT image analyses. The comparison showed that the BAMBOO code reasonably predicts deformation of large diameter pin bundles under the BDI condition by assuming that pin bowing and cladding oval distortion are the major deformation mechanisms, the same as in the case of small diameter pin bundles. In addition, the BAMBOO analysis results confirmed that cladding oval distortion effectively suppresses BDI in large diameter pin bundles as well as in small diameter pin bundles.

An immunohistochemical study of APG-2 protein in the rat hippocampus after transient forebrain ischemia.

PubMed

Lee, Mun-Yong; Choi, Yun-Sik; Choi, Jeong-Sun; Min, Do Sik; Chun, Myung-Hoon; Kim, Ok Nyu; Lee, Sang Bok; Kim, Seong Yun

2002-01-11

The cellular localization and spatiotemporal expression pattern of APG-2 protein, a member of the heat shock protein 110 family, were investigated in the rat hippocampus after transient forebrain ischemia. The spatiotemporal patterns of immunoreactivity of both APG-2 and glial fibrillary acidic protein were very similar, indicating that reactive astrocytes express APG-2, which was confirmed by double immunofluorescence histochemistry. Colocalization of APG-2 and a neuronal marker NeuN in the neurons of the CA2 and CA3 subfields was also confirmed.

Lateralized activation of Cluster N in the brains of migratory songbirds

PubMed Central

Liedvogel, Miriam; Feenders, Gesa; Wada, Kazuhiro; Troje, Nikolaus F.; Jarvis, Erich D.; Mouritsen, Henrik

2008-01-01

Cluster N is a cluster of forebrain regions found in night-migratory songbirds that shows high activation of activity-dependent gene expression during night-time vision. We have suggested that Cluster N may function as a specialized night-vision area in night-migratory birds and that it may be involved in processing light-mediated magnetic compass information. Here, we investigated these ideas. We found a significant lateralized dominance of Cluster N activation in the right hemisphere of European robins (Erithacus rubecula). Activation predominantly originated from the contralateral (left) eye. Garden warblers (Sylvia borin) tested under different magnetic field conditions and under monochromatic red light did not show significant differences in Cluster N activation. In the fairly sedentary Sardinian warbler (Sylvia melanocephala), which belongs to the same phyolgenetic clade, Cluster N showed prominent activation levels, similar to that observed in garden warblers and European robins. Thus, it seems that Cluster N activation occurs at night in all species within predominantly migratory groups of birds, probably because such birds have the capability of switching between migratory and sedentary life styles. The activation studies suggest that although Cluster N is lateralized, as is the dependence on magnetic compass orientation, either Cluster N is not involved in magnetic processing or the magnetic modulations of the primary visual signal, forming the basis for the currently supported light-dependent magnetic compass mechanism, are relatively small such that activity-dependent gene expression changes are not sensitive enough to pick them up. PMID:17331212

Hemispheric asymmetry in new neurons in adulthood is associated with vocal learning and auditory memory.

PubMed

Tsoi, Shuk C; Aiya, Utsav V; Wasner, Kobi D; Phan, Mimi L; Pytte, Carolyn L; Vicario, David S

2014-01-01

Many brain regions exhibit lateral differences in structure and function, and also incorporate new neurons in adulthood, thought to function in learning and in the formation of new memories. However, the contribution of new neurons to hemispheric differences in processing is unknown. The present study combines cellular, behavioral, and physiological methods to address whether 1) new neuron incorporation differs between the brain hemispheres, and 2) the degree to which hemispheric lateralization of new neurons correlates with behavioral and physiological measures of learning and memory. The songbird provides a model system for assessing the contribution of new neurons to hemispheric specialization because songbird brain areas for vocal processing are functionally lateralized and receive a continuous influx of new neurons in adulthood. In adult male zebra finches, we quantified new neurons in the caudomedial nidopallium (NCM), a forebrain area involved in discrimination and memory for the complex vocalizations of individual conspecifics. We assessed song learning and recorded neural responses to song in NCM. We found significantly more new neurons labeled in left than in right NCM; moreover, the degree of asymmetry in new neuron numbers was correlated with the quality of song learning and strength of neuronal memory for recently heard songs. In birds with experimentally impaired song quality, the hemispheric difference in new neurons was diminished. These results suggest that new neurons may contribute to an allocation of function between the hemispheres that underlies the learning and processing of complex signals.

Hemispheric Asymmetry in New Neurons in Adulthood Is Associated with Vocal Learning and Auditory Memory

PubMed Central

Wasner, Kobi D.; Phan, Mimi L.; Pytte, Carolyn L.; Vicario, David S.

2014-01-01

Many brain regions exhibit lateral differences in structure and function, and also incorporate new neurons in adulthood, thought to function in learning and in the formation of new memories. However, the contribution of new neurons to hemispheric differences in processing is unknown. The present study combines cellular, behavioral, and physiological methods to address whether 1) new neuron incorporation differs between the brain hemispheres, and 2) the degree to which hemispheric lateralization of new neurons correlates with behavioral and physiological measures of learning and memory. The songbird provides a model system for assessing the contribution of new neurons to hemispheric specialization because songbird brain areas for vocal processing are functionally lateralized and receive a continuous influx of new neurons in adulthood. In adult male zebra finches, we quantified new neurons in the caudomedial nidopallium (NCM), a forebrain area involved in discrimination and memory for the complex vocalizations of individual conspecifics. We assessed song learning and recorded neural responses to song in NCM. We found significantly more new neurons labeled in left than in right NCM; moreover, the degree of asymmetry in new neuron numbers was correlated with the quality of song learning and strength of neuronal memory for recently heard songs. In birds with experimentally impaired song quality, the hemispheric difference in new neurons was diminished. These results suggest that new neurons may contribute to an allocation of function between the hemispheres that underlies the learning and processing of complex signals. PMID:25251077

Signal detection by active, noisy hair bundles

NASA Astrophysics Data System (ADS)

O'Maoiléidigh, Dáibhid; Salvi, Joshua D.; Hudspeth, A. J.

2018-05-01

Vertebrate ears employ hair bundles to transduce mechanical movements into electrical signals, but their performance is limited by noise. Hair bundles are substantially more sensitive to periodic stimulation when they are mechanically active, however, than when they are passive. We developed a model of active hair-bundle mechanics that predicts the conditions under which a bundle is most sensitive to periodic stimulation. The model relies only on the existence of mechanotransduction channels and an active adaptation mechanism that recloses the channels. For a frequency-detuned stimulus, a noisy hair bundle's phase-locked response and degree of entrainment as well as its detection bandwidth are maximized when the bundle exhibits low-amplitude spontaneous oscillations. The phase-locked response and entrainment of a bundle are predicted to peak as functions of the noise level. We confirmed several of these predictions experimentally by periodically forcing hair bundles held near the onset of self-oscillation. A hair bundle's active process amplifies the stimulus preferentially over the noise, allowing the bundle to detect periodic forces less than 1 pN in amplitude. Moreover, the addition of noise can improve a bundle's ability to detect the stimulus. Although, mechanical activity has not yet been observed in mammalian hair bundles, a related model predicts that active but quiescent bundles can oscillate spontaneously when they are loaded by a sufficiently massive object such as the tectorial membrane. Overall, this work indicates that auditory systems rely on active elements, composed of hair cells and their mechanical environment, that operate on the brink of self-oscillation.

Sexual dimorphism in BDNF signaling after neonatal hypoxia-ischemia and treatment with necrostatin-1

PubMed Central

Chavez-Valdez, Raul; Martin, Lee J.; Razdan, Sheila; Gauda, Estelle B.; Northington, Frances J.

2014-01-01

Brain injury due to neonatal hypoxia-ischemia (HI) is more homogenously severe in male than in female mice. Because, necrostatin-1 (nec-1) prevents injury progression only in male mice, we hypothesized that changes in BDNF signaling after HI and nec-1 are also sex-specific providing differential conditions to promote recovery of those more severely injured. The increased aromatization of testosterone in male mice during early development and the link between 17-β-estradiol (E2) levels and BDNF transcription substantiate this hypothesis. Hence, we aimed to investigate if sexual differences in BDNF signaling existed in forebrain and diencephalon after HI and HI/ nec-1 and their correlation with estrogen receptors (ER). C57B6 mice (p7) received nec-1(0.1 μL[8μM]) or vehicle (veh) intracerebroventricularly after HI. At 24h after HI, BDNF levels increased in both sexes in forebrain without evidence of TrkB activation. At 96h after HI, BDNF levels in forebrain decreased below those seen in control mice of both sexes. Additionally, only in female mice, truncated TrkB (Tc.TrkB) and p75ntr levels increased in forebrain and diencephalon. In both, forebrain and diencephalon, nec-1 treatment increased BDNF levels and TrkB activation in male mice while, prevented Tc.TrkB and p75ntr increases in female mice. While E2 levels were unchanged by HI or HI/ nec-1 in either sex or treatment, ERα: ERβ ratios were increased in diencephalon of nec-1 treated male mice and directly correlated with BDNF levels. Neonatal HI produces sex-specific signaling changes in the BDNF system, that are differentially modulated by nec-1. The regional differences in BDNF levels may be a consequence of injury severity after HI, but sexual differences in response to nec-1 after HI may represent a differential thalamo-cortical preservation or alternatively off-target regional effect of nec-1. The biological significance of ERα predominance and its correlation with BDNF levels is still unclear. PMID:24361177

The role of gastrulation brain homeobox 2 (gbx2) in the development of the ventral telencephalon in zebrafish embryos.

PubMed

Wang, Zhe; Nakayama, Yukiko; Tsuda, Sachiko; Yamasu, Kyo

During vertebrate brain development, the gastrulation brain homeobox 2 gene (gbx2) is expressed in the forebrain, but its precise roles are still unknown. In this study, we addressed this issue in zebrafish (Danio rerio) first by carefully examining gbx2 expression in the developing forebrain. We showed that gbx2 was expressed in the telencephalon during late somitogenesis, from 18h post-fertilization (hpf) to 24 hpf, and in the thalamic primordium after 26 hpf. In contrast, another gbx gene, gbx1, was expressed in the anterior-most ventral telencephalon after 36 hpf. Thus, the expression patterns of these two gbx genes did not overlap, arguing against their redundant function in the forebrain. Two-color fluorescence in situ hybridization (FISH) showed close relationships between the telencephalic expression of gbx2 and other forebrain-forming genes, suggesting that their interactions contribute to the regionalization of the telencephalon. FISH further revealed that gbx2 is expressed in the ventricular region of the telencephalon. By using transgenic fish in which gbx2 can be induced by heat shock, we found that gbx2 induction at 16 hpf repressed the expression of emx3, dlx2a, and six3b in the ventral telencephalon. Among secreted factor genes, bmp2b and wnt1 were repressed in the vicinity of the gbx2 domain in the telencephalon. The expression of forebrain-forming genes was examined in mutant embryos lacking gbx2, showing emx3 and dlx2a to be upregulated in the subpallium at 24 hpf. Taken together, these findings indicate that gbx2 contributes to the development of the subpallium through its repressive activities against other telencephalon-forming genes. We further showed that inhibiting FGF signaling and activating Wnt signaling repressed gbx2 and affected the regionalization of the telencephalon, supporting a functional link between gbx2, intracellular signaling, and telencephalon development. Copyright © 2017 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.

Regulation of the orexigenic neuropeptide, enkephalin, by PPARδ and fatty acids in neurons of the hypothalamus and forebrain.

PubMed

Poon, Kinning; Alam, Mohammad; Karatayev, Olga; Barson, Jessica R; Leibowitz, Sarah F

2015-12-01

Ingestion of a high-fat diet composed mainly of the saturated fatty acid, palmitic (PA), and the unsaturated fatty acid, oleic (OA), stimulates transcription in the brain of the opioid neuropeptide, enkephalin (ENK), which promotes intake of substances of abuse. To understand possible underlying mechanisms, this study examined the nuclear receptors, peroxisome proliferator-activated receptors (PPARs), and tested in hypothalamic and forebrain neurons from rat embryos whether PPARs regulate endogenous ENK and the fatty acids themselves affect these PPARs and ENK. The first set of experiments demonstrated that knocking down PPARδ, but not PPARα or PPARγ, increased ENK transcription, activation of PPARδ by an agonist decreased ENK levels, and PPARδ neurons coexpressed ENK, suggesting that PPARδ negatively regulates ENK. In the second set of experiments, PA treatment of hypothalamic and forebrain neurons had no effect on PPARδ protein while stimulating ENK mRNA and protein, whereas OA increased both mRNA and protein levels of PPARδ in forebrain neurons while having no effect on ENK mRNA and increasing ENK levels. These findings show that PA has a strong, stimulatory effect on ENK and weak effect on PPARδ protein, whereas OA has a strong stimulatory effect on PPARδ and weak effect on ENK, consistent with the inhibitory effect of PPARδ on ENK. They suggest a function for PPARδ, perhaps protective in nature, in embryonic neurons exposed to fatty acids from a fat-rich diet and provide evidence for a mechanism contributing to differential effects of saturated and monounsaturated fatty acids on neurochemical systems involved in consummatory behavior. Our findings show that PPARδ in forebrain and hypothalamic neurons negatively regulates enkephalin (ENK), a peptide known to promote ingestive behavior. This inverse relationship is consistent with our additional findings, that a saturated (palmitic; PA) compared to a monounsaturated fatty acid (oleic; OA) has a strong stimulatory effect on ENK and weak effect on PPARδ. These results suggest that PPARδ protects against the neuronal effects of fatty acids, which differentially affect neurochemical systems involved in ingestive behavior. © 2015 International Society for Neurochemistry.

Absence of Prenatal Forebrain Defects in the Dp(16)1Yey/+ Mouse Model of Down Syndrome

PubMed Central

Goodliffe, Joseph W.; Olmos-Serrano, Jose Luis; Aziz, Nadine M.; Pennings, Jeroen L.A.; Guedj, Faycal; Bianchi, Diana W.

2016-01-01

Studies in humans with Down syndrome (DS) show that alterations in fetal brain development are followed by postnatal deficits in neuronal numbers, synaptic plasticity, and cognitive and motor function. This same progression is replicated in several mouse models of DS. Dp(16)1Yey/+ (hereafter called Dp16) is a recently developed mouse model of DS in which the entire region of mouse chromosome 16 that is homologous to human chromosome 21 has been triplicated. As such, Dp16 mice may more closely reproduce neurodevelopmental changes occurring in humans with DS. Here, we present the first comprehensive cellular and behavioral study of the Dp16 forebrain from embryonic to adult stages. Unexpectedly, our results demonstrate that Dp16 mice do not have prenatal brain defects previously reported in human fetal neocortex and in the developing forebrains of other mouse models, including microcephaly, reduced neurogenesis, and abnormal cell proliferation. Nevertheless, we found impairments in postnatal developmental milestones, fewer inhibitory forebrain neurons, and deficits in motor and cognitive performance in Dp16 mice. Therefore, although this new model does not express prenatal morphological phenotypes associated with DS, abnormalities in the postnatal period appear sufficient to produce significant cognitive deficits in Dp16. SIGNIFICANCE STATEMENT Down syndrome (DS) leads to intellectual disability. Several mouse models have increased our understanding of the neuropathology of DS and are currently being used to test therapeutic strategies. A new mouse model that contains an expanded number of DS-related genes, known as Dp(16)1Yey/+ (Dp16), has been generated recently. We sought to determine whether the extended triplication creates a better phenocopy of DS-related brain pathologies. We measured embryonic development, forebrain maturation, and perinatal/adult behavior and revealed an absence of prenatal phenotypes in Dp16 fetal brain, but specific cellular and behavioral deficits after the first 2 postnatal weeks. These results uncover important differences in prenatal phenotype between Dp16 animals and humans with DS and other DS mouse models. PMID:26961948

Crossed Module Bundle Gerbes; Classification, String Group and Differential Geometry

NASA Astrophysics Data System (ADS)

Jurčo, Branislav

We discuss nonabelian bundle gerbes and their differential geometry using simplicial methods. Associated to any crossed module there is a simplicial group NC, the nerve of the 1-category defined by the crossed module and its geometric realization |NC|. Equivalence classes of principal bundles with structure group |NC| are shown to be one-to-one with stable equivalence classes of what we call crossed module gerbes bundle gerbes. We can also associate to a crossed module a 2-category C'. Then there are two equivalent ways how to view classifying spaces of NC-bundles and hence of |NC|-bundles and crossed module bundle gerbes. We can either apply the W-construction to NC or take the nerve of the 2-category C'. We discuss the string group and string structures from this point of view. Also a simplicial principal bundle can be equipped with a simplicial connection and a B-field. It is shown how in the case of a simplicial principal NC-bundle these simplicial objects give the bundle gerbe connection and the bundle gerbe B-field.

Advances in Surface Plasmon Resonance Imaging allowing for quantitative measurement of laterally heterogeneous samples

NASA Astrophysics Data System (ADS)

Raegen, Adam; Reiter, Kyle; Clarke, Anthony; Lipkowski, Jacek; Dutcher, John

2012-02-01

The Surface Plasmon Resonance (SPR) phenomenon is routinely exploited to qualitatively probe changes to materials on metallic surfaces for use in probes and sensors. Unfortunately, extracting truly quantitative information is usually limited to a select few cases -- uniform absorption/desorption of small biomolecules and films, in which a continuous ``slab'' model is a good approximation. We present advancements in the SPR technique that expand the number of cases for which the technique can provide meaningful results. Use of a custom, angle-scanning SPR imaging system, together with a refined data analysis method, allow for quantitative kinetic measurements of laterally heterogeneous systems. The degradation of cellulose microfibrils and bundles of microfibrils due to the action of cellulolytic enzymes will be presented as an excellent example of the capabilities of the SPR imaging system.

Diverse Roads to Relapse: A Discriminative Cue Signaling Cocaine Availability Is More Effective in Renewing Cocaine Seeking in Goal Trackers Than Sign Trackers and Depends on Basal Forebrain Cholinergic Activity.

PubMed

Pitchers, Kyle K; Phillips, Kyra B; Jones, Jonte L; Robinson, Terry E; Sarter, Martin

2017-07-26

Stimuli associated with taking drugs are notorious instigators of relapse. There is, however, considerable variation in the motivational properties of such stimuli, both as a function of the individual and the nature of the stimulus. The behavior of some individuals (sign trackers, STs) is especially influenced by cues paired with reward delivery, perhaps because they are prone to process information via dopamine-dependent, cue-driven, incentive salience systems. Other individuals (goal trackers, GTs) are better able to incorporate higher-order contextual information, perhaps because of better executive/attentional control over behavior, which requires frontal cortical cholinergic activity. We hypothesized, therefore, that a cue that "sets the occasion" for drug taking (a discriminative stimulus, DS) would reinstate cocaine seeking more readily in GTs than STs and that this would require intact cholinergic neurotransmission. To test this, male STs and GTs were trained to self-administer cocaine using an intermittent access schedule with periods of cocaine availability and unavailability signaled by a DS + and a DS - , respectively. Thereafter, half of the rats received an immunotoxic lesion that destroyed 40-50% of basal forebrain cholinergic neurons and later, after extinction training, were tested for the ability of noncontingent presentations of the DS + to reinstate cocaine seeking behavior. The DS + was much more effective in reinstating cocaine seeking in GTs than STs and this effect was abolished by cholinergic losses despite the fact that all rats continued to orient to the DS + We conclude that vulnerability to relapse involves interactions between individual cognitive-motivational biases and the form of the drug cue encountered. SIGNIFICANCE STATEMENT The most predictable outcome of a diagnosis of addiction is a high chance for relapse. When addicts encounter cues previously associated with drug, their attention may be unduly attracted to such cues and these cues can evoke motivational states that instigate and maintain drug-seeking behavior. Although sign-tracking rats were previously demonstrated to exhibit greater relapse vulnerability to Pavlovian drug cues paired with drug delivery, here, we demonstrate that their counterparts, the goal trackers, are more vulnerable if the drug cue acts to signal drug availability and that the forebrain cholinergic system mediates such vulnerability. Given the importance of contextual cues for triggering relapse and the human cognitive-cholinergic capacity for the processing of such cues, goal trackers model essential aspects of relapse vulnerability. Copyright © 2017 the authors 0270-6474/17/377198-11$15.00/0.

