bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cross-Modal Attention Effects in the Vestibular Cortex during Attentive Tracking of Moving Objects
Authors: Frank Sebastian M. , Sun Liwei , Forster Lisa , Tse Peter U. , Greenlee Mark W. 
Published: November 2016

The midposterior fundus of the Sylvian fissure in the human brain is central to the cortical processing of vestibular cues. At least two vestibular areas are located at this site: the parietoinsular vestibular cortex (PIVC) and the posterior insular cortex (PIC). It is now well established that activity in sensory systems is subject to cross-modal attention effects. Attending to a stimulus in one sensory modality enhances activity in the corresponding cortical sensory system, but simultaneously suppresses activity in other sensory systems. Here, we wanted to probe whether such cross-modal attention effects also target the vestibular system. To this end, we used a visual multiple-object tracking task. By parametrically varying the number of tracked targets, we could measure the effect of attentional load on the PIVC and the PIC while holding the perceptual load constant. Participants performed the tracking task during functional magnetic resonance imaging. Results show that, compared with passive viewing of object motion, activity during object tracking was suppressed in the PIVC and enhanced in the PIC. Greater attentional load, induced by increasing the number of tracked targets, was associated with a corresponding increase in the suppression of activity in the PIVC. Activity in the anterior part of the PIC decreased with increasing load, whereas load effects were absent in the posterior PIC. Results of a control experiment show that attention-induced suppression in the PIVC is stronger than any suppression evoked by the visual stimulus per se. Overall, our results suggest that attention has a cross-modal modulatory effect on the vestibular cortex during visual object tracking.SIGNIFICANCE STATEMENTIn this study we investigate cross-modal attention effects in the human vestibular cortex. We applied the visual multiple-object tracking task because it is known to evoke attentional load effects on neural activity in visual motion-processing and attention-processing areas. Here we demonstrate a load-dependent effect of attention on the activation in the vestibular cortex, despite constant visual motion stimulation. We find that activity in the parietoinsular vestibular cortex is more strongly suppressed the greater the attentional load on the visual tracking task. These findings suggest cross-modal attentional modulation in the vestibular cortex.
Pericytes as Inducers of Rapid, Matrix Metalloproteinase-9-Dependent Capillary Damage during Ischemia
Authors: Underly Robert G. , Levy Manuel , Hartmann David A. , Grant Roger I. , Watson Ashley N. , Shih Andy Y. 
Published: November 2016

Blood–brain barrier disruption (BBB) and release of toxic blood molecules into the brain contributes to neuronal injury during stroke and other cerebrovascular diseases. While pericytes are builders and custodians of the BBB in the normal brain, their impact on BBB integrity during ischemia remains unclear. We imaged pericyte-labeled transgenic mice within vivotwo-photon microscopy to examine the relationship between pericytes and blood plasma leakage during photothrombotic occlusion of cortical capillaries. Upon cessation of capillary flow, we observed that plasma leakage occurred with three times greater frequency in regions where pericyte somata adjoined the endothelium. Pericyte somata covered only 7% of the total capillary length in cortex, indicating that a disproportionate amount of leakage occurred from a small fraction of the capillary bed. Plasma leakage was preceded by rapid activation of matrix metalloproteinase (MMP) at pericyte somata, which was visualized at high resolutionin vivousing a fluorescent probe for matrix metalloproteinase-2/9 activity, fluorescein isothiocyanate (FITC)-gelatin. Coinjection of an MMP-9 inhibitor, but not an MMP-2 inhibitor, reduced pericyte-associated FITC-gelatin fluorescence and plasma leakage. These results suggest that pericytes contribute to rapid and localized proteolytic degradation of the BBB during cerebral ischemia.SIGNIFICANCE STATEMENTPericytes are a key component of the neurovascular unit and are essential for normal BBB function. However, during acute ischemia, we find that pericytes are involved in creating rapid and heterogeneous BBB disruption in the capillary bed. The mechanism by which pericytes contribute to BBB damage warrants further investigation, as it may yield new therapeutic targets for acute stroke injury and other neurological diseases involving capillary flow impairment.
NMDARs Adapt to Neurotoxic HIV Protein Tat Downstream of a GluN2A–Ubiquitin Ligase Signaling Pathway
Authors: Green Matthew V. , Thayer Stanley A. 
Published: November 2016