Estradiol-dependent Modulation of Serotonergic Markers in Auditory Areas of a Seasonally Breeding Songbird

PubMed Central

Matragrano, Lisa L.; Sanford, Sara E.; Salvante, Katrina G.; Beaulieu, Michaël; Sockman, Keith W.; Maney, Donna L.

2011-01-01

Because no organism lives in an unchanging environment, sensory processes must remain plastic so that in any context, they emphasize the most relevant signals. As the behavioral relevance of sociosexual signals changes along with reproductive state, the perception of those signals is altered by reproductive hormones such as estradiol (E2). We showed previously that in white-throated sparrows, immediate early gene responses in the auditory pathway of females are selective for conspecific male song only when plasma E2 is elevated to breeding-typical levels. In this study, we looked for evidence that E2-dependent modulation of auditory responses is mediated by serotonergic systems. In female nonbreeding white-throated sparrows treated with E2, the density of fibers immunoreactive for serotonin transporter innervating the auditory midbrain and rostral auditory forebrain increased compared with controls. E2 treatment also increased the concentration of the serotonin metabolite 5-HIAA in the caudomedial mesopallium of the auditory forebrain. In a second experiment, females exposed to 30 min of conspecific male song had higher levels of 5-HIAA in the caudomedial nidopallium of the auditory forebrain than birds not exposed to song. Overall, we show that in this seasonal breeder, (1) serotonergic fibers innervate auditory areas; (2) the density of those fibers is higher in females with breeding-typical levels of E2 than in nonbreeding, untreated females; and (3) serotonin is released in the auditory forebrain within minutes in response to conspecific vocalizations. Our results are consistent with the hypothesis that E2 acts via serotonin systems to alter auditory processing. PMID:21942431

Basal forebrain amnesia: does the nucleus accumbens contribute to human memory?

PubMed Central

Goldenberg, G.; Schuri, U.; Gromminger, O.; Arnold, U.

1999-01-01

OBJECTIVE—To analyse amnesia caused by basal forebrain lesions.
METHODS—A single case study of a patient with amnesia after bleeding into the anterior portion of the left basal ganglia. Neuropsychological examination included tests of attention, executive function, working memory, recall, and recognition of verbal and non-verbal material, and recall from remote semantic and autobiographical memory. The patient's MRI and those of other published cases of basal forebrain amnesia were reviewed to specify which structures within the basal forebrain are crucial for amnesia.
RESULTS—Attention and executive function were largely intact. There was anterograde amnesia for verbal material which affected free recall and recognition. With both modes of testing the patient produced many false positive responses and intrusions when lists of unrelated words had been memorised. However, he confabulated neither on story recall nor in day to day memory, nor in recall from remote memory. The lesion affected mainly the nucleus accumbens, but encroached on the inferior limb of the capsula interna and the most ventral portion of the nucleus caudatus and globus pallidus, and there was evidence of some atrophy of the head of the caudate nucleus. The lesion spared the nucleus basalis Meynert, the diagnonal band, and the septum, which are the sites of cholinergic cell concentrations.
CONCLUSIONS—It seems unlikely that false positive responses were caused by insufficient strategic control of memory retrieval. This speaks against a major role of the capsular lesion which might disconnect the prefrontal cortex from the thalamus. It is proposed that the lesion of the nucleus accumbens caused amnesia.

 PMID:10406982

Mu opioid receptors in GABAergic forebrain neurons moderate motivation for heroin and palatable food

PubMed Central

Charbogne, Pauline; Gardon, Olivier; Martín-García, Elena; Keyworth, Helen L.; Matsui, Aya; Mechling, Anna E.; Bienert, Thomas; Nasseef, Taufiq; Robé, Anne; Moquin, Luc; Darcq, Emmanuel; Ben Hamida, Sami; Robledo, Patricia; Matifas, Audrey; Befort, Katia; Gavériaux-Ruff, Claire; Harsan, Laura-Adela; Von Everfeldt, Dominik; Hennig, Jurgen; Gratton, Alain; Kitchen, Ian; Bailey, Alexis; Alvarez, Veronica A.; Maldonado, Rafael; Kieffer, Brigitte L.

2016-01-01

BACKGROUND Mu opioid receptors (MORs) are central to pain control, drug reward and addictive behaviors, but underlying circuit mechanisms have been poorly explored by genetic approaches. Here we investigate the contribution of MORs expressed in GABAergic forebrain neurons to major biological effects of opiates, and also challenge the canonical disinhibition model of opiate reward. METHODS We used Dlx5/6-mediated recombination to create conditional Oprm1 mice in GABAergic forebrain neurons. We characterized the genetic deletion by histology, electrophysiology and microdialysis, probed neuronal activation by c-Fos immunohistochemistry and resting state-functional magnetic resonance imaging, and investigated main behavioral responses to opiates, including motivation to obtain heroin and palatable food. RESULTS Mutant mice showed MOR transcript deletion mainly in the striatum. In the ventral tegmental area (VTA), local MOR activity was intact, and reduced activity was only observed at the level of striatonigral afferents. Heroin-induced neuronal activation was modified at both sites, and whole-brain functional networks were altered in live animals. Morphine analgesia was not altered, neither was physical dependence to chronic morphine. In contrast, locomotor effects of heroin were abolished, and heroin-induced catalepsy was increased. Place preference to heroin was not modified, but remarkably, motivation to obtain heroin and palatable food was enhanced in operant self-administration procedures. CONCLUSIONS Our study reveals dissociable MOR functions across mesocorticolimbic networks. Thus beyond a well-established role in reward processing, operating at the level of local VTA neurons, MORs also moderate motivation for appetitive stimuli within forebrain circuits that drive motivated behaviors. PMID:28185645

Regulation of the orexigenic neuropeptide, enkephalin, by PPARδ and fatty acids in neurons of the hypothalamus and forebrain

PubMed Central

Poon, Kinning; Alam, Mohammad; Karatayev, Olga; Barson, Jessica R.; Leibowitz, Sarah F.

2015-01-01

Ingestion of a high-fat diet composed mainly of the saturated fatty acid, palmitic (PA), and the unsaturated fatty acid, oleic (OA), stimulates transcription in the brain of the opioid neuropeptide, enkephalin (ENK), which promotes intake of substances of abuse. To understand possible underlying mechanisms, this study examined the nuclear receptors, peroxisome proliferator-activated receptors (PPARs), and tested in hypothalamic and forebrain neurons from rat embryos whether PPARs regulate endogenous ENK and the fatty acids themselves affect these PPARs and ENK. The first set of experiments demonstrated that knocking down PPARδ, but not PPARα or PPARγ, increased ENK transcription, activation of PPARδ by an agonist decreased ENK levels, and PPARδ neurons coexpressed ENK, suggesting that PPARδ negatively regulates ENK. In the second set of experiments, PA treatment of hypothalamic and forebrain neurons had no effect on PPARδ protein while stimulating ENK mRNA and protein, whereas OA increased both mRNA and protein levels of PPARδ in forebrain neurons while having no effect on ENK mRNA and increasing ENK levels. These findings show that PA has a stronger, stimulatory effect on ENK and weaker effect on PPARδ protein, whereas OA has a stronger stimulatory effect on PPARδ and weaker effect on ENK, consistent with the inhibitory effect of PPARδ on ENK. They suggest a function for PPARδ, perhaps protective in nature, in embryonic neurons exposed to fatty acids from a fat-rich diet and provide evidence for a mechanism contributing to differential effects of saturated and monounsaturated fatty acids on neurochemical systems involved in consummatory behavior. PMID:26332891

Ablation of cdk4 and cdk6 affects proliferation of basal progenitor cells in the developing dorsal and ventral forebrain.

PubMed

Grison, Alice; Gaiser, Carine; Bieder, Andrea; Baranek, Constanze; Atanasoski, Suzana

2018-03-23

Little is known about the molecular players driving proliferation of neural progenitor cells (NPCs) during embryonic mouse development. Here, we demonstrate that proliferation of NPCs in the developing forebrain depends on a particular combination of cell cycle regulators. We have analyzed the requirements for members of the cyclin-dependent kinase (cdk) family using cdk-deficient mice. In the absence of either cdk4 or cdk6, which are both regulators of the G1 phase of the cell cycle, we found no significant effects on the proliferation rate of cortical progenitor cells. However, concomitant loss of cdk4 and cdk6 led to a drastic decrease in the proliferation rate of NPCs, specifically the basal progenitor cells of both the dorsal and ventral forebrain at embryonic day 13.5 (E13.5). Moreover, basal progenitors in the forebrain of Cdk4;Cdk6 double mutant mice exhibited altered cell cycle characteristics. Cdk4;cdk6 deficiency led to an increase in cell cycle length and cell cycle exit of mutant basal progenitor cells in comparison to controls. In contrast, concomitant ablation of cdk2 and cdk6 had no effect on the proliferation of NCPs. Together, our data demonstrate that the expansion of the basal progenitor pool in the developing telencephalon is dependent on the presence of distinct combinations of cdk molecules. Our results provide further evidence for differences in the regulation of proliferation between apical and basal progenitors during cortical development. © 2018 Wiley Periodicals, Inc. Develop Neurobiol, 2018. © 2018 Wiley Periodicals, Inc.

Thyroid hormone regulates the expression of the sonic hedgehog signaling pathway in the embryonic and adult Mammalian brain.

PubMed

Desouza, Lynette A; Sathanoori, Malini; Kapoor, Richa; Rajadhyaksha, Neha; Gonzalez, Luis E; Kottmann, Andreas H; Tole, Shubha; Vaidya, Vidita A

2011-05-01

Thyroid hormone is important for development and plasticity in the immature and adult mammalian brain. Several thyroid hormone-responsive genes are regulated during specific developmental time windows, with relatively few influenced across the lifespan. We provide novel evidence that thyroid hormone regulates expression of the key developmental morphogen sonic hedgehog (Shh), and its coreceptors patched (Ptc) and smoothened (Smo), in the early embryonic and adult forebrain. Maternal hypo- and hyperthyroidism bidirectionally influenced Shh mRNA in embryonic forebrain signaling centers at stages before fetal thyroid hormone synthesis. Further, Smo and Ptc expression were significantly decreased in the forebrain of embryos derived from hypothyroid dams. Adult-onset thyroid hormone perturbations also regulated expression of the Shh pathway bidirectionally, with a significant induction of Shh, Ptc, and Smo after hyperthyroidism and a decline in Smo expression in the hypothyroid brain. Short-term T₃ administration resulted in a significant induction of cortical Shh mRNA expression and also enhanced reporter gene expression in Shh(+/LacZ) mice. Further, acute T₃ treatment of cortical neuronal cultures resulted in a rapid and significant increase in Shh mRNA, suggesting direct effects. Chromatin immunoprecipitation assays performed on adult neocortex indicated enhanced histone acetylation at the Shh promoter after acute T₃ administration, providing further support that Shh is a thyroid hormone-responsive gene. Our results indicate that maternal and adult-onset perturbations of euthyroid status cause robust and region-specific changes in the Shh pathway in the embryonic and adult forebrain, implicating Shh as a possible mechanistic link for specific neurodevelopmental effects of thyroid hormone.

Developments of sulcal pattern and subcortical structures of the forebrain in cynomolgus monkey fetuses: 7-tesla magnetic resonance imaging provides high reproducibility of gross structural changes.

PubMed

Sawada, Kazuhiko; Sun, Xue-Zhi; Fukunishi, Katsuhiro; Kashima, Masatoshi; Sakata-Haga, Hiromi; Tokado, Hiroshi; Aoki, Ichio; Fukui, Yoshihiro

2009-09-01

The aim of this study was to spatio-temporally clarify gross structural changes in the forebrain of cynomolgus monkey fetuses using 7-tesla magnetic resonance imaging (MRI). T(1)-weighted coronal, horizontal, and sagittal MR slices of fixed left cerebral hemispheres were obtained from one male fetus at embryonic days (EDs) 70-150. The timetable for fetal sulcation by MRI was in good agreement with that by gross observations, with a lag time of 10-30 days. A difference in detectability of some sulci seemed to be associated with the length, depth, width, and location of the sulci. Furthermore, MRI clarified the embryonic days of the emergence of the callosal (ED 70) and circular (ED 90) sulci, which remained unpredictable under gross observations. Also made visible by the present MRI were subcortical structures of the forebrain such as the caudate nucleus, globus pallidus, putamen, major subdivisions of the thalamus, and hippocampal formation. Their adult-like features were formed by ED 100, corresponding to the onset of a signal enhancement in the gray matter, which reflects neuronal maturation. The results reveal a highly reproducible level of gross structural changes in the forebrain using a high spatial 7-tesla MRI. The present MRI study clarified some changes that are difficult to demonstrate nondestructively using only gross observations, for example, the development of cerebral sulci located on the deep portions of the cortex, as well as cortical and subcortical neuronal maturation.

Is Chronic Curcumin Supplementation Neuroprotective Against Ischemia for Antioxidant Activity, Neurological Deficit, or Neuronal Apoptosis in an Experimental Stroke Model?

PubMed

Altinay, Serdar; Cabalar, Murat; Isler, Cihan; Yildirim, Funda; Celik, Duygu S; Zengi, Oguzhan; Tas, Abdurrahim; Gulcubuk, Ahmet

2017-01-01

To investigate the neuroprotective effect of chronic curcumin supplementation on the rat forebrain prior to ischemia and reperfusion. Forebrain ischemia was induced by bilateral common carotid artery occlusion for 1/2 hour, followed by reperfusion for 72 hours. Older rats were divided into five groups: Group I received 300 mg/kg oral curcumin for 21 days before ischemia and 300 mg/kg intraperitoneal curcumin after ischemia; Group II received 300 mg/kg intraperitoneal curcumin after ischemia; Group III received 300 mg/kg oral curcumin for 21 days before ischemia; Group IV had only ischemia; Group V was the sham-operated group. The forebrain was rapidly dissected for biochemical parameter assessment and histopathological examination. In forebrain tissue, enzyme activities of superoxide dismutase, glutathione peroxidase, and catalase were significantly higher in Group I than Groups II or III (p < 0.05) while xanthine dehydrogenase and malondialdehyde enzyme activities and concentrations of interleukin-6 and TNF-alpha were significantly lower in Group I when compared to Groups II and III (p < 0.05). A significant reduction in neurological score was observed after 24 and 72 hours in the curcumin-treated groups compared with the ischemic group. We also found a marked reduction in apoptotic index after 72 hours in the groups receiving curcumin. Significantly more TUNEL-positive cells were observed in the ischemic group compared to those treated with curcumin. We demonstrated the neuroprotective effect of chronic curcumin supplement on biochemical parameters, neurological scores and apoptosis following ischemia and reperfusion injury in rats.

Transformation from a pure time delay to a mixed time and phase delay representation in the auditory forebrain pathway.

PubMed

Vonderschen, Katrin; Wagner, Hermann

2012-04-25

Birds and mammals exploit interaural time differences (ITDs) for sound localization. Subsequent to ITD detection by brainstem neurons, ITD processing continues in parallel midbrain and forebrain pathways. In the barn owl, both ITD detection and processing in the midbrain are specialized to extract ITDs independent of frequency, which amounts to a pure time delay representation. Recent results have elucidated different mechanisms of ITD detection in mammals, which lead to a representation of small ITDs in high-frequency channels and large ITDs in low-frequency channels, resembling a phase delay representation. However, the detection mechanism does not prevent a change in ITD representation at higher processing stages. Here we analyze ITD tuning across frequency channels with pure tone and noise stimuli in neurons of the barn owl's auditory arcopallium, a nucleus at the endpoint of the forebrain pathway. To extend the analysis of ITD representation across frequency bands to a large neural population, we employed Fourier analysis for the spectral decomposition of ITD curves recorded with noise stimuli. This method was validated using physiological as well as model data. We found that low frequencies convey sensitivity to large ITDs, whereas high frequencies convey sensitivity to small ITDs. Moreover, different linear phase frequency regimes in the high-frequency and low-frequency ranges suggested an independent convergence of inputs from these frequency channels. Our results are consistent with ITD being remodeled toward a phase delay representation along the forebrain pathway. This indicates that sensory representations may undergo substantial reorganization, presumably in relation to specific behavioral output.

Anatomical approach to permanent His bundle pacing: Optimizing His bundle capture.

PubMed

Vijayaraman, Pugazhendhi; Dandamudi, Gopi

2016-01-01

Permanent His bundle pacing is a physiological alternative to right ventricular pacing. In this article we describe our approach to His bundle pacing in patients with AV nodal and intra-Hisian conduction disease. It is essential for the implanters to understand the anatomic variations of the His bundle course and its effect on the type of His bundle pacing achieved. We describe several case examples to illustrate our anatomical approach to permanent His bundle pacing in this article. Copyright © 2016 Elsevier Inc. All rights reserved.

Warps, grids and curvature in triple vector bundles

NASA Astrophysics Data System (ADS)

Flari, Magdalini K.; Mackenzie, Kirill

2018-06-01

A triple vector bundle is a cube of vector bundle structures which commute in the (strict) categorical sense. A grid in a triple vector bundle is a collection of sections of each bundle structure with certain linearity properties. A grid provides two routes around each face of the triple vector bundle, and six routes from the base manifold to the total manifold; the warps measure the lack of commutativity of these routes. In this paper we first prove that the sum of the warps in a triple vector bundle is zero. The proof we give is intrinsic and, we believe, clearer than the proof using decompositions given earlier by one of us. We apply this result to the triple tangent bundle T^3M of a manifold and deduce (as earlier) the Jacobi identity. We further apply the result to the triple vector bundle T^2A for a vector bundle A using a connection in A to define a grid in T^2A . In this case the curvature emerges from the warp theorem.

Neuroregulatory and neuroendocrine GnRH pathways in the hypothalamus and forebrain of the baboon.

PubMed

Marshall, P E; Goldsmith, P C

1980-07-14

The distribution of neurons containing gonadotropin-releasing hormone (GnRH) in the baboon hypothalamus and forebrain was studied immunocytochemically by light and electron microscopy. GnRH was present in the perikarya, axonal and dendritic processes of immunoreactive neurons. Three populations of GnRH neurons could be distinguished. Most of the GnRH neurons which are assumed to directly influence the anterior pituitary were in the medial basal hypothalamus. Other cells that projected to the median eminence were found scattered throughout the hypothalamus. A second, larger population of neurons apparently was not involved with control of the anterior pituitary. These neurons were generally found within afferent and efferent pathways of the hypothalamus and forebrain, and may receive external information affecting reproduction. A few neurons projecting to the median eminence were also observed sending collaterals to other brain areas. Thus, in addition to their neuroendocrine role, these cells possibly have neuroregulatory functions. The inference is made that these bifunctional neurons, together with the widely observed GnRH-GnRH cellular interactions may help to synchronize ovulation and sexual behavior.

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

PubMed

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

2016-03-01

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

Identification of a transient Sox5 expressing progenitor population in the neonatal ventral forebrain by a novel cis-regulatory element

PubMed Central

Hao, Hailing; Li, Ying; Tzatzalos, Evangeline; Gilbert, Jordana; Zala, Dhara; Bhaumik, Mantu; Cai, Li

2014-01-01

Precise control of lineage-specific gene expression in the neural stem/progenitor cells is crucial for generation of the diversity of neuronal and glial cell types in the central nervous system (CNS). The mechanism underlying such gene regulation, however, is not fully elucidated. Here, we report that a 377 bp evolutionarily conserved DNA fragment (CR5), located approximately 32 kbp upstream of Olig2 transcription start site, acts as a cis-regulator for gene expression in the development of the neonatal forebrain. CR5 is active in a time-specific and brain region-restricted manner. CR5 activity is not detected in the embryonic stage, but it is exclusively in a subset of Sox5+ cells in the neonatal ventral forebrain. Furthermore, we show that Sox5 binding motif in CR5 is important for this cell-specific gene regulatory activity; mutation of Sox5 binding motif in CR5 alters reporter gene expression with different cellular composition. Together, our study provides new insights into the regulation of cell-specific gene expression during CNS development. PMID:24954155

Neural Crest-Derived Mesenchymal Cells Require Wnt Signaling for Their Development and Drive Invagination of the Telencephalic Midline

PubMed Central

Choe, Youngshik; Zarbalis, Konstantinos S.; Pleasure, Samuel J.