HIV-associated neurocognitive disorder (HAND) affects approximately half of HIV-infected patients. Infected non-neuronal cells release neurotoxic factors such as the viral protein transactivator of transcription (Tat) that potentiate NMDAR function. NMDARs regulate synaptic changes observed after exposure to HIV proteins, which may underlie cognitive impairment in HAND patients. Here, we used patch-clamp recording to measure NMDAR-mediated currents in rat hippocampal cultures after exposure to Tat. Tat (4–16 h) potentiated NMDA-evoked whole-cell current and increased the NMDAR:AMPAR ratio of evoked EPSCs. Potentiated currents adapted back to baseline amplitudes after 24 h of exposure to Tat. Pharmacological inhibition of GluN2A-containing NMDARs prevented adaptation, but inhibition of GluN2B-containing NMDARs did not. Pharmacological and genetic approaches determined that potentiated NMDARs activated the kinase Akt, which then activated the E3 ubiquitin ligase Mdm2. Inhibition of protein synthesis prevented adaptation, suggesting that Mdm2 altered gene expression, possibly through its well known target p53. Expression of GFP-tagged GluN1 subunits resulted in fluorescent puncta that colocalized with synaptic markers. Tat (24 h) caused an Mdm2-dependent loss of NMDAR puncta on a timescale similar to adaption of NMDAR function. Activation of the Mdm2 pathway degrades PSD-95, a scaffolding protein that clusters NMDARs at the synapse and enhances their function. Adaptation to the continued presence of excitotoxins that potentiate NMDARs such as HIV Tat may protect from excessive NMDAR activation while also contributing to the synaptic loss that correlates with cognitive decline in HAND.SIGNIFICANCE STATEMENTSynaptodendritic damage correlates with cognitive decline in HIV-associated neurocognitive disorder (HAND). In a cell culture model, we show that the HIV protein transactivator of transcription (Tat) initially potentiates NMDARs that then adapt to the presence of the toxin. Adaptation of NMDAR function was mediated by a GluN2A/Akt/Mdm2 pathway not previously linked to neuroinflammatory disorders such as HAND. Activation of this pathway caused a loss of synaptic NMDAR clusters. Decreased NMDAR function may result from a homeostatic response gone awry and underlie impaired synaptic function in HAND.
Activation of Pedunculopontine Glutamate Neurons Is Reinforcing
Authors: Yoo Ji Hoon , Zell Vivien , Wu Johnathan , Punta Cindy , Ramajayam Nivedita , Shen Xinyi , Faget Lauren , Lilascharoen Varoth , Lim Byung Kook , Hnasko Thomas S. 
Published: November 2016

Dopamine transmission from midbrain ventral tegmental area (VTA) neurons underlies behavioral processes related to motivation and drug addiction. The pedunculopontine tegmental nucleus (PPTg) is a brainstem nucleus containing glutamate-, acetylcholine-, and GABA-releasing neurons with connections to basal ganglia and limbic brain regions. Here we investigated the role of PPTg glutamate neurons in reinforcement, with an emphasis on their projections to VTA dopamine neurons. We used cell-type-specific anterograde tracing and optogenetic methods to selectively label and manipulate glutamate projections from PPTg neurons in mice. We used anatomical, electrophysiological, and behavioral assays to determine their patterns of connectivity and ascribe functional roles in reinforcement. We found that photoactivation of PPTg glutamate cell bodies could serve as a direct positive reinforcer on intracranial self-photostimulation assays. Further, PPTg glutamate neurons directly innervate VTA; photostimulation of this pathway preferentially excites VTA dopamine neurons and is sufficient to induce behavioral reinforcement. These results demonstrate that ascending PPTg glutamate projections can drive motivated behavior, and PPTg to VTA synapses may represent an important target relevant to drug addiction and other mental health disorders.SIGNIFICANCE STATEMENTUncovering brain circuits underlying reward-seeking is an important step toward understanding the circuit bases of drug addiction and other psychiatric disorders. The dopaminergic system emanating from the ventral tegmental area (VTA) plays a key role in regulating reward-seeking behaviors. We used optogenetics to demonstrate that the pedunculopontine tegmental nucleus sends glutamatergic projections to VTA dopamine neurons, and that stimulation of this circuit promotes behavioral reinforcement. The findings support a critical role for pedunculopontine tegmental nucleus glutamate neurotransmission in modulating VTA dopamine neuron activity and behavioral reinforcement.
Reduced Efficacy of the KCC2 Cotransporter Promotes Epileptic Oscillations in a Subiculum Network Model
Authors: Buchin Anatoly , Chizhov Anton , Huberfeld Gilles , Miles Richard , Gutkin Boris S. 
Published: November 2016