2014-01-01

Embryonic neural crest cells contribute to the development of the craniofacial mesenchyme, forebrain meninges and perivascular cells. In this study, we investigated the function of ß-catenin signaling in neural crest cells abutting the dorsal forebrain during development. In the absence of ß-catenin signaling, neural crest cells failed to expand in the interhemispheric region and produced ectopic smooth muscle cells instead of generating dermal and calvarial mesenchyme. In contrast, constitutive expression of stabilized ß-catenin in neural crest cells increased the number of mesenchymal lineage precursors suggesting that ß-catenin signaling is necessary for the expansion of neural crest-derived mesenchymal cells. Interestingly, the loss of neural crest-derived mesenchymal stem cells (MSCs) leads to failure of telencephalic midline invagination and causes ventricular system defects. This study shows that ß-catenin signaling is required for the switch of neural crest cells to MSCs and mediates the expansion of MSCs to drive the formation of mesenchymal structures of the head. Furthermore, loss of these structures causes striking defects in forebrain morphogenesis. PMID:24516524

Agmatine protection against chlorpromazine-induced forebrain cortex injury in rats

PubMed Central

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

2016-01-01

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

On the properties of a bundle of flexible actin filaments in an optical trap

NASA Astrophysics Data System (ADS)

Perilli, Alessia; Pierleoni, Carlo; Ciccotti, Giovanni; Ryckaert, Jean-Paul

2016-06-01

We establish the statistical mechanics framework for a bundle of Nf living and uncrosslinked actin filaments in a supercritical solution of free monomers pressing against a mobile wall. The filaments are anchored normally to a fixed planar surface at one of their ends and, because of their limited flexibility, they grow almost parallel to each other. Their growing ends hit a moving obstacle, depicted as a second planar wall, parallel to the previous one and subjected to a harmonic compressive force. The force constant is denoted as the trap strength while the distance between the two walls as the trap length to make contact with the experimental optical trap apparatus. For an ideal solution of reactive filaments and free monomers at fixed free monomer chemical potential μ1, we obtain the general expression for the grand potential from which we derive averages and distributions of relevant physical quantities, namely, the obstacle position, the bundle polymerization force, and the number of filaments in direct contact with the wall. The grafted living filaments are modeled as discrete Wormlike chains, with F-actin persistence length ℓp, subject to discrete contour length variations ±d (the monomer size) to model single monomer (de)polymerization steps. Rigid filaments (ℓp = ∞), either isolated or in bundles, all provide average values of the stalling force in agreement with Hill's predictions Fs H = N f k B T ln ( ρ 1 / ρ 1 c) / d , independent of the average trap length. Here ρ1 is the density of free monomers in the solution and ρ1c its critical value at which the filament does not grow nor shrink in the absence of external forces. Flexible filaments (ℓp < ∞) instead, for values of the trap strength suitable to prevent their lateral escape, provide an average bundle force and an average trap length slightly larger than the corresponding rigid cases (few percents). Still the stalling force remains nearly independent on the average trap length, but results from the product of two strongly L-dependent contributions: the fraction of touching filaments ∝ (" separators=" < L >O . T .) 2 and the single filament buckling force ∝ (" separators=" < L >O . T .) - 2 .

Decreased locomotor and investigatory exploration after denervation of catecholamine terminal fields in the forebrain of rats.

PubMed

Dubois, A B; Ogilvy, C S

1978-12-01

1. Pressures on the right and left sides of the tails of swimming bluefish were measured and found to have a range of +5.9 to -5.9 cm H2O. The pressures were resolved into their forward and lateral vectorial components of force to allow calculation of forward and lateral force and power at speeds ranging from 0.26 to 0.87 m/s. 2. The peak to peak changes in force of acceleration of the body, measured with a forward accelerometer averaged 209 g or 2.05 N at 0.48 m/s, and were compared with the maximum to minimum excursions of forward tail force averaging 201 g or 1.97 N at the same speed. The mean difference was 8 g, S.D. of the mean difference +/-29, SE. of mean difference +/-10 g. 3. Mean tail thrust was calculated as the time average of tail force in the forward direction. It averaged 65 g , or 0.64 N, at 0.48 m/s. The mean forward power was 0.34 N m/s at 0.48 m/s. The drag of the gauges and wires accounted for 10% of this figure. 4. The mean lateral power of the tail was 1.28 N m/s at a mean speed of 0.48 m/s. 5. The propulsive efficiency of the tail, calculated as the ratio of forward power to forward plus lateral power, was found to be 0.20 S.D.+/-0.04, S.E.+/-0.01 and was not related to speed. This suggests that 80% of the mechanical power of the tail was wasted. Turbulence in the water may have contributed to this large drag and low tail efficiency.

The differences of the precommissural and postcommissural fornix in the hippocampal location: a diffusion tensor tractography study.

PubMed

Jang, Sung Ho; Yeo, Sang Seok

2017-04-01

The precommissural fornix and postcommissural fornix have different connections to the basal forebrain and septal region, and mammillary body, respectively. However, little is known about the differences of the precommissural fornix and postcommissural fornix in the hippocampal location. In this study, using diffusion tensor tractography, we investigated the differences of the precommissural fornix and postcommissural fornix in the hippocampal location. We recruited 25 healthy volunteers for this study. For reconstruction of the precommissural fornix and postcommissural fornix, we placed the seed region of interest on the septal nucleus, and the mammillary body, respectively. The target regions of interest (ROI) was given on the crus of the fornix on the coronal image. Evaluations of the anatomical location of the precommissural fornix and postcommissural fornix were performed using the highest probabilistic location in the hippocampal formation. The precommissural fornix and postcommissural fornix were located at an average of 83.9 and 87.5% between the lateral margin of the red nucleus and collateral sulcus on the axial plane, and 77.2 and 81.4% between the lateral margin of the midbrain and the inferior longitudinal fasciculus on the coronal plane. Significant differences of location in the medio-lateral direction were observed in the axial and coronal plane (p < 0.05). However, no significant differences of location in the antero-posterior direction were observed between precommissrual and postcommissural fornix (p > 0.05). The reconstructed precommissural fornix and postcommissural fornix were connected to the cornu ammonis 1(CA1) of the hippocampus, and the precommissural fornix was located more laterally to the postcommissural fornix in the CA1.

Double-bundle anterior cruciate ligament reconstruction is superior to single-bundle reconstruction in terms of revision frequency: a study of 22,460 patients from the Swedish National Knee Ligament Register.

PubMed

Svantesson, Eleonor; Sundemo, David; Hamrin Senorski, Eric; Alentorn-Geli, Eduard; Musahl, Volker; Fu, Freddie H; Desai, Neel; Stålman, Anders; Samuelsson, Kristian

2017-12-01

Studies comparing single- and double-bundle anterior cruciate ligament (ACL) reconstructions often include a combined analysis of anatomic and non-anatomic techniques. The purpose of this study was to compare the revision rates between single- and double-bundle ACL reconstructions in the Swedish National Knee Ligament Register with regard to surgical variables as determined by the anatomic ACL reconstruction scoring checklist (AARSC). Patients from the Swedish National Knee Ligament Register who underwent either single- or double-bundle ACL reconstruction with hamstring tendon autograft during the period 2007-2014 were included. The follow-up period started with primary ACL reconstruction, and the outcome measure was set as revision surgery. An online questionnaire based on the items of the AARSC was used to determine the surgical technique implemented in the single-bundle procedures. These were organized into subgroups based on surgical variables, and the revision rates were compared with the double-bundle ACL reconstruction. Hazard ratios (HR) with 95% confidence interval (CI) was calculated and adjusted for confounders by Cox regression. A total of 22,460 patients were included in the study, of which 21,846 were single-bundle and 614 were double-bundle ACL reconstruction. Double-bundle ACL reconstruction had a revision frequency of 2.0% (n = 12) and single-bundle 3.2% (n = 689). Single-bundle reconstruction had an increased risk of revision surgery compared with double-bundle [adjusted HR 1.98 (95% CI 1.12-3.51), p = 0.019]. The subgroup analysis showed a significantly increased risk of revision surgery in patients undergoing single-bundle with anatomic technique using transportal drilling [adjusted HR 2.51 (95% CI 1.39-4.54), p = 0.002] compared with double-bundle ACL reconstruction. Utilizing a more complete anatomic technique according to the AARSC lowered the hazard rate considerably when transportal drilling was performed but still resulted in significantly increased risk of revision surgery compared with double-bundle ACL reconstruction [adjusted HR 1.87 (95% CI 1.04-3.38), p = 0.037]. Double-bundle ACL reconstruction is associated with a lower risk of revision surgery than single-bundle ACL reconstruction. Single-bundle procedures performed using transportal femoral drilling technique had significantly higher risk of revision surgery compared with double-bundle. However, a reference reconstruction with transportal drilling defined as a more complete anatomic reconstruction reduces the risk of revision surgery considerably. III.

Damage to cochlear efferents following AF64A intoxication.

PubMed

Smith, D W; Mount, R J

1993-07-01

Damage to cochlear efferents in chinchillas was assessed using transmission electron microscopy following unilateral treatment with the cholinotoxin ethylcholine mustard aziridinium ion (AF64A). AF64A was diluted in artificial perilymph to concentrations ranging from 0.5 to 100 microM. Survival times ranged from 1 to 12 weeks. At concentrations above 10 microM, widespread damage was noted to efferent fibers within the inner spiral bundle (ISB), tunnel spiral bundle (TSB), tunnel radial fibers (TRF) and efferent terminals at the base of OHCs. This damage included degeneration of fibers and terminals, delamination of mitochondria, vacuolization, and loss of cell membrane. However, at high concentrations, non-specific damage was also noted as thinnings or discontinuities of the membrane of OHCs and afferent fibers. At concentrations between 3 and 10 microM, selective damage was observed to efferent fibers within the ISB, TSB, TRF, and to terminals at the base of the OHCs, with all other structures appearing normal. At concentrations of 0.5 and 1 microM, damage was limited to efferent fibers within the TSB and ISB below the inner hair cells. In general, insult was greatest to middle- and basal-turn efferents, and longer survival times did not produce greater damage to, or loss of, efferents. These data suggest that at low concentrations, AF64A produces a partial yet selective degeneration of cochlear efferents within both the medial and lateral tracts, and that at the lowest concentrations used in these studies, AF64A produces a preferential insult on lateral olivocochlear efferents.

Morphology of the utricular otolith organ in the toadfish, Opsanus tau.

PubMed

Boyle, Richard; Ehsanian, Reza; Mofrad, Alireza; Popova, Yekaterina; Varelas, Joseph

2018-06-15

The utricle provides the vestibular reflex pathways with the sensory codes of inertial acceleration of self-motion and head orientation with respect to gravity to control balance and equilibrium. Here we present an anatomical description of this structure in the adult oyster toadfish and establish a morphological basis for interpretation of subsequent functional studies. Light, scanning, and transmission electron microscopy techniques were applied to visualize the sensory epithelium at varying levels of detail, its neural innervation and its synaptic organization. Scanning electron microscopy was used to visualize otolith mass and morphological polarization patterns of hair cells. Afferent nerve fibers were visualized following labeling with biocytin, and light microscope images were used to make three-dimensional (3-D) reconstructions of individual labeled afferents to identify dendritic morphology with respect to epithelial location. Transmission electron micrographs were compiled to create a serial 3-D reconstruction of a labeled afferent over a segment of its dendritic field and to examine the cell-afferent synaptic contacts. Major observations are: a well-defined striola, medial and lateral extra-striolar regions with a zonal organization of hair bundles; prominent lacinia projecting laterally; dependence of hair cell density on macular location; narrow afferent dendritic fields that follow the hair bundle polarization; synaptic specializations issued by afferents are typically directed towards a limited number of 7-13 hair cells, but larger dendritic fields in the medial extra-striola can be associated with > 20 hair cells also; and hair cell synaptic bodies can be confined to only an individual afferent or can synapse upon several afferents. © 2018 Wiley Periodicals, Inc.

Ultrastructure of Wax-Producing Structures on the Integument of the Melaleuca Psyllid Boreioglycaspis melaleucae (Hemiptera: Psyllidae), with Honeydew Excretion Behavior in Males and Females

PubMed Central

Ammar, El-Desouky; Hentz, Matthew; Hall, David G.; Shatters, Robert G.

2015-01-01

The melaleuca psyllid, Boreioglycaspis melaleucae (Hemiptera: Psyllidae), was introduced to Florida as a biological control agent against Melaleuca quinquenervia, an invasive evergreen tree that has invaded large areas of Florida Everglades. Colonies of B. melaleucae nymphs are normally covered by white waxy secretions, and nymphs of various instars produce long bundles of white waxy filaments extending laterally and posteriorly from their abdomen. Scanning electron microscopy of ‘naturally waxed’ and ‘dewaxed’ nymphs (cleaned from wax) revealed two types of wax pore plates located dorsally and laterally on the integument of posterior abdominal segments starting with the 4th segment. Type-1 wax pore plates, with raised rim, peripheral groove, slits and pits, produce long ribbons and filaments of waxy secretions that are wound together forming long wax bundles, whereas type-2 wax pore plates, with slits only, produce shorter wax curls. Additionally, in both nymphs and adult females, the circumanal ring contained ornate rows of wax pores that produce wax filaments covering their honeydew excretions. Video recordings with stereomicroscopy showed that adult females produce whitish honeydew balls, powerfully propelled away from their body, probably to get these sticky excretions away from their eggs and newly hatched nymphs. Adult males, however, produce clear droplets of honeydew immediately behind them, simply by bending the posterior end of the abdomen downward. The possible role(s) of waxy secretions by nymphs and adults of B. melaleucae in reducing contamination of their colonies with honeydew, among other possibilities, are discussed. PMID:25793934

The expression of PTEN in the development of mouse cochlear lateral wall.

PubMed

Dong, Y; Sui, L; Yamaguchi, F; Kamitori, K; Hirata, Y; Hossain, A; Noguchi, C; Katagi, A; Nishio, M; Suzuki, A; Lou, X; Tokuda, M

2014-01-31

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor gene that regulates various cell processes including proliferation, growth, synaptogenesis, neural and glioma stem/progenitor cell renewal. In addition, PTEN can regulate sensory cell proliferation and differentiation of hair bundles in the mammalian cochlea. In this study we use immunofluorescence, Western blot and reverse transcriptase-polymerase chain reaction (RT-PCR) to reveal the expression of PTEN in the developing cochlear lateral wall, which is crucial for regulating K(+) homeostasis. Relatively high levels of PTEN are initially expressed in the marginal cells (MCs) of the lateral wall at embryonic day (E) 17.5 when they start to differentiate. Similarly high levels are subsequently expressed in differentiating root cells (RCs) at postnatal day (P) 3 and then in spiral ligament fibrocytes (SLFs) at P 10. In the mature cochlea, PTEN expression is low or undetectable in MCs and SLFs but it remains high in RCs and their processes. The expression pattern for PTEN in the developing lateral wall suggests that it plays a critical role in the differentiation of the cellular pathways that regulate K(+) homeostasis in the cochlea. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

Moisture separator reheater with round tube bundle

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

Byerley, W. M.

1984-11-27

A moisture separator reheater having a central chamber with cylindrical wall protions and a generally round tube bundle, the tube bundle having arcuate plates disposed on each side of the bundle which form a wrapper on each side of the bundle and having a tongue and groove juncture between the wrapper and cylindrical wall portions to provide a seal therebetween and a track for installing and removing the tube bundle from the central chamber.

["Habitual" left branch block alternating with 2 "disguised" bracnch block].

PubMed

Lévy, S; Jullien, G; Mathieu, P; Mostefa, S; Gérard, R

1976-10-01

Two cases of alternating left bundle branch block and "masquerading block" (with left bundle branch morphology in the stnadard leads and right bundle branch block morphology in the precordial leads) were studied by serial tracings and his bundle electrocardiography. In case 1 "the masquerading" block was associated with a first degree AV block related to a prolongation of HV interval. This case is to our knowledge the first cas of alternating bundle branch block in which his bundle activity was recorded in man. In case 2, the patient had atrial fibrilation and His bundle recordings were performed while differents degrees of left bundle branch block were present: The mechanism of the alternation and the concept of "masquerading" block are discussed. It is suggested that this type of block represents a right bundle branch block associated with severe lesions of the "left system".

Characterization of active hair-bundle motility by a mechanical-load clamp

NASA Astrophysics Data System (ADS)

Salvi, Joshua D.; Maoiléidigh, Dáibhid Ó.; Fabella, Brian A.; Tobin, Mélanie; Hudspeth, A. J.

2015-12-01

Active hair-bundle motility endows hair cells with several traits that augment auditory stimuli. The activity of a hair bundle might be controlled by adjusting its mechanical properties. Indeed, the mechanical properties of bundles vary between different organisms and along the tonotopic axis of a single auditory organ. Motivated by these biological differences and a dynamical model of hair-bundle motility, we explore how adjusting the mass, drag, stiffness, and offset force applied to a bundle control its dynamics and response to external perturbations. Utilizing a mechanical-load clamp, we systematically mapped the two-dimensional state diagram of a hair bundle. The clamp system used a real-time processor to tightly control each of the virtual mechanical elements. Increasing the stiffness of a hair bundle advances its operating point from a spontaneously oscillating regime into a quiescent regime. As predicted by a dynamical model of hair-bundle mechanics, this boundary constitutes a Hopf bifurcation.

Bundled payments in orthopedic surgery.

PubMed

Bushnell, Brandon D

2015-02-01

As a result of reading this article, physicians should be able to: 1. Describe the concept of bundled payments and the potential applications of bundled payments in orthopedic surgery. 2. For specific situations, outline a clinical episode of care, determine the participants in a bundling situation, and define care protocols and pathways. 3. Recognize the importance of resource utilization management, quality outcome measurement, and combined economic-clinical value in determining the value of bundled payment arrangements. 4. Identify the implications of bundled payments for practicing orthopedists, as well as the legal issues and potential future directions of this increasingly popular alternative payment method. Bundled payments, the idea of paying a single price for a bundle of goods and services, is a financial concept familiar to most American consumers because examples appear in many industries. The idea of bundled payments has recently gained significant momentum as a financial model with the potential to decrease the significant current costs of health care. Orthopedic surgery as a field of medicine is uniquely positioned for success in an environment of bundled payments. This article reviews the history, logistics, and implications of the bundled payment model relative to orthopedic surgery. Copyright 2015, SLACK Incorporated.

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

PubMed

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

2012-06-01

Distribution of (10)B in different regions of rat normal brain was studied. Two groups were chosen as control and trial. Trial group received 2 ml of neutral boron compound. 2, 4 and 6 h after the injection brain removed, coronal sections of forebrain, midbrain and hindbrain were sandwiched between two pieces of polycarbonate. Autoradiography plots of (10)B distribution showed significant differences in three regions with the highest (10)B concentration in the forebrain during 4 h after injection. Copyright © 2012 Elsevier Ltd. All rights reserved.

Quantitative study of bundle size effect on thermal conductivity of single-walled carbon nanotubes

NASA Astrophysics Data System (ADS)

Feng, Ya; Inoue, Taiki; An, Hua; Xiang, Rong; Chiashi, Shohei; Maruyama, Shigeo

2018-05-01

Compared with isolated single-walled carbon nanotubes (SWNTs), thermal conductivity is greatly impeded in SWNT bundles; however, the measurement of the bundle size effect is difficult. In this study, the number of SWNTs in a bundle was determined based on the transferred horizontally aligned SWNTs on a suspended micro-thermometer to quantitatively study the effect of the bundle size on thermal conductivity. Increasing the bundle size significantly degraded the thermal conductivity. For isolated SWNTs, thermal conductivity was approximately 5000 ± 1000 W m-1 K-1 at room temperature, three times larger than that of the four-SWNT bundle. The logarithmical deterioration of thermal conductivity resulting from the increased bundle size can be attributed to the increased scattering rate with neighboring SWNTs based on the kinetic theory.

Spinal surgery: variations in health care costs and implications for episode-based bundled payments.

PubMed

Ugiliweneza, Beatrice; Kong, Maiying; Nosova, Kristin; Huang, Kevin T; Babu, Ranjith; Lad, Shivanand P; Boakye, Maxwell

2014-07-01

Retrospective, observational. To simulate what episodes of care in spinal surgery might look like in a bundled payment system and to evaluate the associated costs and characteristics. Episode-based payment bundling has received considerable attention as a potential method to help curb the rise in health care spending and is being investigated as a new payment model as part of the Affordable Care Act. Although earlier studies investigated bundled payments in a number of surgical settings, very few focused on spine surgery, specifically. We analyzed data from MarketScan. Patients were included in the study if they underwent cervical or lumbar spinal surgery during 2000-2009, had at least 2-year preoperative and 90-day postoperative follow-up data. Patients were grouped on the basis of their diagnosis-related group (DRG) and then tracked in simulated episodes-of-care/payment bundles that lasted for the duration of 30, 60, and 90 days after the discharge from the index-surgical hospitalization. The total cost associated with each episode-of-care duration was measured and characterized. A total of 196,918 patients met our inclusion criteria. Significant variation existed between DRGs, ranging from $11,180 (30-day bundle, DRG 491) to $107,642 (30-day bundle, DRG 456). There were significant cost variations within each individual DRG. Postdischarge care accounted for a relatively small portion of overall bundle costs (range, 4%-8% in 90-day bundles). Total bundle costs remained relatively flat as bundle-length increased (total average cost of 30-day bundle: $33,522 vs. $35,165 for 90-day bundle). Payments to hospitals accounted for the largest portion of bundle costs (76%). There exists significant variation in total health care costs for patients who undergo spinal surgery, even within a given DRG. Better characterization of impacts of a bundled payment system in spine surgery is important for understanding the costs of index procedure hospital, physician services, and postoperative care on potential future health care policy decision making. N/A.

Nurses' perceptions of a pressure ulcer prevention care bundle: a qualitative descriptive study.

PubMed

Roberts, Shelley; McInnes, Elizabeth; Wallis, Marianne; Bucknall, Tracey; Banks, Merrilyn; Chaboyer, Wendy

2016-01-01

Pressure ulcer prevention is a critical patient safety indicator for acute care hospitals. An innovative pressure ulcer prevention care bundle targeting patient participation in their care was recently tested in a cluster randomised trial in eight Australian hospitals. Understanding nurses' perspectives of such an intervention is imperative when interpreting results and translating evidence into practice. As part of a process evaluation for the main trial, this study assessed nurses' perceptions of the usefulness and impact of a pressure ulcer prevention care bundle intervention on clinical practice. This qualitative descriptive study involved semi-structured interviews with nursing staff at four Australian hospitals that were intervention sites for a cluster randomised trial testing a pressure ulcer prevention care bundle. Four to five participants were purposively sampled at each site. A trained interviewer used a semi-structured interview guide to question participants about their perceptions of the care bundle. Interviews were digitally recorded, transcribed and analysed using thematic analysis. Eighteen nurses from four hospitals participated in the study. Nurses' perceptions of the intervention are described in five themes: 1) Awareness of the pressure ulcer prevention care bundle and its similarity to current practice; 2) Improving awareness, communication and participation with the pressure ulcer prevention care bundle; 3) Appreciating the positive aspects of patient participation in care; 4) Perceived barriers to engaging patients in the pressure ulcer prevention care bundle; and 5) Partnering with nursing staff to facilitate pressure ulcer prevention care bundle implementation. Overall, nurses found the care bundle feasible and acceptable. They identified a number of benefits from the bundle, including improved communication, awareness and participation in pressure ulcer prevention care among patients and staff. However, nurses thought the care bundle was not appropriate or effective for all patients, such as those who were cognitively impaired. Perceived enablers to implementation of the bundle included facilitation through effective communication and dissemination of evidence about the care bundle; strong leadership and ability to influence staff behaviour; and simplicity of the care bundle.

MOX fuel assembly design

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

Reese, A.P.; Crowther, R.L. Jr.

1992-02-18

This patent describes improvement in a boiling water reactor core having a plurality of vertically upstanding fuel bundles; each fuel bundle containing longitudinally extending sealed rods with fissile material therein; the improvement comprises the fissile material including a mixture of uranium and recovered plutonium in rods of the fuel bundle at locations other than the corners of the fuel bundle; and, neutron absorbing material being located in rods of the fuel bundle at rod locations adjacent the corners of the fuel bundles whereby the neutron absorbing material has decreased shielding from the plutonium and maximum exposure to thermal neutrons formore » shaping the cold reactivity shutdown zone in the fuel bundle.« less

Polycation induced actin bundles.

PubMed

Muhlrad, Andras; Grintsevich, Elena E; Reisler, Emil

2011-04-01

Three polycations, polylysine, the polyamine spermine and the polycationic protein lysozyme were used to study the formation, structure, ionic strength sensitivity and dissociation of polycation-induced actin bundles. Bundles form fast, simultaneously with the polymerization of MgATP-G-actins, upon the addition of polycations to solutions of actins at low ionic strength conditions. This indicates that nuclei and/or nascent filaments bundle due to attractive, electrostatic effect of polycations and the neutralization of repulsive interactions of negative charges on actin. The attractive forces between the filaments are strong, as shown by the low (in nanomolar range) critical concentration of their bundling at low ionic strength. These bundles are sensitive to ionic strength and disassemble partially in 100 mM NaCl, but both the dissociation and ionic strength sensitivity can be countered by higher polycation concentrations. Cys374 residues of actin monomers residing on neighboring filaments in the bundles can be cross-linked by the short span (5.4Å) MTS-1 (1,1-methanedyl bismethanethiosulfonate) cross-linker, which indicates a tight packing of filaments in the bundles. The interfilament cross-links, which connect monomers located on oppositely oriented filaments, prevent disassembly of bundles at high ionic strength. Cofilin and the polysaccharide polyanion heparin disassemble lysozyme induced actin bundles more effectively than the polylysine-induced bundles. The actin-lysozyme bundles are pathologically significant as both proteins are found in the pulmonary airways of cystic fibrosis patients. Their bundles contribute to the formation of viscous mucus, which is the main cause of breathing difficulties and eventual death in this disorder. Copyright © 2011 Elsevier B.V. All rights reserved.

Protocolised approach to end-of-life care in the ICU--the ICU PALCare Pilot Project.

PubMed

Rajamani, A; Barrett, E; Weisbrodt, L; Bourne, J; Palejs, P; Gresham, R; Huang, S

2015-05-01

International literature on end-of-life care in intensive care units (ICUs) supports the use of 'protocol bundles', which is not common practice in our 18-bed adult general ICU in Sydney, New South Wales. We conducted a prospective observational study to identify problems related to end-of-life care practices and to determine whether there was a need to develop protocol bundles. Any ICU patient who had 'withdrawal' of life-sustaining treatment to facilitate a comfortable death was eligible. Exclusion criteria included organ donors, unsuitable family dynamics and lack of availability of research staff to obtain family consent. Process-of-care measures were collected using a standardised form. Satisfaction ratings were obtained using de-identified questionnaire surveys given to the healthcare staff shortly after the withdrawal of therapy and to the families 30 days later. Twenty-three patients were enrolled between June 2011 and July 2012. Survey questionnaires were given to 25 family members and 30 healthcare staff, with a high completion rate (24 family members [96%] and 28 staff [93.3%]). Problems identified included poor documentation of family meetings (39%) and symptom management. Emotional/spiritual support was not offered to families (39.1%) or ICU staff (0%). The overall level of end-of-life care was good. The overwhelming majority of families and healthcare staff were highly satisfied with the care provided. Problems identified related to communication documentation and lack of spiritual/emotional support. To address these problems, targeted measures would be more useful than the adoption of protocol bundles. Alternate models of satisfaction surveys may be needed.

The ultrastructure of mono- and holocentric plant centromeres: an immunological investigation by structured illumination microscopy and scanning electron microscopy.

PubMed

Wanner, Gerhard; Schroeder-Reiter, Elizabeth; Ma, Wei; Houben, Andreas; Schubert, Veit

2015-12-01

The spatial distribution of the three centromere-associated proteins α-tubulin, CENH3, and phosphorylated histone H2A (at threonine 120, H2AThr120ph) was analysed by indirect immunodetection at monocentric cereal chromosomes and at the holocentric chromosomes of Luzula elegans by super-resolution light microscopy and scanning electron microscopy (SEM). Using structured illumination microscopy (SIM) as the super-resolution technique on squashed specimens and SEM on uncoated isolated specimens, the three-dimensional (3D) distribution of the proteins was visualized at the centromeres. Technical aspects of 3D SEM are explained in detail. We show that CENH3 forms curved "pads" mainly around the lateral centromeric region in the primary constriction of metacentric chromosomes. H2AThr120ph is present in both the primary constriction and in the pericentromere. α-tubulin-labeled microtubule bundles attach to CENH3-containing chromatin structures, either in single bundles with a V-shaped attachment to the centromere or in split bundles to bordering pericentromeric flanks. In holocentric L. elegans chromosomes, H2AThr120ph is located predominantly in the centromeric groove of each chromatid as proven by subsequent FIB/FESEM ablation and 3D reconstruction. α-tubulin localizes to the edges of the groove. In both holocentric and monocentric chromosomes, no additional intermediate structures between microtubules and the centromere were observed. We established models of the distribution of CENH3, H2AThr120ph and the attachment sites of microtubules for metacentric and holocentric plant chromosomes.

Electrophysiologic and histologic observations of chronic atrioventricular block induced by closed-chest catheter desiccation with radiofrequency energy.

PubMed

Huang, S K; Bharati, S; Lev, M; Marcus, F I

1987-07-01

Direct-current or laser energy has been used to induce atrioventricular (AV) block, but certain complications associated with this type of energy have been reported. We have previously documented that radiofrequency (RF) energy can effectively and safely induce acute AV block in closed-chest dogs during the 4-7 days of follow-up. This study was undertaken to determine if the ablation was permanent and to define the chronic pathology and site of AV block. Complete AV block was successfully achieved in four dogs immediately after ablation with a bipolar "standard" RF output (750 kHz) delivered between the tip electrode of a standard 7F USCI catheter and an external patch electrode on the left lateral chest wall. During 2 months of follow-up, three dogs had persistent complete AV block with a stable escape rhythm; the other had persistent 2:1 AV block. Repeat His bundle recordings were performed at 2 months prior to sacrifice of the dogs. Supra-His AV block was noted in two dogs; His bundle potential could not be recorded in another two. Histologically, the damaged area was well delineated. In all animals, the AV node and, in some dogs, part of the His bundle were completely replaced by granulation tissue and/or cartilage. There was fatty infiltration and also chronic inflammatory cells around the lesions. Neither perforation, hemorrhage nor vacuolation was seen in the adjacent area. Thrombus was not present. It is concluded that RF energy can effectively achieve chronic AV block and produce well-circumscribed pathological lesions.

Development of a femoral template for computer-assisted tunnel placement in anatomical double-bundle ACL reconstruction.

PubMed

Luites, J W H; Wymenga, A B; Blankevoort, L; Kooloos, J M G; Verdonschot, N

2011-01-01

Femoral graft placement is an important factor in the success of anterior cruciate ligament (ACL) reconstruction. In addition to improving the accuracy of femoral tunnel placement, Computer Assisted Surgery (CAS) can be used to determine the anatomic location. This is achieved by using a 3D femoral template which indicates the position of the anatomical ACL center based on endoscopically measurable landmarks. This study describes the development and application of this method. The template is generated through statistical shape analysis of the ACL insertion, with respect to the anteromedial (AM) and posterolateral (PL) bundles. The ligament insertion data, together with the osteocartilage edge on the lateral notch, were mapped onto a cylinder fitted to the intercondylar notch surface (n = 33). Anatomic variation, in terms of standard variation of the positions of the ligament centers in the template, was within 2.2 mm. The resulting template was programmed in a computer-assisted navigation system for ACL replacement and its accuracy and precision were determined on 31 femora. It was found that with the navigation system the AM and PL tunnels could be positioned with an accuracy of 2.5 mm relative to the anatomic insertion centers; the precision was 2.4 mm. This system consists of a template that can easily be implemented in 3D computer navigation software. Requiring no preoperative images and planning, the system provides adequate accuracy and precision to position the entrance of the femoral tunnels for anatomical single- or double-bundle ACL reconstruction.

Hyperedge bundling: Data, source code, and precautions to modeling-accuracy bias to synchrony estimates.

PubMed

Wang, Sheng H; Lobier, Muriel; Siebenhühner, Felix; Puoliväli, Tuomas; Palva, Satu; Palva, J Matias

2018-06-01

It has not been well documented that MEG/EEG functional connectivity graphs estimated with zero-lag-free interaction metrics are severely confounded by a multitude of spurious interactions (SI), i.e., the false-positive "ghosts" of true interactions [1], [2]. These SI are caused by the multivariate linear mixing between sources, and thus they pose a severe challenge to the validity of connectivity analysis. Due to the complex nature of signal mixing and the SI problem, there is a need to intuitively demonstrate how the SI are discovered and how they can be attenuated using a novel approach that we termed hyperedge bundling. Here we provide a dataset with software with which the readers can perform simulations in order to better understand the theory and the solution to SI. We include the supplementary material of [1] that is not directly relevant to the hyperedge bundling per se but reflects important properties of the MEG source model and the functional connectivity graphs. For example, the gyri of dorsal-lateral cortices are the most accurately modeled areas; the sulci of inferior temporal, frontal and the insula have the least modeling accuracy. Importantly, we found the interaction estimates are heavily biased by the modeling accuracy between regions, which means the estimates cannot be straightforwardly interpreted as the coupling between brain regions. This raise a red flag that the conventional method of thresholding graphs by estimate values is rather suboptimal: because the measured topology of the graph reflects the geometric property of source-model instead of the cortical interactions under investigation.

Nonabelian Bundle Gerbes, Their Differential Geometry and Gauge Theory

NASA Astrophysics Data System (ADS)

Aschieri, Paolo; Cantini, Luigi; Jurčo, Branislav

2005-03-01

Bundle gerbes are a higher version of line bundles, we present nonabelian bundle gerbes as a higher version of principal bundles. Connection, curving, curvature and gauge transformations are studied both in a global coordinate independent formalism and in local coordinates. These are the gauge fields needed for the construction of Yang-Mills theories with 2-form gauge potential.

Bundled payment fails to gain a foothold In California: the experience of the IHA bundled payment demonstration.

PubMed

Ridgely, M Susan; de Vries, David; Bozic, Kevin J; Hussey, Peter S

2014-08-01

To determine whether bundled payment could be an effective payment model for California, the Integrated Healthcare Association convened a group of stakeholders (health plans, hospitals, ambulatory surgery centers, physician organizations, and vendors) to develop, through a consensus process, the methods and means of implementing bundled payment. In spite of a high level of enthusiasm and effort, the pilot did not succeed in its goal to implement bundled payment for orthopedic procedures across multiple payers and hospital-physician partners. An evaluation of the pilot documented a number of barriers, such as administrative burden, state regulatory uncertainty, and disagreements about bundle definition and assumption of risk. Ultimately, few contracts were signed, which resulted in insufficient volume to test hypotheses about the impact of bundled payment on quality and costs. Although bundled payment failed to gain a foothold in California, the evaluation provides lessons for future bundled payment initiatives. Project HOPE—The People-to-People Health Foundation, Inc.

Double-bundle ACL reconstruction can improve rotational stability.

PubMed

Yagi, Masayoshi; Kuroda, Ryosuke; Nagamune, Kouki; Yoshiya, Shinichi; Kurosaka, Masahiro

2007-01-01

Double-bundle anterior cruciate ligament (ACL) reconstruction reproduces anteromedial and posterolateral bundles, and thus has theoretical advantages over conventional single-bundle reconstruction in controlling rotational torque in vitro. However, its superiority in clinical practice has not been proven. We analyzed rotational stability with three reconstruction techniques in 60 consecutive patients who were randomly divided into three groups (double-bundle, anteromedial single-bundle, posterolateral single-bundle). In the reconstructive procedure, the hamstring tendon was harvested and used as a free tendon graft. Followup examinations were performed 1 year after surgery. Anteroposterior laxity of the knee was examined with a KT-1000 arthrometer, whereas rotatory instability, as elicited by the pivot shift test, was assessed using a new measurement system incorporating three-dimensional electromagnetic sensors. Routine clinical evaluations, including KT examination, demonstrated no differences among the three groups. However, using the new measurement system, patients with double-bundle ACL reconstruction showed better pivot shift control of complex instability than patients with anteromedial and posterolateral single-bundle reconstruction.

Transcriptional maturation of the mouse auditory forebrain.

PubMed

Hackett, Troy A; Guo, Yan; Clause, Amanda; Hackett, Nicholas J; Garbett, Krassimira; Zhang, Pan; Polley, Daniel B; Mirnics, Karoly

2015-08-14

The maturation of the brain involves the coordinated expression of thousands of genes, proteins and regulatory elements over time. In sensory pathways, gene expression profiles are modified by age and sensory experience in a manner that differs between brain regions and cell types. In the auditory system of altricial animals, neuronal activity increases markedly after the opening of the ear canals, initiating events that culminate in the maturation of auditory circuitry in the brain. This window provides a unique opportunity to study how gene expression patterns are modified by the onset of sensory experience through maturity. As a tool for capturing these features, next-generation sequencing of total RNA (RNAseq) has tremendous utility, because the entire transcriptome can be screened to index expression of any gene. To date, whole transcriptome profiles have not been generated for any central auditory structure in any species at any age. In the present study, RNAseq was used to profile two regions of the mouse auditory forebrain (A1, primary auditory cortex; MG, medial geniculate) at key stages of postnatal development (P7, P14, P21, adult) before and after the onset of hearing (~P12). Hierarchical clustering, differential expression, and functional geneset enrichment analyses (GSEA) were used to profile the expression patterns of all genes. Selected genesets related to neurotransmission, developmental plasticity, critical periods and brain structure were highlighted. An accessible repository of the entire dataset was also constructed that permits extraction and screening of all data from the global through single-gene levels. To our knowledge, this is the first whole transcriptome sequencing study of the forebrain of any mammalian sensory system. Although the data are most relevant for the auditory system, they are generally applicable to forebrain structures in the visual and somatosensory systems, as well. The main findings were: (1) Global gene expression patterns were tightly clustered by postnatal age and brain region; (2) comparing A1 and MG, the total numbers of differentially expressed genes were comparable from P7 to P21, then dropped to nearly half by adulthood; (3) comparing successive age groups, the greatest numbers of differentially expressed genes were found between P7 and P14 in both regions, followed by a steady decline in numbers with age; (4) maturational trajectories in expression levels varied at the single gene level (increasing, decreasing, static, other); (5) between regions, the profiles of single genes were often asymmetric; (6) GSEA revealed that genesets related to neural activity and plasticity were typically upregulated from P7 to adult, while those related to structure tended to be downregulated; (7) GSEA and pathways analysis of selected functional networks were not predictive of expression patterns in the auditory forebrain for all genes, reflecting regional specificity at the single gene level. Gene expression in the auditory forebrain during postnatal development is in constant flux and becomes increasingly stable with age. Maturational changes are evident at the global through single gene levels. Transcriptome profiles in A1 and MG are distinct at all ages, and differ from other brain regions. The database generated by this study provides a rich foundation for the identification of novel developmental biomarkers, functional gene pathways, and targeted studies of postnatal maturation in the auditory forebrain.

The development and general morphology of the telencephalon of actinopterygian fishes: synopsis, documentation and commentary.