Pharmacoresistant epilepsy is a chronic neurological condition in which a basal brain hyperexcitability results in paroxysmal hypersynchronous neuronal discharges. Human temporal lobe epilepsy has been associated with dysfunction or loss of the potassium-chloride cotransporter KCC2 in a subset of pyramidal cells in the subiculum, a key structure generating epileptic activities. KCC2 regulates intraneuronal chloride and extracellular potassium levels by extruding both ions. Absence of effective KCC2 may alter the dynamics of chloride and potassium levels during repeated activation of GABAergic synapses due to interneuron activity. In turn, such GABAergic stress may itself affect Cl−regulation. Such changes in ionic homeostasis may switch GABAergic signaling from inhibitory to excitatory in affected pyramidal cells and also increase neuronal excitability. Possibly these changes contribute to periodic bursting in pyramidal cells, an essential component in the onset of ictal epileptic events. We tested this hypothesis with a computational model of a subicular network with realistic connectivity. The pyramidal cell model explicitly incorporated the cotransporter KCC2 and its effects on the internal/external chloride and potassium levels. Our network model suggested the loss of KCC2 in a critical number of pyramidal cells increased external potassium and intracellular chloride concentrations leading to seizure-like field potential oscillations. These oscillations included transient discharges leading to ictal-like field events with frequency spectra asin vitro. Restoration of KCC2 function suppressed seizure activity and thus may present a useful therapeutic option. These simulations therefore suggest that reduced KCC2 cotransporter activity alone may underlie the generation of ictal discharges.SIGNIFICANCE STATEMENTIon regulation in the brain is a major determinant of neural excitability. Intracellular chloride in neurons, a partial determinant of the resting potential and the inhibitory reversal potentials, is regulated together with extracellular potassium via kation chloride cotransporters. During temporal lobe epilepsy, the homeostatic regulation of intracellular chloride is impaired in pyramidal cells, yet how this dysregulation may lead to seizures has not been explored. Using a realistic neural network model describing ion mechanisms, we show that chloride homeostasis pathology provokes seizure activity analogous to recordings from epileptogenic brain tissue. We show that there is a critical percentage of pathological cells required for seizure initiation. Our model predicts that restoration of the chloride homeostasis in pyramidal cells could be a viable antiepileptic strategy.
Tracking the Time Course of Top-Down Contextual Effects on Motor Responses during Action Comprehension
Authors: Amoruso Lucia , Finisguerra Alessandra , Urgesi Cosimo 
Published: November 2016

Context plays a key role in coding high-level components of others' behavior, including the goal and the intention of an observed action. However, little is known about its possible role in shaping lower levels of action processing, such as simulating action kinematics and muscular activity. Furthermore, there is no evidence regarding the time course and the neural mechanisms subserving this modulation. To address these issues, we combined single-pulse transcranial magnetic stimulation and motor-evoked potentials while healthy humans watched videos of everyday actions embedded in congruent, incongruent, or ambiguous contexts. Video endings were occluded from view and participants had to predict action unfolding. Transcranial magnetic stimulation was delivered at 80, 240, and 400 ms after action onset. An earlier selective facilitation of motor resonance occurring at 240 ms was observed for actions embedded in congruent contexts, compared with those occurring in incongruent and ambiguous ones. Later on, at 400 ms, a selective inhibition of motor resonance was found for actions embedded in incongruent contexts, compared with those taking place in congruent and ambiguous ones. No modulations were observed at 80 ms. Together, these findings indicate that motor resonance can be modulated by contextual information with different timings, depending on the (in)congruency between the different levels of action representation. Furthermore, the different time course of these effects suggests that they stem from partially independent mechanisms, with the early facilitation directly involving M1, and the later inhibition recruiting high-level structures outside the motor system.SIGNIFICANCE STATEMENTPrevious studies indicate that, when we observe other people's actions, the context in which actions take place influences intention understanding. However, little is known about the precise mechanisms involved in the contextual modulation of action representation (i.e., inhibition vs facilitation) and how they unfold in time. The present study sheds light on these aspects. Specifically, we show an early top-down facilitation (at ∼240 ms) and a later inhibition (at ∼400 ms) of motor resonance in response to actions observed in congruent and incongruent contexts, respectively.
ADrosophilaModel of Neuronopathic Gaucher Disease Demonstrates Lysosomal-Autophagic Defects and Altered mTOR Signalling and Is Functionally Rescued by Rapamycin
Authors: Kinghorn Kerri J. , Grönke Sebastian , Castillo-Quan Jorge Iván , Woodling Nathaniel S. , Li Li , Sirka Ernestas , Gegg Matthew , Mills Kevin , Hardy John , Bjedov Ivana , Partridge Linda 
Published: November 2016