PubMed

Nieuwenhuys, Rudolf

2011-01-01

The Actinopterygii or ray-finned fishes comprise, in addition to the large superorder of teleosts, four other superorders, namely the cladistians, the chondrosteans, the ginglymodes, and the halecomorphs, each with a limited number of species. The telencephalon of actinopterygian fishes differs from that in all other vertebrates in that it consists of a pair of solid lobes. Lateral ventricles surrounded by nervous tissue are entirely lacking. At the end of the nineteenth century, the theory was advanced that the unusual configuration of the forebrain in actinopterygians results from an outward bending or eversion of its lateral walls. This theory was accepted by some authors, rejected or neglected by others, and modified by some other authors. The present paper is based on the data derived from the literature, complemented by new observations on a large collection of histological material comprising specimens of all five actinopterygian superorders. The paper consists of three parts. In the first, a survey of the development of the telencephalon in actinopterygian fishes is presented. The data collected show clearly that an outward bending or eversion of the pallial parts of the solid hemispheres is the principal morphogenetic event in all five actinopterygian superorders. In all of these superorders, except for the cladistians, eversion is coupled with a marked thickening of the pallial walls. In the second part, some aspects of the general morphology of the telencephalon in mature actinopterygians are highlighted. It is pointed out that (1) the degree of eversion varies considerably among the various actinopterygian groups; (2) eversion leads to the transformation of the telencephalic roof plate into a wide membrane or tela choroidea, which is bilaterally attached to the lateral or ventrolateral aspect of the solid hemispheres; (3) the lines of attachment or taeniae of the tela choroidea form the most important landmarks in the telencephalon of actinopterygians, indicating the sites where the greatly enlarged ventricular surface of the hemispheres ends and its reduced meningeal surface begins; (4) the meningeal surface of the telencephalon shows in most actinopterygians bilaterally a longitudinally oriented sulcus externus, the depth of which is generally positively correlated with the degree of eversion; (5) a distinct lateral olfactory tract, occupying a constant topological position close to the taenia, is present in all actinopterygians studied; and (6) this tract is not homologous to the tract of the same name in the evaginated and inverted forebrains of other groups of vertebrates. In the third and final section, the concept that the structural organization of the pallium in actinopterygians can be fully explained by a simple eversion of its walls, and the various theories, according to which the eversion is complicated by extensive shifts of its constituent cell groups, are discussed and evaluated. It is concluded that there are no reasons to doubt that the pallium of actinopterygian fishes is the product of a simple and complete eversion. © The Author(s) 2010. This article is published with open access at Springerlink.com

Risk of Revision Was Not Reduced by a Double-bundle ACL Reconstruction Technique: Results From the Scandinavian Registers.

PubMed

Aga, Cathrine; Kartus, Jüri-Tomas; Lind, Martin; Lygre, Stein Håkon Låstad; Granan, Lars-Petter; Engebretsen, Lars

2017-10-01

Double-bundle anterior cruciate ligament (ACL) reconstruction has demonstrated improved biomechanical properties and moderately better objective outcomes compared with single-bundle reconstructions. This could make an impact on the rerupture rate and reduce the risk of revisions in patients undergoing double-bundle ACL reconstruction compared with patients reconstructed with a traditional single-bundle technique. The National Knee Ligament Registers in Scandinavia provide information that can be used to evaluate the revision outcome after ACL reconstructions. The purposes of the study were (1) to compare the risk of revision between double-bundle and single-bundle reconstructions, reconstructed with autologous hamstring tendon grafts; (2) to compare the risk of revision between double-bundle hamstring tendon and single-bundle bone-patellar tendon-bone autografts; and (3) to compare the hazard ratios for the same two research questions after Cox regression analysis was performed. Data collection of primary ACL reconstructions from the National Knee Ligament Registers in Denmark, Norway, and Sweden from July 1, 2005, to December 31, 2014, was retrospectively analyzed. A total of 60,775 patients were included in the study; 994 patients were reconstructed with double-bundle hamstring tendon grafts, 51,991 with single-bundle hamstring tendon grafts, and 7790 with single-bundle bone-patellar tendon-bone grafts. The double-bundle ACL-reconstructed patients were compared with the two other groups. The risk of revision for each research question was detected by the risk ratio, hazard ratio, and the corresponding 95% confidence intervals. Kaplan-Meier analysis was used to estimate survival at 1, 2, and 5 years for the three different groups. Furthermore, a Cox proportional hazard regression model was applied and the hazard ratios were adjusted for country, age, sex, meniscal or chondral injury, and utilized fixation devices on the femoral and tibial sides. There were no differences in the crude risk of revision between the patients undergoing the double-bundle technique and the two other groups. A total of 3.7% patients were revised in the double-bundle group (37 of 994 patients) versus 3.8% in the single-bundle hamstring tendon group (1952 of 51,991; risk ratio, 1.01; 95% confidence interval (CI), 0.73-1.39; p = 0.96), and 2.8% of the patients were revised in the bone-patellar tendon-bone group (219 of the 7790 bone-patellar tendon-bone patients; risk ratio, 0.76; 95% CI, 0.54-1.06; p = 0.11). Cox regression analysis with adjustment for country, age, sex, menisci or cartilage injury, and utilized fixation device on the femoral and tibial sides, did not reveal any further difference in the risk of revision between the single-bundle hamstring tendon and double-bundle hamstring tendon groups (hazard ratio, 1.18; 95% CI, 0.85-1.62; p = 0.33), but the adjusted hazard ratio showed a lower risk of revision in the single-bundle bone-patellar tendon-bone group compared with the double-bundle group (hazard ratio, 0.62; 95% CI, 0.43-0.90; p = 0.01). Comparisons of the graft revision rates reported separately for each country revealed that double-bundle hamstring tendon reconstructions in Sweden had a lower hazard ratio compared with the single-bundle hamstring tendon reconstructions (hazard ratio, 1.00 versus 1.89; 95% CI, 1.09-3.29; p = 0.02). Survival at 5 years after index surgery was 96.0% for the double-bundle group, 95.4% for the single-bundle hamstring tendon group, and 97.0% for the single-bundle bone-patellar tendon-bone group. Based on the data from all three national registers, the risk of revision was not influenced by the reconstruction technique in terms of using single- or double-bundle hamstring tendons, although national differences in survival existed. Using bone-patellar tendon-bone grafts lowered the risk of revision compared with double-bundle hamstring tendon grafts. These findings should be considered when deciding what reconstruction technique to use in ACL-deficient knees. Future studies identifying the reasons for graft rerupture in single- and double-bundle reconstructions would be of interest to understand the findings of the present study. Level III, therapeutic study.

Moderate hypothermia suppresses jugular venous superoxide anion radical, oxidative stress, early inflammation, and endothelial injury in forebrain ischemia/reperfusion rats.

PubMed

Koda, Yoichi; Tsuruta, Ryosuke; Fujita, Motoki; Miyauchi, Takashi; Kaneda, Kotaro; Todani, Masaki; Aoki, Tetsuya; Shitara, Masaki; Izumi, Tomonori; Kasaoka, Shunji; Yuasa, Makoto; Maekawa, Tsuyoshi

2010-01-22

The aim of this study was to assess the effect of moderate hypothermia (MH) on generation of jugular venous superoxide radical (O2-.), oxidative stress, early inflammation, and endothelial injury in forebrain ischemia/reperfusion (FBI/R) rats. Twenty-one Wistar rats were allocated to a control group (n=7, 37 degrees C), a pre-MH group (n=7, 32 degrees C before ischemia), and a post-MH group (n=7, 32 degrees C after reperfusion). MH was induced before induction of ischemia in the pre-MH group and just after reperfusion in the post-MH group. Forebrain ischemia was induced by occlusion of bilateral common carotid arteries with hemorrhagic hypotension for 10 min, followed by reperfusion. O(2)(-)(.) in the jugular vein was measured from the produced current using a novel O2-. sensor. The O2-. current showed a gradual increase during forebrain ischemia in the control and post-MH groups but was attenuated in the pre-MH group. Following reperfusion, the current showed a marked increase in the control group but was strongly attenuated in the pre- and post-MH groups. Concentrations of malondialdehyde, high-mobility group box 1 (HMGB1) protein, and intercellular adhesion molecule-1 (ICAM-1) in the brain and plasma 120 min after reperfusion in the pre- and post-MH groups were significantly lower than those in the control group, except for plasma HMGB1 in the post-MH group. In conclusion, MH suppressed O2-. measured in the jugular vein, oxidative stress, early inflammation, and endothelial injury in FBI/R rats. Copyright 2009 Elsevier B.V. All rights reserved.

FOREBRAIN AND HINDBRAIN DEVELOPMENT IN ZEBRAFISH IS SENSITIVE TO ETHANOL EXPOSURE INVOLVING AGRIN, FGF AND SONIC HEDGEHOG FUNCTION

PubMed Central

Zhang, Chengjin; Ojiaku, Princess; Cole, Gregory J.

2014-01-01

BACKGROUND Ethanol is a teratogen that affects numerous developmental processes in the nervous system, which includes development and survival of GABAergic and glutamatergic neurons. Possible molecular mechanisms accounting for ethanol’s effects on nervous system development include perturbed fibroblast growth factor (Fgf) and Sonic hedgehog (Shh) signaling. In zebrafish, forebrain GABAergic neuron development is dependent on Fgf19 and Shh signaling. The present study was conducted to test the hypothesis that ethanol affects GABAergic and glutamatergic neuron development by disrupting Fgf, Shh, and agrin function. METHODS Zebrafish embryos were exposed to varying concentrations of ethanol during a range of developmental stages, in the absence or presence of morpholino oligonucleotides (MOs) that disrupt agrin or Shh function. In situ hybridization was employed to analyze glutamic acid decarboxylase (GAD1) gene expression, as well as markers of glutamatergic neurons. RESULTS Acute ethanol exposure results in marked reduction in GAD1 gene expression in forebrain and hindbrain, and reduction of glutamatergic neuronal markers in hindbrain. Subthreshold ethanol exposure, combined with agrin or Shh MO treatment, produces a similar diminution in expression of markers for GABAergic and glutamatergic neurons. Consistent with the ethanol effects on Fgf and Shh pathways, Fgf19, Fgf8 or Shh mRNA overexpression rescues ethanol-induced decreases in GAD1 and atonal1a gene expression. CONCLUSIONS These studies demonstrate that GABAergic and glutamatergic neuron development in zebrafish forebrain or cerebellum is sensitive to ethanol exposure, and provides additional evidence that a signaling pathway involving agrin, Fgfs and Shh may be a critical target of ethanol exposure during zebrafish embryogenesis. PMID:23184466

Effect of ischemic preconditioning on antioxidant status in the gerbil hippocampal CA1 region after transient forebrain ischemia

PubMed Central

Park, Seung Min; Park, Chan Woo; Lee, Tae-Kyeong; Cho, Jeong Hwi; Park, Joon Ha; Lee, Jae-Chul; Chen, Bai Hui; Shin, Bich-Na; Ahn, Ji Hyeon; Tae, Hyun-Jin; Shin, Myoung Cheol; Ohk, Taek Geun; Cho, Jun Hwi; Won, Moo-Ho; Choi, Soo Young; Kim, In Hye

2016-01-01

Ischemic preconditioning (IPC) is a condition of sublethal transient global ischemia and exhibits neuroprotective effects against subsequent lethal ischemic insult. We, in this study, examined the neuroprotective effects of IPC and its effects on immunoreactive changes of antioxidant enzymes including superoxide dismutase (SOD) 1 and SOD2, catalase (CAT) and glutathione peroxidase (GPX) in the gerbil hippocampal CA1 region after transient forebrain ischemia. Pyramidal neurons of the stratum pyramidale (SP) in the hippocampal CA1 region of animals died 5 days after lethal transient ischemia without IPC (8.6% (ratio of remanent neurons) of the sham-operated group); however, IPC prevented the pyramidal neurons from subsequent lethal ischemic injury (92.3% (ratio of remanent neurons) of the sham-operated group). SOD1, SOD2, CAT and GPX immunoreactivities in the sham-operated animals were easily detected in pyramidal neurons in the stratum pyramidale (SP) of the hippocampal CA1 region, while all of these immunoreactivities were rarely detected in the stratum pyramidale at 5 days after lethal transient ischemia without IPC. Meanwhile, their immunoreactivities in the sham-operated animals with IPC were similar to (SOD1, SOD2 and CAT) or higher (GPX) than those in the sham-operated animals without IPC. Furthermore, their immunoreactivities in the stratum pyramidale of the ischemia-operated animals with IPC were steadily maintained after lethal ischemia/reperfusion. Results of western blot analysis for SOD1, SOD2, CAT and GPX were similar to immunohistochemical data. In conclusion, IPC maintained or increased the expression of antioxidant enzymes in the stratum pyramidale of the hippocampal CA1 region after subsequent lethal transient forebrain ischemia and IPC exhibited neuroprotective effects in the hippocampal CA1 region against transient forebrain ischemia. PMID:27630689

Immunization Against Specific Fragments of Neurotrophin p75 Receptor Protects Forebrain Cholinergic Neurons in the Olfactory Bulbectomized Mice

PubMed Central

Bobkova, Natalia; Vorobyov, Vasily; Medvinskaya, Natalia; Nesterova, Inna; Tatarnikova, Olga; Nekrasov, Pavel; Samokhin, Alexander; Deev, Alexander; Sengpiel, Frank; Koroev, Dmitry; Volpina, Olga

2016-01-01

Alzheimer’s disease (AD) is characterized by progressive cognitive impairment associated with marked cholinergic neuron loss and amyloid-β (Aβ) peptide accumulation in the brain. The cytotoxicity in AD is mediated, at least in part, by Aβ binding with the extracellular domain of the p75 neurotrophin receptor (p75NTR), localized predominantly in the membranes of acetylcholine-producing neurons in the basal forebrain. Hypothesizing that an open unstructured loop of p75NTR might be the effective site for Aβ binding, we have immunized both olfactory bulbectomized (OBX) and sham-operated (SO) mice (n = 82 and 49, respectively) with synthetic peptides, structurally similar to different parts of the loops, aiming to block them by specific antibodies. OBX-mice have been shown in previous studies, and confirmed in the present one, to be characterized by typical behavioral, morphological, and biochemical AD hallmarks, including cholinergic deficits in forebrain neurons. Immunization of OBX- or SO-mice with KLH conjugated fragments of p75NTR induced high titers of specific serum antibodies for each of nine chosen fragments. However, maximal protective effects on spatial memory, evaluated in a Morris water maze, and on activity of choline acetyltransferase in forebrain neurons, detected by immunoreactivity to specific antibodies, were revealed only for peptides with amino acid residue sequences of 155–164 and 167–176. We conclude that the approach based on immunological blockade of specific p75NTR sites, linked with the cytotoxicity, is a useful and effective tool for study of AD-associated mechanisms and for development of highly selective therapy of cholinergic malfunctioning in AD patients. PMID:27163825

Mu Opioid Receptors in Gamma-Aminobutyric Acidergic Forebrain Neurons Moderate Motivation for Heroin and Palatable Food.

PubMed

Charbogne, Pauline; Gardon, Olivier; Martín-García, Elena; Keyworth, Helen L; Matsui, Aya; Mechling, Anna E; Bienert, Thomas; Nasseef, Taufiq; Robé, Anne; Moquin, Luc; Darcq, Emmanuel; Ben Hamida, Sami; Robledo, Patricia; Matifas, Audrey; Befort, Katia; Gavériaux-Ruff, Claire; Harsan, Laura-Adela; von Elverfeldt, Dominik; Hennig, Jurgen; Gratton, Alain; Kitchen, Ian; Bailey, Alexis; Alvarez, Veronica A; Maldonado, Rafael; Kieffer, Brigitte L

2017-05-01

Mu opioid receptors (MORs) are central to pain control, drug reward, and addictive behaviors, but underlying circuit mechanisms have been poorly explored by genetic approaches. Here we investigate the contribution of MORs expressed in gamma-aminobutyric acidergic forebrain neurons to major biological effects of opiates, and also challenge the canonical disinhibition model of opiate reward. We used Dlx5/6-mediated recombination to create conditional Oprm1 mice in gamma-aminobutyric acidergic forebrain neurons. We characterized the genetic deletion by histology, electrophysiology, and microdialysis; probed neuronal activation by c-Fos immunohistochemistry and resting-state functional magnetic resonance imaging; and investigated main behavioral responses to opiates, including motivation to obtain heroin and palatable food. Mutant mice showed MOR transcript deletion mainly in the striatum. In the ventral tegmental area, local MOR activity was intact, and reduced activity was only observed at the level of striatonigral afferents. Heroin-induced neuronal activation was modified at both sites, and whole-brain functional networks were altered in live animals. Morphine analgesia was not altered, and neither was physical dependence to chronic morphine. In contrast, locomotor effects of heroin were abolished, and heroin-induced catalepsy was increased. Place preference to heroin was not modified, but remarkably, motivation to obtain heroin and palatable food was enhanced in operant self-administration procedures. Our study reveals dissociable MOR functions across mesocorticolimbic networks. Thus, beyond a well-established role in reward processing, operating at the level of local ventral tegmental area neurons, MORs also moderate motivation for appetitive stimuli within forebrain circuits that drive motivated behaviors. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Thyroid Hormone Regulates the Expression of the Sonic Hedgehog Signaling Pathway in the Embryonic and Adult Mammalian Brain

PubMed Central

Desouza, Lynette A.; Sathanoori, Malini; Kapoor, Richa; Rajadhyaksha, Neha; Gonzalez, Luis E.; Kottmann, Andreas H.; Tole, Shubha

2011-01-01

Thyroid hormone is important for development and plasticity in the immature and adult mammalian brain. Several thyroid hormone-responsive genes are regulated during specific developmental time windows, with relatively few influenced across the lifespan. We provide novel evidence that thyroid hormone regulates expression of the key developmental morphogen sonic hedgehog (Shh), and its coreceptors patched (Ptc) and smoothened (Smo), in the early embryonic and adult forebrain. Maternal hypo- and hyperthyroidism bidirectionally influenced Shh mRNA in embryonic forebrain signaling centers at stages before fetal thyroid hormone synthesis. Further, Smo and Ptc expression were significantly decreased in the forebrain of embryos derived from hypothyroid dams. Adult-onset thyroid hormone perturbations also regulated expression of the Shh pathway bidirectionally, with a significant induction of Shh, Ptc, and Smo after hyperthyroidism and a decline in Smo expression in the hypothyroid brain. Short-term T3 administration resulted in a significant induction of cortical Shh mRNA expression and also enhanced reporter gene expression in Shh+/LacZ mice. Further, acute T3 treatment of cortical neuronal cultures resulted in a rapid and significant increase in Shh mRNA, suggesting direct effects. Chromatin immunoprecipitation assays performed on adult neocortex indicated enhanced histone acetylation at the Shh promoter after acute T3 administration, providing further support that Shh is a thyroid hormone-responsive gene. Our results indicate that maternal and adult-onset perturbations of euthyroid status cause robust and region-specific changes in the Shh pathway in the embryonic and adult forebrain, implicating Shh as a possible mechanistic link for specific neurodevelopmental effects of thyroid hormone. PMID:21363934

Anandamide enhances extracellular levels of adenosine and induces sleep: an in vivo microdialysis study.

PubMed

Murillo-Rodriguez, Eric; Blanco-Centurion, Carlos; Sanchez, Cristina; Piomelli, Daniele; Shiromani, Priyattam J

2003-12-15

The principal component of marijuana, delta-9-tetrahydrocannabinol increases sleep in humans. Endogenous cannabinoids, such as N-arachidonoylethanolamine (anandamide), also increase sleep. However, the mechanism by which these molecules promote sleep is not known but might involve a sleep-inducing molecule such as adenosine. Microdialysis samples were collected from the basal forebrain in order to detect levels of adenosine before and after injection of anandamide. Rats were implanted for sleep studies, and a cannula was placed in the basal forebrain to collect microdialysis samples. Samples were analyzed using high-performance liquid chromatography. Basic neuroscience research laboratory. Three-month-old male F344 rats. At the start of the lights-on period, animals received systemic injections of dimethyl sulfoxide (vehicle), anandamide, SR141716A (cannabinoid receptor 1 [CB1] antagonist), or SR141716A and anandamide. One hour after injections, microdialysis samples were collected (5 microL) from the basal forebrain every hour over a 20-minute period for 5 hours. The samples were immediately analyzed via high-performance liquid chromatography for adenosine levels. Sleep was also recorded continuously over the same period. Anandamide increased adenosine levels compared to vehicle controls with the peak levels being reached during the third hour after drug injection. There was a significant increase in slow-wave sleep during the third hour. The induction in sleep and the rise in adenosine were blocked by the CB1-receptor antagonist, SR141716A. Anandamide increased adenosine levels in the basal forebrain and also increased sleep. The soporific effects of anandamide were mediated by the CB1 receptor, since the effects were blocked by the CB1-receptor antagonist. These findings identify a potential therapeutic use of endocannabinoids to induce sleep in conditions where sleep may be severely attenuated.

Effects of acute and chronic stress on telencephalic neurochemistry and gene expression in rainbow trout (Oncorhynchus mykiss).

PubMed

Moltesen, Maria; Laursen, Danielle Caroline; Thörnqvist, Per-Ove; Andersson, Madelene Åberg; Winberg, Svante; Höglund, Erik

2016-12-15

By filtering relevant sensory inputs and initiating stress responses, the brain is an essential organ in stress coping and adaptation. However, exposure to chronic or repeated stress can lead to allostatic overload, where neuroendocrinal and behavioral reactions to stress become maladaptive. This work examines forebrain mechanisms involved in allostatic processes in teleost fishes. Plasma cortisol, forebrain serotonergic (5-HTergic) neurochemistry, and mRNA levels of corticotropin-releasing factor (CRF), CRF-binding protein (CRF-BP), CRF receptors (CRFR1 and CRFR2), mineralocorticoid receptor (MR), glucocorticoid receptors (GR1 and GR2) and serotonin type 1A (5-HT 1A ) receptors (5-HT 1Aα and 5-HT 1Aβ ) were investigated at 1 h before and 0, 1 and 4 h after acute stress, in two groups of rainbow trout held in densities of 25 and 140 kg m -3 for 28 days. Generally, being held at 140 kg m -3 resulted in a less pronounced cortisol response. This effect was also reflected in lower forebrain 5-HTergic turnover, but not in mRNA levels in any of the investigated genes. This lends further support to reports that allostatic load causes fish to be incapable of mounting a proper cortisol response to an acute stressor, and suggests that changes in forebrain 5-HT metabolism are involved in allostatic processes in fish. Independent of rearing densities, mRNA levels of 5-HT 1Aα and MR were downregulated 4 h post-stress compared with values 1 h post-stress, suggesting that these receptors are under feedback control and take part in the downregulation of the hypothalamic-pituitary-interrenal (HPI) axis after exposure to an acute stressor. © 2016. Published by The Company of Biologists Ltd.

Deficits in Docosahexaenoic Acid Accrual during Adolescence Reduce Rat Forebrain White Matter Microstructural Integrity: An in vivo Diffusion Tensor Imaging Study.

PubMed

McNamara, Robert K; Schurdak, Jennifer D; Asch, Ruth H; Peters, Bart D; Lindquist, Diana M

2018-01-01

Neuropsychiatric disorders that frequently initially emerge during adolescence are associated with deficits in the omega-3 (n-3) fatty acid docosahexaenoic acid (DHA), elevated proinflammatory signaling, and regional reductions in white matter integrity (WMI). This study determined the effects of altering brain DHA accrual during adolescence on WMI in the rat brain by diffusion tensor imaging (DTI), and investigated the potential mediating role of proinflammatory signaling. During periadolescent development, male rats were fed a diet deficient in n-3 fatty acids (DEF, n = 20), a fish oil-fortified diet containing preformed DHA (FO, n = 20), or a control diet (CON, n = 20). In adulthood, DTI scans were performed and brain WMI was determined using voxelwise tract-based spatial statistics (TBSS). Postmortem fatty acid composition, peripheral (plasma IL-1β, IL-6, and C-reactive protein [CRP]) and central (IL-1β and CD11b mRNA) proinflammatory markers, and myelin basic protein (MBP) mRNA expression were determined. Compared with CON rats, forebrain DHA levels were lower in DEF rats and higher in FO rats. Compared with CON rats, DEF rats exhibited greater radial diffusivity (RD) and mean diffusivity in the right external capsule, and greater axial diffusivity in the corpus callosum genu and left external capsule. DEF rats also exhibited greater RD than FO rats in the right external capsule. Forebrain MBP expression did not differ between groups. Compared with CON rats, central (IL-1β and CD11b) and peripheral (IL-1β and IL-6) proinflammatory markers were not different in DEF rats, and DEF rats exhibited lower CRP levels. These findings demonstrate that deficits in adolescent DHA accrual negatively impact forebrain WMI, independently of elevated proinflammatory signaling. © 2017 S. Karger AG, Basel.

SN56 neuronal cell death after 24 h and 14 days chlorpyrifos exposure through glutamate transmission dysfunction, increase of GSK-3β enzyme, β-amyloid and tau protein levels.

PubMed

Moyano, Paula; Frejo, María Teresa; Anadon, María José; García, José Manuel; Díaz, María Jesús; Lobo, Margarita; Sola, Emma; García, Jimena; Del Pino, Javier

2018-06-01

Chlorpyrifos (CPF) is an organophosphate insecticide described to induce cognitive disorders, both after acute and repeated administration. However, the mechanisms through which it induces these effects are unknown. CPF has been reported to produce basal forebrain cholinergic neuronal cell death, involved on learning and memory regulation, which could be the cause of such cognitive disorders. Neuronal cell death was partially mediated by oxidative stress generation, P75 NTR and α 7 -nAChRs gene expression alteration triggered through acetylcholinesterase (AChE) variants disruption, suggesting other mechanisms are involved. In this regard, CPF induces Aβ and tau proteins production and activation of GSK3β enzyme and alters glutamatergic transmission, which have been related with basal forebrain cholinergic neuronal cell death and development of cognitive disorders. According to these data, we hypothesized that CPF induces basal forebrain cholinergic neuronal cell death through induction of Aβ and tau proteins production, activation of GSK-3β enzyme and disruption of glutamatergic transmission. We evaluated this hypothesis in septal SN56 basal forebrain cholinergic neurons, after 24 h and 14 days CPF exposure. This study shows that CPF increases glutamate levels, upregulates GSK-3β gene expression, and increases the production of Aβ and phosphorylated tau proteins and all these effects reduced cell viability. CPF increases glutaminase activity and upregulates the VGLUT1 gene expression, which could mediate the disruption of glutamatergic transmission. Our present results provide new understanding of the mechanisms contributing to the harmful effects of CPF, and its possible relevance in the pathogenesis of neurodegenerative diseases. Copyright © 2018 Elsevier B.V. All rights reserved.

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

PubMed

MacDonald, Ryan B; Debiais-Thibaud, Mélanie; Martin, Kyle; Poitras, Luc; Tay, Boon-Hui; Venkatesh, Byrappa; Ekker, Marc

2010-05-26

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

FUEL ELEMENT INTERLOCKING ARRANGEMENT

DOEpatents

Fortescue, P.; Nicoll, D.

1963-01-01

This patent relates to a system for mutually interlocking a multiplicity of elongated, parallel, coextensive, upright reactor fuel elements so as to render a laterally selfsupporting bundle, while admitting of concurrent, selective, vertical withdrawal of a sizeable number of elements without any of the remaining elements toppling, Each element is provided with a generally rectangular end cap. When a rank of caps is aligned in square contact, each free edge centrally defines an outwardly profecting dovetail, and extremitally cooperates with its adjacent cap by defining a juxtaposed half of a dovetail- receptive mortise. Successive ranks are staggered to afford mating of their dovetails and mortises. (AEC)

Anomalous cosmic ray interaction events for investigations in the SSC and Space Station era - 'Long lived she-devil phenomena'

NASA Technical Reports Server (NTRS)

Takahashi, Y.

1985-01-01

Observational data on anomalous cosmic-ray interaction events are compiled, classified, and briefly characterized. The events are divided into three groups: those confirmed by later observation or experiment, those shown to be the result of observational or analytical error, and those still unexplained. Among the phenomena in the latter group are magnetic-monopole candidates, fractionally charged particles, massive stable particles, anomalons, proton-decay and neutron-oscillation candidates, muon bundles, narrow showers, anomalous photons, fanlike phenomena, quark-gluon-plasma candidates, and anomalous long-range delta rays.

Short Lingual Osteotomy Using a Piezosurgery Ultrasonic Bone-Cutting Device During Sagittal Split Ramus Osteotomy.

PubMed

Kawase-Koga, Yoko; Mori, Yoshiyuki; Kanno, Yuki; Hoshi, Kazuto; Takato, Tsuyoshi

2015-10-01

Short lingual osteotomy is a useful method for the performance of sagittal split ramus osteotomy involving interference between the proximal and distal bone fragments when lateral differences exist in the setback distance. However, this procedure occasionally results in abnormal fracture and nerve injury; expert surgical skill is thus required. We herein describe a novel technique involving the use of an ultrasonic bone-cutting device (Piezosurgery; Mectron Medical Technology, Carasco, Italy) for vertical osteotomy posterior to the mandibular foramen. Successful short lingual osteotomy was performed using this technique with avoidance of abnormal fracture and neurovascular bundle damage.

Hyaluronic acid is increased in the skin and urine in patients with amyotrophic lateral sclerosis

NASA Technical Reports Server (NTRS)

Ono, S.; Imai, T.; Yamauchi, M.; Nagao, K.

1996-01-01

We performed morphological studies of skin and measured glycosaminoglycans in the urine from patients with sporadic amyotrophic lateral sclerosis (ALS) and control subjects. The wide spaces separating collagen bundles reacted strongly with alcian blue stain in ALS patients and stained more markedly as ALS progressed. Staining with alcian blue was virtually eliminated by Streptomyces hyaluronidase. The urinary excretion of hyaluronic acid (HA) (mg/day) was significantly increased (P < 0.01) in ALS patients compared with that of control subjects, and there was a significant positive correlation between the excreted amount of HA and the duration of illness in advanced ALS patients with a duration of more than 2 years from clinical onset (r = 0.72, P < 0.02). We suggest that sporadic ALS includes a metabolic disorder of HA in which an accumulation of HA in the skin is linked to an increased urinary excretion of HA.

Heat Transfer Analysis in Wire Bundles for Aerospace Vehicles

NASA Technical Reports Server (NTRS)

Rickman, S. L.; Iamello, C. J.

2016-01-01

Design of wiring for aerospace vehicles relies on an understanding of "ampacity" which refers to the current carrying capacity of wires, either, individually or in wire bundles. Designers rely on standards to derate allowable current flow to prevent exceedance of wire temperature limits due to resistive heat dissipation within the wires or wire bundles. These standards often add considerable margin and are based on empirical data. Commercial providers are taking an aggressive approach to wire sizing which challenges the conventional wisdom of the established standards. Thermal modelling of wire bundles may offer significant mass reduction in a system if the technique can be generalized to produce reliable temperature predictions for arbitrary bundle configurations. Thermal analysis has been applied to the problem of wire bundles wherein any or all of the wires within the bundle may carry current. Wire bundles present analytical challenges because the heat transfer path from conductors internal to the bundle is tortuous, relying on internal radiation and thermal interface conductance to move the heat from within the bundle to the external jacket where it can be carried away by convective and radiative heat transfer. The problem is further complicated by the dependence of wire electrical resistivity on temperature. Reduced heat transfer out of the bundle leads to higher conductor temperatures and, hence, increased resistive heat dissipation. Development of a generalized wire bundle thermal model is presented and compared with test data. The steady state heat balance for a single wire is derived and extended to the bundle configuration. The generalized model includes the effects of temperature varying resistance, internal radiation and thermal interface conductance, external radiation and temperature varying convective relief from the free surface. The sensitivity of the response to uncertainties in key model parameters is explored using Monte Carlo analysis.

78 FR 76987 - Adjustment of Determination of Compulsory License Rates for Mechanical and Digital Phonorecords

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-20

... service bundles, music bundles, paid locker services, and purchased content locker services. The technical... downloads, limited offerings, mixed service bundles, music bundles, paid locker services, and purchased...

Cost-Effectiveness of a Central Venous Catheter Care Bundle

PubMed Central

Halton, Kate A.; Cook, David; Paterson, David L.; Safdar, Nasia; Graves, Nicholas

2010-01-01

Background A bundled approach to central venous catheter care is currently being promoted as an effective way of preventing catheter-related bloodstream infection (CR-BSI). Consumables used in the bundled approach are relatively inexpensive which may lead to the conclusion that the bundle is cost-effective. However, this fails to consider the nontrivial costs of the monitoring and education activities required to implement the bundle, or that alternative strategies are available to prevent CR-BSI. We evaluated the cost-effectiveness of a bundle to prevent CR-BSI in Australian intensive care patients. Methods and Findings A Markov decision model was used to evaluate the cost-effectiveness of the bundle relative to remaining with current practice (a non-bundled approach to catheter care and uncoated catheters), or use of antimicrobial catheters. We assumed the bundle reduced relative risk of CR-BSI to 0.34. Given uncertainty about the cost of the bundle, threshold analyses were used to determine the maximum cost at which the bundle remained cost-effective relative to the other approaches to infection control. Sensitivity analyses explored how this threshold alters under different assumptions about the economic value placed on bed-days and health benefits gained by preventing infection. If clinicians are prepared to use antimicrobial catheters, the bundle is cost-effective if national 18-month implementation costs are below $1.1 million. If antimicrobial catheters are not an option the bundle must cost less than $4.3 million. If decision makers are only interested in obtaining cash-savings for the unit, and place no economic value on either the bed-days or the health benefits gained through preventing infection, these cost thresholds are reduced by two-thirds. Conclusions A catheter care bundle has the potential to be cost-effective in the Australian intensive care setting. Rather than anticipating cash-savings from this intervention, decision makers must be prepared to invest resources in infection control to see efficiency improvements. PMID:20862246

Cost-effectiveness of a central venous catheter care bundle.

PubMed

Halton, Kate A; Cook, David; Paterson, David L; Safdar, Nasia; Graves, Nicholas

2010-09-17

A bundled approach to central venous catheter care is currently being promoted as an effective way of preventing catheter-related bloodstream infection (CR-BSI). Consumables used in the bundled approach are relatively inexpensive which may lead to the conclusion that the bundle is cost-effective. However, this fails to consider the nontrivial costs of the monitoring and education activities required to implement the bundle, or that alternative strategies are available to prevent CR-BSI. We evaluated the cost-effectiveness of a bundle to prevent CR-BSI in Australian intensive care patients. A Markov decision model was used to evaluate the cost-effectiveness of the bundle relative to remaining with current practice (a non-bundled approach to catheter care and uncoated catheters), or use of antimicrobial catheters. We assumed the bundle reduced relative risk of CR-BSI to 0.34. Given uncertainty about the cost of the bundle, threshold analyses were used to determine the maximum cost at which the bundle remained cost-effective relative to the other approaches to infection control. Sensitivity analyses explored how this threshold alters under different assumptions about the economic value placed on bed-days and health benefits gained by preventing infection. If clinicians are prepared to use antimicrobial catheters, the bundle is cost-effective if national 18-month implementation costs are below $1.1 million. If antimicrobial catheters are not an option the bundle must cost less than $4.3 million. If decision makers are only interested in obtaining cash-savings for the unit, and place no economic value on either the bed-days or the health benefits gained through preventing infection, these cost thresholds are reduced by two-thirds. A catheter care bundle has the potential to be cost-effective in the Australian intensive care setting. Rather than anticipating cash-savings from this intervention, decision makers must be prepared to invest resources in infection control to see efficiency improvements.

Adhering to a national surgical care bundle reduces the risk of surgical site infections

PubMed Central

Hopmans, Titia E. M.; Soetens, Loes C.; Wille, Jan C.; Geerlings, Suzanne E.; Vos, Margreet C.; van Benthem, Birgit H. B.; de Greeff, Sabine C.

2017-01-01

Background In 2008, a bundle of care to prevent Surgical Site Infections (SSIs) was introduced in the Netherlands. The bundle consisted of four elements: antibiotic prophylaxis according to local guidelines, no hair removal, normothermia and ‘hygiene discipline’ in the operating room (i.e. number of door movements). Dutch hospitals were advised to implement the bundle and to measure the outcome. This study’s goal was to assess how effective the bundle was in reducing SSI risk. Methods Hospitals assessed whether their staff complied with each of the bundle elements and voluntary reported compliance data to the national SSI surveillance network (PREZIES). From PREZIES data, we selected data from 2009 to 2014 relating to 13 types of surgical procedures. We excluded surgeries with missing (non)compliance data, and calculated for each remaining surgery with reported (non)compliance data the level of compliance with the bundle (that is, being compliant with 0, 1, 2, 3, or 4 of the elements). Subsequently, we used this level of compliance to assess the effect of bundle compliance on the SSI risk, using multilevel logistic regression techniques. Results 217 489 surgeries were included, of which 62 486 surgeries (29%) had complete bundle reporting. Within this group, the SSI risk was significantly lower for surgeries with complete bundle compliance compared to surgeries with lower compliance levels. Odds ratios ranged from 0.63 to 0.86 (risk reduction of 14% to 37%), while a 13% risk reduction was demonstrated for each point increase in compliance-level. Sensitivity analysis indicated that due to analysing reported bundles only, we probably underestimated the total effect of implementing the bundle. Conclusions This study demonstrated that adhering to a surgical care bundle significantly reduced the risk of SSIs. Reporting of and compliance with the bundle compliance can, however, still be improved. Therefore an even greater effect might be achieved. PMID:28877223

Neuroprotection by safinamide in the 6-hydroxydopamine model of Parkinson's disease.

PubMed

Sadeghian, Mona; Mullali, Gizem; Pocock, Jennifer M; Piers, Thomas; Roach, Arthur; Smith, Kenneth J

2016-08-01

Current therapies in Parkinson's disease mainly treat symptoms rather than provide effective neuroprotection. We examined the effects of safinamide (monoamine oxidase B and sodium channel blocker) on microglial activation and the degeneration of dopaminergic neurons in a rat model of PD in vivo, and on microglia in vitro. Rats received unilateral stereotaxic injection of 6-hydroxydopamine into the medial forebrain bundle on day 0: The contralateral side served as control. Safinamide or vehicle was delivered from days 0 or 1, for 7 days, via sub-cutaneous mini-pumps. In vehicle-treated rats 6-hydroxydopamine caused a significant increase in the number of activated MHC-II(+) microglia compared with the contralateral side, and only 50% of the dopaminergic neurons survived in the ipsilateral SNc. In contrast, rats treated daily with safinamide 50 and 150 mg/ml (on day 0 or 1) exhibited a significantly reduced number of activated microglia (55% reduction at 150 mg/ml) and a significant protection of dopaminergic neurons (80% of neurons survived) (P < 0.001) compared with vehicle-treated controls. Rasagiline, a monoamine oxidase B inhibitor, and lamotrigine, a sodium channel blocking drug, also protected dopaminergic neurons, indicating that safinamide may act by either or both mechanisms. Safinamide also reduced the activation of microglial cells in response to lipopolysaccharide exposure in vitro. Safinamide therapy suppresses microglial activation and protects dopaminergic neurons from degeneration in the 6-hydroxydopamine model of PD, suggesting that the drug not only treats symptoms but also provides neuroprotection. © 2015 British Neuropathological Society.

What can rodent models tell us about apathy and associated neuropsychiatric symptoms in Parkinson's disease?

PubMed Central

Magnard, R; Vachez, Y; Carcenac, C; Krack, P; David, O; Savasta, M; Boulet, S; Carnicella, S

2016-01-01

In addition to classical motor symptoms, Parkinson's disease (PD) patients display incapacitating neuropsychiatric manifestations, such as apathy, anhedonia, depression and anxiety. These hitherto generally neglected non-motor symptoms, have gained increasing interest in medical and scientific communities over the last decade because of the extent of their negative impact on PD patients' quality of life. Although recent clinical and functional imaging studies have provided useful information, the pathophysiology of apathy and associated affective impairments remains elusive. Our aim in this review is to summarize and discuss recent advances in the development of rodent models of PD-related neuropsychiatric symptoms using neurotoxin lesion-based approaches. The data collected suggest that bilateral and partial lesions of the nigrostriatal system aimed at inducing reliable neuropsychiatric-like deficits while avoiding severe motor impairments that may interfere with behavioral evaluation, is a more selective and efficient strategy than medial forebrain bundle lesions. Moreover, of all the different classes of pharmacological agents, D2/D3 receptor agonists such as pramipexole appear to be the most efficient treatment for the wide range of behavioral deficits induced by dopaminergic lesions. Lesion-based rodent models, therefore, appear to be relevant tools for studying the pathophysiology of the non-motor symptoms of PD. Data accumulated so far confirm the causative role of dopaminergic depletion, especially in the nigrostriatal system, in the development of behavioral impairments related to apathy, depression and anxiety. They also put forward D2/D3 receptors as potential targets for the treatment of such neuropsychiatric symptoms in PD. PMID:26954980

Platelet-derived growth factor-BB has neurorestorative effects and modulates the pericyte response in a partial 6-hydroxydopamine lesion mouse model of Parkinson's disease.

PubMed

Padel, Thomas; Özen, Ilknur; Boix, Jordi; Barbariga, Marco; Gaceb, Abderahim; Roth, Michaela; Paul, Gesine

2016-10-01

Parkinson's disease (PD) is a neurodegenerative disease where the degeneration of the nigrostriatal pathway leads to specific motor deficits. There is an unmet medical need for regenerative treatments that stop or reverse disease progression. Several growth factors have been investigated in clinical trials to restore the dopaminergic nigrostriatal pathway damaged in PD. Platelet-derived growth factor-BB (PDGF-BB), a molecule that recruits pericytes to stabilize microvessels, was recently investigated in a phase-1 clinical trial, showing a dose-dependent increase in dopamine transporter binding in the putamen of PD patients. Interestingly, evidence is accumulating that PD is paralleled by microvascular changes, however, whether PDGF-BB modifies pericytes in PD is not known. Using a pericyte reporter mouse strain, we investigate the functional and restorative effect of PDGF-BB in a partial 6-hydroxydopamine medial forebrain bundle lesion mouse model of PD, and whether this restorative effect is accompanied by changes in pericyte features. We demonstrate that a 2-week treatment with PDGF-BB leads to behavioural recovery using several behavioural tests, and partially restores the nigrostriatal pathway. Interestingly, we find that pericytes are activated in the striatum of PD lesioned mice and that these changes are reversed by PDGF-BB treatment. The modulation of brain pericytes may contribute to the PDGF-BB-induced neurorestorative effects, PDGF-BB allowing for vascular stabilization in PD. Pericytes might be a new cell target of interest for future regenerative therapies. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Quantitative structure-activity relationship analysis of the pharmacology of para-substituted methcathinone analogues.

PubMed

Bonano, J S; Banks, M L; Kolanos, R; Sakloth, F; Barnier, M L; Glennon, R A; Cozzi, N V; Partilla, J S; Baumann, M H; Negus, S S

2015-05-01

Methcathinone (MCAT) is a potent monoamine releaser and parent compound to emerging drugs of abuse including mephedrone (4-CH3 MCAT), the para-methyl analogue of MCAT. This study examined quantitative structure-activity relationships (QSAR) for MCAT and six para-substituted MCAT analogues on (a) in vitro potency to promote monoamine release via dopamine and serotonin transporters (DAT and SERT, respectively), and (b) in vivo modulation of intracranial self-stimulation (ICSS), a behavioural procedure used to evaluate abuse potential. Neurochemical and behavioural effects were correlated with steric (Es ), electronic (σp ) and lipophilic (πp ) parameters of the para substituents. For neurochemical studies, drug effects on monoamine release through DAT and SERT were evaluated in rat brain synaptosomes. For behavioural studies, drug effects were tested in male Sprague-Dawley rats implanted with electrodes targeting the medial forebrain bundle and trained to lever-press for electrical brain stimulation. MCAT and all six para-substituted analogues increased monoamine release via DAT and SERT and dose- and time-dependently modulated ICSS. In vitro selectivity for DAT versus SERT correlated with in vivo efficacy to produce abuse-related ICSS facilitation. In addition, the Es values of the para substituents correlated with both selectivity for DAT versus SERT and magnitude of ICSS facilitation. Selectivity for DAT versus SERT in vitro is a key determinant of abuse-related ICSS facilitation by these MCAT analogues, and steric aspects of the para substituent of the MCAT scaffold (indicated by Es ) are key determinants of this selectivity. © 2014 The British Pharmacological Society.

Exercise-induced rescue of tongue function without striatal dopamine sparing in a rat neurotoxin model of Parkinson disease.

PubMed

Ciucci, Michelle R; Schaser, Allison J; Russell, John A

2013-09-01

Unilateral lesions to the medial forebrain bundle with 6-hydroxydopamine (6-OHDA) lead to force and timing deficits during a complex licking task. We hypothesized that training targeting tongue force generation during licking would improve timing and force measures and also lead to striatal dopamine sparing. Nine month-old male Fisher344/Brown Norway rats were used in this experiment. Sixteen rats were in the control condition and received tongue exercise (n=8) or no exercise (n=8). Fourteen rats were in the 6-OHDA lesion condition and underwent tongue exercise (n=7) and or no exercise (n=7). Following 4 weeks of training and post-training measures, all animals underwent bilateral stimulation of the hypoglossal nerves to measure muscle contractile properties and were then transcardially perfused and brain tissues collected for immunohistochemistry to examine striatal dopamine content. Results demonstrated that exercise animals performed better for maximal force, average force, and press rate than their no-exercise counterparts, and the 6-OHDA animals that underwent exercise performed as well as the Control No Exercise group. Interestingly, there were no group differences for tetanic muscle force, despite behavioral recovery of forces. Additionally, behavioral and neurochemical analyses indicate that there were no differences in striatal dopamine. Thus, targeted exercise can improve tongue force and timing deficits related to 6-OHDA lesions and this exercise likely has a central, versus peripheral (muscle strength) mechanism. However, this mechanism is not related to sparing of striatal dopamine content. Copyright © 2013 Elsevier B.V. All rights reserved.

Distribution of FMRFamide-like immunoreactivity in the brain, retina and nervus terminalis of the sockeye salmon parr, Oncorhynchus nerka.

PubMed

Ostholm, T; Ekström, P; Ebbesson, S O

1990-09-01

Neurons displaying FMRFamide(Phe - Met - Arg - Phe - NH2)-like immunoreactivity have recently been implicated in neural plasticity in salmon. We now extend these findings by describing the extent of the FMRF-like immunoreactive (FMRF-IR) system in the brain, retina and olfactory system of sockeye salmon parr using the indirect peroxidase anti-peroxidase technique. FMRF-IR perikarya were found in the periventricular hypothalamus, mesencephalic laminar nucleus, nucleus nervi terminalis and retina (presumed amacrine cells), and along the olfactory nerves. FMRF-IR fibers were distributed throughout the brain with highest densities in the ventral area of the telencephalon, in the medial forebrain bundle, and at the borders between layers III/IV and IV/V in the optic tectum. High densities of immunoreactive fibers were also observed in the area around the torus semicircularis, in the medial hypothalamus, median raphe, ventromedial tegmentum, and central gray. In the retina, immunopositive fibers were localized to the inner plexiform layer, but several fiber elements were also found in the outer plexiform layer. The olfactory system displayed FMRF-IR fibers in the epithelium and along the olfactory nerves. These findings differ from those reported in other species as follows: (i) FMRF-IR cells in the retina have not previously been reported in teleosts; (ii) the presence of FMRF-IR fibers in the outer plexiform layer of the retina is a new finding for any species; (iii) the occurrence of immunopositive cells in the mesencephalic laminar nucleus has to our knowledge not been demonstrated previously.

Consequences of partial and severe dopaminergic lesion on basal ganglia oscillatory activity and akinesia.

PubMed

Tseng, Kuei Y; Kargieman, Lucila; Gacio, Sebastian; Riquelme, Luis A; Murer, M Gustavo

2005-11-01

Severe chronic dopamine (DA) depletion increases the proportion of neurons in the basal ganglia that fire rhythmic bursts of action potential (LFO units) synchronously with the cortical oscillations. Here we report on how different levels of mesencephalic DA denervation affect substantia nigra pars reticulata (SNpr) neuronal activity in the rat and its relationship to akinesia (stepping test). Chronic nigrostriatal lesion induced with 0 (control group), 4, 6 or 8 microg of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle resulted in a dose-dependent decrease of tyrosine hydroxylase positive (TH+) neurons in the SN and ventral tegmental area (VTA). Although 4 microg of 6-OHDA reduced the number of TH+ neurons in the SN by approximately 60%, both stepping test performance and SNpr neuronal activity remained indistinguishable from control animals. By contrast, animals that received 6 microg of 6-OHDA showed a marked reduction of TH+ cells in the SN ( approximately 75%) and VTA ( approximately 55%), a significant stepping test deficit and an increased proportion of LFO units. These changes were not dramatically enhanced with 8 microg 6-OHDA, a dose that induced an extensive DA lesion (> 95%) in the SN and approximately 70% reduction of DA neurons in the VTA. These results suggest a threshold level of DA denervation for both the appearance of motor deficits and LFO units. Thus, the presence of LFO activity in the SNpr is not related to a complete nigrostriatal DA neuron depletion (ultimate stage parkinsonism); instead, it may reflect a functional disruption of cortico-basal ganglia dynamics associated with clinically relevant stages of the disease.

Quantitative structure–activity relationship analysis of the pharmacology of para-substituted methcathinone analogues

PubMed Central

Bonano, J S; Banks, M L; Kolanos, R; Sakloth, F; Barnier, M L; Glennon, R A; Cozzi, N V; Partilla, J S; Baumann, M H; Negus, S S

2015-01-01

Background and Purpose Methcathinone (MCAT) is a potent monoamine releaser and parent compound to emerging drugs of abuse including mephedrone (4-CH3 MCAT), the para-methyl analogue of MCAT. This study examined quantitative structure–activity relationships (QSAR) for MCAT and six para-substituted MCAT analogues on (a) in vitro potency to promote monoamine release via dopamine and serotonin transporters (DAT and SERT, respectively), and (b) in vivo modulation of intracranial self-stimulation (ICSS), a behavioural procedure used to evaluate abuse potential. Neurochemical and behavioural effects were correlated with steric (Es), electronic (σp) and lipophilic (πp) parameters of the para substituents. Experimental Approach For neurochemical studies, drug effects on monoamine release through DAT and SERT were evaluated in rat brain synaptosomes. For behavioural studies, drug effects were tested in male Sprague-Dawley rats implanted with electrodes targeting the medial forebrain bundle and trained to lever-press for electrical brain stimulation. Key Results MCAT and all six para-substituted analogues increased monoamine release via DAT and SERT and dose- and time-dependently modulated ICSS. In vitro selectivity for DAT versus SERT correlated with in vivo efficacy to produce abuse-related ICSS facilitation. In addition, the Es values of the para substituents correlated with both selectivity for DAT versus SERT and magnitude of ICSS facilitation. Conclusions and Implications Selectivity for DAT versus SERT in vitro is a key determinant of abuse-related ICSS facilitation by these MCAT analogues, and steric aspects of the para substituent of the MCAT scaffold (indicated by Es) are key determinants of this selectivity. PMID:25438806

1,2,3,4-Tetrahydroisoquinoline protects terminals of dopaminergic neurons in the striatum against the malonate-induced neurotoxicity.

PubMed

Lorenc-Koci, Elzbieta; Gołembiowska, Krystyna; Wardas, Jadwiga

2005-07-27

Malonate, a reversible inhibitor of the mitochondrial enzyme succinate dehydrogenase, is frequently used as a model neurotoxin to produce lesion of the nigrostriatal dopaminergic system in animals due to particular sensitivity of dopamine neurons to mild energy impairment. This model of neurotoxicity was applied in our study to explore neuroprotective potential of 1,2,3,4-tetrahydroisoquinoline (TIQ), an endo- and exogenous substance whose function in the mammalian brain, despite extensive studies, has not been elucidated so far. Injection of malonate at a dose of 3 mumol unilaterally into the rat left medial forebrain bundle resulted in the 54% decrease in dopamine (DA) concentration in the ipsilateral striatum and, depending on the examined striatum regions, caused 24-44% reduction in [3H]GBR12,935 binding to the dopamine transporter (DAT). TIQ (50 mg/kg i.p.) administered 4 h before malonate infusion and next once daily for successive 7 days prevented both these effects of malonate. Such TIQ treatment restored DA content and DAT binding almost to the control level. The results of the present study indicate that TIQ may act as a neuroprotective agent in the rat brain. An inhibition of the enzymatic activities of monoamine oxidase and gamma-glutamyl transpeptidase as well as an increase in the striatal levels of glutathione and nitric oxide found after TIQ administration and reported in our earlier studies are considered to be potential factors that may be involved in the TIQ-mediated protection of dopamine terminals from malonate toxicity.

Nicotine is neuroprotective when administered before but not after nigrostriatal damage in rats and monkeys.

PubMed

Huang, Luping Z; Parameswaran, Neeraja; Bordia, Tanuja; Michael McIntosh, J; Quik, Maryka

2009-05-01

Nicotine reduces dopaminergic deficits in parkinsonian animals when administered before nigrostriatal damage. Here we tested whether nicotine is also beneficial when given to rats and monkeys with pre-existing nigrostriatal damage. Rats were administered nicotine before and after a unilateral 6-hydroxydopamine lesion of the medial forebrain bundle, and the results compared with those in which rats received nicotine only after lesioning. Nicotine pre-treatment attenuated behavioral deficits and lessened lesion-induced losses of the striatal dopamine transporter, and alpha6beta2* and alpha4beta2* nicotinic receptors (nAChRs). By contrast, nicotine administered 2 weeks after lesioning, when 6-hydroxydopamine-induced neurodegenerative effects are essentially complete, did not improve these same measures. Similar results were observed in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys. Nicotine did not enhance striatal markers when administered to monkeys with pre-existing nigrostriatal damage, in contrast to previous data that showed improvements when nicotine was given to monkeys before lesioning. These combined findings in two animal models suggest that nicotine is neuroprotective rather than neurorestorative against nigrostriatal damage. Receptor studies with (125)I-alpha-conotoxinMII and the alpha-conotoxinMII analog E11A were next performed to determine whether nicotine treatment pre- or post-lesioning differentially affected expression of alpha6alpha4beta2* and alpha6(nonalpha4)beta2* nAChR subtypes in striatum. The observations suggest that protection against nigrostriatal damage may be linked to striatal alpha6alpha4beta2* nAChRs.

Ab initio density functional theory investigation of electronic properties of semiconducting single-walled carbon nanotube bundles

NASA Astrophysics Data System (ADS)

Moradian, Rostam; Behzad, Somayeh; Azadi, Sam

2008-09-01

By using ab initio density functional theory we investigated the structural and electronic properties of semiconducting (7, 0), (8, 0) and (10, 0) carbon nanotube bundles. The energetic and electronic evolutions of nanotubes in the bundling process are also studied. The effects of inter-tube coupling on the electronic dispersions of semiconducting carbon nanotube bundles are demonstrated. Our results show that the inter-tube coupling decreases the energy gap in semiconducting nanotubes. We found that bundles of (7, 0) and (8, 0) carbon nanotubes have metallic feature, while (10, 0) bundle is a semiconductor with an energy gap of 0.22 eV. To clarify our results the band structures of isolated and bundled nanotubes are compared.

Relationships Between Tibiofemoral Contact Forces and Cartilage Morphology at 2 to 3 Years After Single-Bundle Hamstring Anterior Cruciate Ligament Reconstruction and in Healthy Knees.

PubMed

Saxby, David John; Bryant, Adam L; Wang, Xinyang; Modenese, Luca; Gerus, Pauline; Konrath, Jason M; Bennell, Kim L; Fortin, Karine; Wrigley, Tim; Cicuttini, Flavia M; Vertullo, Christopher J; Feller, Julian A; Whitehead, Tim; Gallie, Price; Lloyd, David G

2017-08-01

Prevention of knee osteoarthritis (OA) following anterior cruciate ligament (ACL) rupture and reconstruction is vital. Risk of postreconstruction knee OA is markedly increased by concurrent meniscal injury. It is unclear whether reconstruction results in normal relationships between tibiofemoral contact forces and cartilage morphology and whether meniscal injury modulates these relationships. Since patients with isolated reconstructions (ie, without meniscal injury) are at lower risk for knee OA, we predicted that relationships between tibiofemoral contact forces and cartilage morphology would be similar to those of normal, healthy knees 2 to 3 years postreconstruction. In knees with meniscal injuries, these relationships would be similar to those reported in patients with knee OA, reflecting early degenerative changes. Cross-sectional study; Level of evidence, 3. Three groups were examined: (1) 62 patients who received single-bundle hamstring reconstruction with an intact, uninjured meniscus (mean age, 29.8 ± 6.4 years; mean weight, 74.9 ± 13.3 kg); (2) 38 patients with similar reconstruction with additional meniscal injury (ie, tear, repair) or partial resection (mean age, 30.6 ± 6.6 years; mean weight, 83.3 ± 14.3 kg); and (3) 30 ligament-normal, healthy individuals (mean age, 28.3 ± 5.2 years; mean weight, 74.9 ± 14.9 kg) serving as controls. All patients underwent magnetic resonance imaging to measure the medial and lateral tibial articular cartilage morphology (volumes and thicknesses). An electromyography-driven neuromusculoskeletal model determined medial and lateral tibiofemoral contact forces during walking. General linear models were used to assess relationships between tibiofemoral contact forces and cartilage morphology. In control knees, cartilage was thicker compared with that of isolated and meniscal-injured ACL-reconstructed knees, while greater contact forces were related to both greater tibial cartilage volumes (medial: R 2 = 0.43, β = 0.62, P = .000; lateral: R 2 = 0.19, β = 0.46, P = .03) and medial thicknesses ( R 2 = 0.24, β = 0.48, P = .01). In the overall group of ACL-reconstructed knees, greater contact forces were related to greater lateral cartilage volumes ( R 2 = 0.08, β = 0.28, P = .01). In ACL-reconstructed knees with lateral meniscal injury, greater lateral contact forces were related to greater lateral cartilage volumes ( R 2 = 0.41, β = 0.64, P = .001) and thicknesses ( R 2 = 0.20, β = 0.46, P = .04). At 2 to 3 years postsurgery, ACL-reconstructed knees had thinner cartilage compared with healthy knees, and there were no positive relationships between medial contact forces and cartilage morphology. In lateral meniscal-injured reconstructed knees, greater contact forces were related to greater lateral cartilage volumes and thicknesses, although it was unclear whether this was an adaptive response or associated with degeneration. Future clinical studies may seek to establish whether cartilage morphology can be modified through rehabilitation programs targeting contact forces directly in addition to the current rehabilitation foci of restoring passive and dynamic knee range of motion, knee strength, and functional performance.

Relationships Between Tibiofemoral Contact Forces and Cartilage Morphology at 2 to 3 Years After Single-Bundle Hamstring Anterior Cruciate Ligament Reconstruction and in Healthy Knees

PubMed Central

Saxby, David John; Bryant, Adam L.; Wang, Xinyang; Modenese, Luca; Gerus, Pauline; Konrath, Jason M.; Bennell, Kim L.; Fortin, Karine; Wrigley, Tim; Cicuttini, Flavia M.; Vertullo, Christopher J.; Feller, Julian A.; Whitehead, Tim; Gallie, Price; Lloyd, David G.

2017-01-01

Background: Prevention of knee osteoarthritis (OA) following anterior cruciate ligament (ACL) rupture and reconstruction is vital. Risk of postreconstruction knee OA is markedly increased by concurrent meniscal injury. It is unclear whether reconstruction results in normal relationships between tibiofemoral contact forces and cartilage morphology and whether meniscal injury modulates these relationships. Hypotheses: Since patients with isolated reconstructions (ie, without meniscal injury) are at lower risk for knee OA, we predicted that relationships between tibiofemoral contact forces and cartilage morphology would be similar to those of normal, healthy knees 2 to 3 years postreconstruction. In knees with meniscal injuries, these relationships would be similar to those reported in patients with knee OA, reflecting early degenerative changes. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Three groups were examined: (1) 62 patients who received single-bundle hamstring reconstruction with an intact, uninjured meniscus (mean age, 29.8 ± 6.4 years; mean weight, 74.9 ± 13.3 kg); (2) 38 patients with similar reconstruction with additional meniscal injury (ie, tear, repair) or partial resection (mean age, 30.6 ± 6.6 years; mean weight, 83.3 ± 14.3 kg); and (3) 30 ligament-normal, healthy individuals (mean age, 28.3 ± 5.2 years; mean weight, 74.9 ± 14.9 kg) serving as controls. All patients underwent magnetic resonance imaging to measure the medial and lateral tibial articular cartilage morphology (volumes and thicknesses). An electromyography-driven neuromusculoskeletal model determined medial and lateral tibiofemoral contact forces during walking. General linear models were used to assess relationships between tibiofemoral contact forces and cartilage morphology. Results: In control knees, cartilage was thicker compared with that of isolated and meniscal-injured ACL-reconstructed knees, while greater contact forces were related to both greater tibial cartilage volumes (medial: R 2 = 0.43, β = 0.62, P = .000; lateral: R 2 = 0.19, β = 0.46, P = .03) and medial thicknesses (R 2 = 0.24, β = 0.48, P = .01). In the overall group of ACL-reconstructed knees, greater contact forces were related to greater lateral cartilage volumes (R 2 = 0.08, β = 0.28, P = .01). In ACL-reconstructed knees with lateral meniscal injury, greater lateral contact forces were related to greater lateral cartilage volumes (R 2 = 0.41, β = 0.64, P = .001) and thicknesses (R 2 = 0.20, β = 0.46, P = .04). Conclusion: At 2 to 3 years postsurgery, ACL-reconstructed knees had thinner cartilage compared with healthy knees, and there were no positive relationships between medial contact forces and cartilage morphology. In lateral meniscal-injured reconstructed knees, greater contact forces were related to greater lateral cartilage volumes and thicknesses, although it was unclear whether this was an adaptive response or associated with degeneration. Future clinical studies may seek to establish whether cartilage morphology can be modified through rehabilitation programs targeting contact forces directly in addition to the current rehabilitation foci of restoring passive and dynamic knee range of motion, knee strength, and functional performance. PMID:28894756

Lexical bundles in an advanced INTOCSU writing class and engineering texts: A functional analysis

NASA Astrophysics Data System (ADS)

Alquraishi, Mohammed Abdulrahman

The purpose of this study is to investigate the functions of lexical bundles in two corpora: a corpus of engineering academic texts and a corpus of IEP advanced writing class texts. This study is concerned with the nature of formulaic language in Pathway IEPs and engineering texts, and whether those types of texts show similar or distinctive formulaic functions. Moreover, the study looked into lexical bundles found in an engineering 1.26 million-word corpus and an ESL 65000-word corpus using a concordancing program. The study then analyzed the functions of those lexical bundles and compared them statistically using chi-square tests. Additionally, the results of this investigation showed 236 unique frequent lexical bundles in the engineering corpus and 37 bundles in the pathway corpus. Also, the study identified several differences between the density and functions of lexical bundles in the two corpora. These differences were evident in the distribution of functions of lexical bundles and the minimal overlap of lexical bundles found in the two corpora. The results of this study call for more attention to formulaic language at ESP and EAP programs.

Biological natural retting for determining the hierarchical structuration of banana fibers.

PubMed

Gañán, Piedad; Zuluaga, Robin; Velez, Juan Manuel; Mondragon, Iñaki

2004-10-20

Extraction processes of natural fibers can be performed by different procedures that include mechanical, chemical and biological methods. Each method presents different advantages or drawbacks according to the amount of fiber produced or the quality and properties of fiber bundles obtained. In this study, biological natural retting was satisfactorily used for obtaining banana fibers from plant bunches. However, the most important contribution of this work refers to the description of the hierarchical microstructural ordering present in banana fiber bundles in both bundle surface and inner region. The chemical composition of banana fiber bundles has been evaluated by FTIR spectroscopy. Through exposure time, the fiber bundle configuration presents small variations in composition. The main changes are related to hemicellulose and pectins as they conform the outer walls of the bundle. Hierarchical helicoidal ordering in the bundle surface as well as orientation on the longitudinal axis of the bundle were observed by optical microscopy (OM) and scanning electron microscopy (SEM) for 3-4 microm surface fibers and 10-15 microm inner elementary fibers, respectively. With increasing exposure time, fiber bundle walls lose integrity, as reflected in their mechanical behavior.

Genealogical correspondence of a forebrain centre implies an executive brain in the protostome–deuterostome bilaterian ancestor

PubMed Central

2016-01-01

Orthologous genes involved in the formation of proteins associated with memory acquisition are similarly expressed in forebrain centres that exhibit similar cognitive properties. These proteins include cAMP-dependent protein kinase A catalytic subunit (PKA-Cα) and phosphorylated Ca2+/calmodulin-dependent protein kinase II (pCaMKII), both required for long-term memory formation which is enriched in rodent hippocampus and insect mushroom bodies, both implicated in allocentric memory and both possessing corresponding neuronal architectures. Antibodies against these proteins resolve forebrain centres, or their equivalents, having the same ground pattern of neuronal organization in species across five phyla. The ground pattern is defined by olfactory or chemosensory afferents supplying systems of parallel fibres of intrinsic neurons intersected by orthogonal domains of afferent and efferent arborizations with local interneurons providing feedback loops. The totality of shared characters implies a deep origin in the protostome–deuterostome bilaterian ancestor of elements of a learning and memory circuit. Proxies for such an ancestral taxon are simple extant bilaterians, particularly acoels that express PKA-Cα and pCaMKII in discrete anterior domains that can be properly referred to as brains. PMID:26598732

An essential role for LPA signalling in telencephalon development.

PubMed

Geach, Timothy J; Faas, Laura; Devader, Christelle; Gonzalez-Cordero, Anai; Tabler, Jacqueline M; Brunsdon, Hannah; Isaacs, Harry V; Dale, Leslie

2014-02-01

Lysophosphatidic acid (LPA) has wide-ranging effects on many different cell types, acting through G-protein-coupled receptors such as LPAR6. We show that Xenopus lpar6 is expressed from late blastulae and is enriched in the mesoderm and dorsal ectoderm of early gastrulae. Expression in gastrulae is an early response to FGF signalling. Transcripts for lpar6 are enriched in the neural plate of Xenopus neurulae and loss of function caused forebrain defects, with reduced expression of telencephalic markers (foxg1, emx1 and nkx2-1). Midbrain (en2) and hindbrain (egr2) markers were unaffected. Foxg1 expression requires LPAR6 within ectoderm and not mesoderm. Head defects caused by LPAR6 loss of function were enhanced by co-inhibiting FGF signalling, with defects extending into the hindbrain (en2 and egr2 expression reduced). This is more severe than expected from simple summation of individual defects, suggesting that LPAR6 and FGF have overlapping or partially redundant functions in the anterior neural plate. We observed similar defects in forebrain development in loss-of-function experiments for ENPP2, an enzyme involved in the synthesis of extracellular LPA. Our study demonstrates a role for LPA in early forebrain development.

Shp2 in Forebrain Neurons Regulates Synaptic Plasticity, Locomotion, and Memory Formation in Mice

PubMed Central

Kusakari, Shinya; Saitow, Fumihito; Ago, Yukio; Shibasaki, Koji; Sato-Hashimoto, Miho; Matsuzaki, Yasunori; Kotani, Takenori; Murata, Yoji; Hirai, Hirokazu; Matsuda, Toshio; Suzuki, Hidenori

2015-01-01

Shp2 (Src homology 2 domain-containing protein tyrosine phosphatase 2) regulates neural cell differentiation. It is also expressed in postmitotic neurons, however, and mutations of Shp2 are associated with clinical syndromes characterized by mental retardation. Here we show that conditional-knockout (cKO) mice lacking Shp2 specifically in postmitotic forebrain neurons manifest abnormal behavior, including hyperactivity. Novelty-induced expression of immediate-early genes and activation of extracellular-signal-regulated kinase (Erk) were attenuated in the cerebral cortex and hippocampus of Shp2 cKO mice, suggestive of reduced neuronal activity. In contrast, ablation of Shp2 enhanced high-K+-induced Erk activation in both cultured cortical neurons and synaptosomes, whereas it inhibited that induced by brain-derived growth factor in cultured neurons. Posttetanic potentiation and paired-pulse facilitation were attenuated and enhanced, respectively, in hippocampal slices from Shp2 cKO mice. The mutant mice also manifested transient impairment of memory formation in the Morris water maze. Our data suggest that Shp2 contributes to regulation of Erk activation and synaptic plasticity in postmitotic forebrain neurons and thereby controls locomotor activity and memory formation. PMID:25713104

Forebrain-selective AMPA-receptor antagonism guided by TARP γ-8 as an antiepileptic mechanism.

PubMed

Kato, Akihiko S; Burris, Kevin D; Gardinier, Kevin M; Gernert, Douglas L; Porter, Warren J; Reel, Jon; Ding, Chunjin; Tu, Yuan; Schober, Douglas A; Lee, Matthew R; Heinz, Beverly A; Fitch, Thomas E; Gleason, Scott D; Catlow, John T; Yu, Hong; Fitzjohn, Stephen M; Pasqui, Francesca; Wang, He; Qian, Yuewei; Sher, Emanuele; Zwart, Ruud; Wafford, Keith A; Rasmussen, Kurt; Ornstein, Paul L; Isaac, John T R; Nisenbaum, Eric S; Bredt, David S; Witkin, Jeffrey M

2016-12-01

Pharmacological manipulation of specific neural circuits to optimize therapeutic index is an unrealized goal in neurology and psychiatry. AMPA receptors are important for excitatory synaptic transmission, and their antagonists are antiepileptic. Although efficacious, AMPA-receptor antagonists, including perampanel (Fycompa), the only approved antagonist for epilepsy, induce dizziness and motor impairment. We hypothesized that blockade of forebrain AMPA receptors without blocking cerebellar AMPA receptors would be antiepileptic and devoid of motor impairment. Taking advantage of an AMPA receptor auxiliary protein, TARP γ-8, which is selectively expressed in the forebrain and modulates the pharmacological properties of AMPA receptors, we discovered that LY3130481 selectively antagonized recombinant and native AMPA receptors containing γ-8, but not γ-2 (cerebellum) or other TARP members. Two amino acid residues unique to γ-8 determined this selectivity. We also observed antagonism of AMPA receptors expressed in hippocampal, but not cerebellar, tissue from an patient with epilepsy. Corresponding to this selective activity, LY3130481 prevented multiple seizure types in rats and mice and without motor side effects. These findings demonstrate the first rationally discovered molecule targeting specific neural circuitries for therapeutic advantage.

Cholinergic degeneration and memory loss delayed by vitamin E in a Down syndrome mouse model

PubMed Central

Lockrow, Jason; Prakasam, Annamalai; Huang, Peng; Bimonte-Nelson, Heather; Sambamurti, Kumar; Granholm, Ann-Charlotte

2009-01-01

Down syndrome (DS) individuals develop several neuropathological hallmarks seen in Alzheimer's disease, including cognitive decline and the early loss of cholinergic markers in the basal forebrain. These deficits are replicated in the Ts65Dn mouse, which contains a partial trisomy of murine chromosome 16, the orthologous genetic segment to human chromosome 21. Oxidative stress levels are elevated early in DS, and may contribute to the neurodegeneration seen in these individuals. We evaluated oxidative stress in Ts65Dn mice, and assessed the efficacy of long-term antioxidant supplementation on memory and basal forebrain pathology. We report that oxidative stress was elevated in the adult Ts65Dn brain, and that supplementation with the antioxidant vitamin E effectively reduced these markers. Also, Ts65Dn mice receiving vitamin E exhibited improved performance on a spatial working memory task and showed an attenuation of cholinergic neuron pathology in the basal forebrain. This study provides evidence that vitamin E delays onset of cognitive and morphological abnormalities in a mouse model of DS, and may represent a safe and effective treatment early in the progression of DS neuropathology. PMID:19135442

Birdsong and the neural production of steroids

PubMed Central

Remage-Healey, Luke; London, Sarah E.; Schinger, Barney A.

2009-01-01

The forebrain circuits involved in singing and audition (the ‘song system’) in songbirds exhibit a remarkable capacity to synthesize and respond to steroid hormones. This review considers how local brain steroid production impacts the development, sexual differentiation, and activity of song system circuitry. The songbird forebrain contains all of the enzymes necessary for the de novo synthesis of steroids - including neuroestrogens - from cholesterol. Steroid production enzymes are found in neuronal cell bodies, but they are also expressed in pre-synaptic terminals in the song system, indicating a novel mode of brain steroid delivery to local circuits. The song system expresses nuclear hormone receptors, consistent with local action of brain-derived steroids. Local steroid production also occurs in brain regions that do not express nuclear hormone receptors, suggesting a non-classical mode-of-action. Recent evidence indicates that local steroid levels can change rapidly within the forebrain, in a manner similar to traditional neuromodulators. Lastly, we consider growing evidence for modulatory interactions between brain-derived steroids and neurotransmitter/neuropeptide networks within the song system. Songbirds have therefore emerged as a rich and powerful model system to explore the neural and neurochemical regulation of social behavior. PMID:19589382

Estradiol selectively enhances auditory function in avian forebrain neurons

PubMed Central

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

2012-01-01

Sex steroids modulate vertebrate sensory processing, but the impact of circulating hormone levels on forebrain function remains unclear. We tested the hypothesis that circulating sex steroids modulate single-unit responses in the avian telencephalic auditory nucleus, field L. We mimicked breeding or non-breeding conditions by manipulating plasma 17β-estradiol levels in wild-caught female Gambel’s white-crowned sparrows (Zonotrichia leucophrys gambelii). Extracellular responses of single neurons to tones and conspecific songs presented over a range of intensities revealed that estradiol selectively enhanced auditory function in cells that exhibited monotonic rate-level functions to pure tones. In these cells, estradiol treatment increased spontaneous and maximum evoked firing rates, increased pure tone response strengths and sensitivity, and expanded the range of intensities over which conspecific song stimuli elicited significant responses. Estradiol did not significantly alter the sensitivity or dynamic ranges of cells that exhibited non-monotonic rate-level functions. Notably, there was a robust correlation between plasma estradiol concentrations in individual birds and physiological response properties in monotonic, but not non-monotonic neurons. These findings demonstrate that functionally distinct classes of anatomically overlapping forebrain neurons are differentially regulated by sex steroid hormones in a dose-dependent manner. PMID:23223283

Systemic Injections of Cannabidiol Enhance Acetylcholine Levels from Basal Forebrain in Rats.

PubMed

Murillo-Rodríguez, Eric; Arankowsky-Sandoval, Gloria; Rocha, Nuno Barbosa; Peniche-Amante, Rodrigo; Veras, André Barciela; Machado, Sérgio; Budde, Henning

2018-06-06

Cannabis sativa is a plant that contains more than 500 components, of which the most studied are Δ 9 -tetrahydrocannabinol (Δ 9 -THC) and cannabidiol (CBD). Several studies have indicated that CBD displays neurobiological effects, including wake promotion. Moreover, experimental evidence has shown that injections of CBD enhance wake-related compounds, such as monoamines (dopamine, serotonin, epinephrine, and norepinephrine). However, no clear evidence is available regarding the effects of CBD on additional wake-related neurochemicals such as acetylcholine (ACh). Here, we demonstrate that systemic injections of CBD (0, 5, 10 or 30 mg/kg, i.p.) at the beginning of the lights-on period, increase the extracellular levels of ACh collected from the basal forebrain and measured by microdialysis and HPLC means. Moreover, the time course effects on the contents of ACh were present 5 h post-injection of CBD. Altogether, these data demonstrate that CBD increases ACh levels in a brain region related to wake control. This study is the first to show the effects of ACh levels in CBD-treated rats and suggests that the basal forebrain might be a site of action of CBD for wakefulness modulation.

Down but Not Out: The Consequences of Pretangle Tau in the Locus Coeruleus

PubMed Central

Chalermpalanupap, Termpanit; Weinshenker, David

2017-01-01

Degeneration of locus coeruleus (LC) is an underappreciated hallmark of Alzheimer's disease (AD). The LC is the main source of norepinephrine (NE) in the forebrain, and its degeneration is highly correlated with cognitive impairment and amyloid-beta (Aβ) and tangle pathology. Hyperphosphorylated tau in the LC is among the first detectable AD-like neuropathology in the brain, and while the LC/NE system impacts multiple aspects of AD (e.g., cognition, neuropathology, and neuroinflammation), the functional consequences of hyperphosphorylated tau accrual on LC neurons are not known. Recent evidence suggests that LC neurons accumulate aberrant tau species for decades before frank LC cell body degeneration occurs in AD, suggesting that a therapeutic window exists. In this review, we combine the literature on how pathogenic tau affects forebrain neurons with the known properties and degeneration patterns of LC neurons to synthesize hypotheses on hyperphosphorylated tau-induced dysfunction of LC neurons and the prion-like spread of pretangle tau from the LC to the forebrain. We also propose novel experiments using both in vitro and in vivo models to address the many questions surrounding the impact of hyperphosphorylated tau on LC neurons in AD and its role in disease progression. PMID:29038736

Differentiation of Forebrain and Hippocampal Dopamine 1-Class Receptors, D1R and D5R, in Spatial Learning and Memory

PubMed Central

Sariñana, Joshua; Tonegawa, Susumu

2017-01-01

Activation of prefrontal cortical (PFC), striatal, and hippocampal dopamine 1-class receptors (D1R and D5R) is necessary for normal spatial information processing. Yet the precise role of the D1R versus the D5R in the aforementioned structures, and their specific contribution to the water-maze spatial learning task remains unknown. D1R- and D5R- specific in situ hybridization probes showed that forebrain restricted D1R and D5R KO mice (F-D1R/D5R KO) displayed D1R mRNA deletion in the medial (m)PFC, dorsal and ventral striatum, and the dentate gyrus (DG) of the hippocampus. D5R mRNA deletion was limited to the mPFC, the CA1 and DG hippocampal subregions. F-D1R/D5R KO mice were given water-maze training and displayed subtle spatial latency differences between genotypes and spatial memory deficits during both regular and reversal training. To differentiate forebrain D1R from D5R activation, forebrain restricted D1R KO (F-D1R KO) and D5R KO (F-D5R KO) mice were trained on the water-maze task. F-D1R KO animals exhibited escape latency deficits throughout regular and reversal training as well as spatial memory deficits during reversal training. F-D1R KO mice also showed perseverative behavior during the reversal spatial memory probe test. In contrast, F-D5R KO animals did not present observable deficits on the water-maze task. Because F-D1R KO mice showed water-maze deficits we tested the necessity of hippocampal D1R activation for spatial learning and memory. We trained DG restricted D1R KO (DG-D1R KO) mice on the water-maze task. DG-D1R KO mice did not present detectable spatial memory deficit, but did show subtle deficits during specific days of training. Our data provides evidence that forebrain D5R activation plays a unique role in spatial learning and memory in conjunction with D1R activation. Moreover, these data suggest that mPFC and striatal, but not DG D1R activation are essential for spatial learning and memory. PMID:26174222

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

PubMed Central

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

2016-01-01

Although early-life stress is a significant risk factor for developing anxiety disorders, including posttraumatic stress disorder (PTSD), the underlying mechanisms are unclear. Corticotropin releasing hormone (CRH) is disrupted in individuals with PTSD and early-life stress and hence may mediate the effects of early-life stress on PTSD risk. We hypothesized that CRH hyper-signaling in the forebrain during early development is sufficient to increase response to trauma in adulthood. To test this hypothesis, we induced transient, forebrain-specific, CRH overexpression during early-life (pre-puberty, CRHOEdev) in double-mutant mice (Camk2a-rtta2 × tetO-Crh) and tested their behavioral and gene expression responses to the predator stress model of PTSD in adulthood. In one cohort of CRHOEdev exposed and unexposed mice, avoidance and arousal behaviors were examined 7–15 days after exposure to predator stress. In another cohort, gene expression changes in Crhr1, Crhr2, and Fkbp51 in forebrain of CRHOEdev exposed and unexposed mice were examined 7 days after predator stress. CRHOEdev induced robust increases in startle reactivity and reductions in startle inhibition independently of predator stress in both male and female mice. Avoidance behaviors after predator stress were highly dependent on sex and CRHOEdev exposure. Whereas stressed females exhibited robust avoidance responses that were not altered by CRHOEdev, males developed significant avoidance only when exposed to both CRHOEdev and stress. Quantitative real-time-PCR analysis indicated that CRHOEdev unexposed males exhibit significant changes in Crhr2 expression in the amygdala and bed nucleus stria terminalis in response to stress, whereas males exposed to CRHOEdev did not. Similar to CRHOEdev males, females exhibited no significant Crhr2 gene expression changes in response to stress. Cortical Fkbp51 expression was also significantly reduced by stress and CRHOEdev exposure in males, but not in females. These findings indicate that forebrain CRH hyper-signaling in early-life is sufficient to increase enduring effects of adult trauma and attenuate Crhr2 expression changes in response to stress in males. These data support growing evidence for significant sex differences in response to trauma, and support further study of CRHR2 as a candidate mechanism for PTSD risk. PMID:26538448