Glucocerebrosidase (GBA1) mutations are associated with Gaucher disease (GD), an autosomal recessive disorder caused by functional deficiency of glucocerebrosidase (GBA), a lysosomal enzyme that hydrolyzes glucosylceramide to ceramide and glucose. Neuronopathic forms of GD can be associated with rapid neurological decline (Type II) or manifest as a chronic form (Type III) with a wide spectrum of neurological signs. Furthermore, there is now a well-established link betweenGBA1mutations and Parkinson's disease (PD), with heterozygote mutations inGBA1considered the commonest genetic defect in PD. Here we describe a novelDrosophilamodel of GD that lacks the two flyGBA1orthologs. This knock-out model recapitulates the main features of GD at the cellular level with severe lysosomal defects and accumulation of glucosylceramide in the fly brain. We also demonstrate a block in autophagy flux in association with reduced lifespan, age-dependent locomotor deficits and accumulation of autophagy substrates in dGBA-deficient fly brains. Furthermore, mechanistic target of rapamycin (mTOR) signaling is downregulated in dGBA knock-out flies, with a concomitant upregulation ofMitfgene expression, the fly ortholog of mammalianTFEB, likely as a compensatory response to the autophagy block. Moreover, the mTOR inhibitor rapamycin is able to partially ameliorate the lifespan, locomotor, and oxidative stress phenotypes. Together, our results demonstrate that thisdGBA1-deficient fly model is a useful platform for the further study of the role of lysosomal-autophagic impairment and the potential therapeutic benefits of rapamycin in neuronopathic GD. These results also have important implications for the role of autophagy and mTOR signaling in GBA1-associatedPD.SIGNIFICANCE STATEMENTWe developed aDrosophilamodel of neuronopathic GD by knocking-out the fly orthologs of theGBA1gene, demonstrating abnormal lysosomal pathology in the fly brain. Functioning lysosomes are required for autophagosome-lysosomal fusion in the autophagy pathway. We showin vivothat autophagy is impaired in dGBA-deficient fly brains. In response, mechanistic target of rapamycin (mTOR) activity is downregulated in dGBA-deficient flies and rapamycin ameliorates the lifespan, locomotor, and oxidative stress phenotypes.dGBAknock-out flies also display an upregulation of theDrosophilaortholog of mammalianTFEB,Mitf,a response that is unable to overcome the autophagy block. Together, our results suggest that rapamycin may have potential benefits in the treatment of GD, as well as PD linked toGBA1mutations.
Brown tumor of the jaw after pregnancy and lactation in a MEN1 patient
Authors: Casteràs Anna , Darder Lídia , Zafon Carles , Hueto Juan Antonio , Alberola Margarita , Caubet Enric , Mesa Jordi 
Published: November 2016

Summary
Skeletal manifestations of primary hyperparathyroidism (pHPT) include brown tumors (BT), which are osteoclastic focal lesions often localized in the jaws. Brown tumors are a rare manifestation of pHTP in Europe and USA; however, they are frequent in developing countries, probably related to vitamin D deficiency and longer duration and severity of disease. In the majority of cases, the removal of the parathyroid adenoma is enough for the bone to remineralize, but other cases require surgery. Hyperparathyroidism in MEN1 develops early, and is multiglandular and the timing of surgery remains questionable. To our knowledge, there are no reports of BT in MEN 1 patients. We present a 29-year-old woman with MEN 1 who developed a brown tumor of the jaw 24 months after getting pregnant, while breastfeeding. Serum corrected calcium remained under 2.7 during gestation, and at that point reached a maximum of 2.82 mmol/L. Concomitant PTH was 196 pg/mL, vitamin D 13.7 ng/mL and alkaline phosphatase 150 IU/L. Bone mineral density showed osteopenia on spine and femoral neck (both T-scores = −1.6). Total parathyroidectomy was performed within two weeks, with a failed glandular graft autotransplantation, leading to permanent hypoparathyroidism. Two months after removal of parathyroid glands, the jaw tumor did not shrink; thus, finally it was successfully excised. We hypothesize that higher vitamin D and mineral requirements during maternity may have triggered an accelerated bone resorption followed by appearance of the jaw BT. We suggest to treat pHPT before planning a pregnancy in MEN1 women or otherwise supplement with vitamin D, although this approach may precipitate severe hypercalcemia.

Learning points:

Brown tumors of the jaw can develop in MEN 1 patients with primary hyperparathyroidism at a young age (less than 30 years).

Pregnancy and lactation might trigger brown tumors by increasing mineral and vitamin D requirements.

Early parathyroidectomy is advisable in MEN 1 patients with primary hyperparathyroidism, at least before planning a pregnancy.

Standard bone mineral density does not correlate with the risk of appearance of a brown tumor.

Removal of parathyroid glands does not always lead to the shrinkage of the brown tumor, and surgical excision may be necessary.
Whole exome sequencing of thymic neuroendocrine tumor with ectopic ACTH syndrome
Authors: Li Yanli , Peng Ying , Jiang Xiuli , Cheng Yulong , Zhou Weiwei , Su Tingwei , Xie Jing , Zhong Xu , Song Dalong , Wu Luming , Fan Liwen , Li Min , Hong Jie , Wang Weiqing , Ning Guang , Cao Yanan 
Published: November 2016

Objective
Thymic neuroendocrine tumor is the second-most prevalent cause of ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS), which is a rare disease characterized by ectopic ACTH oversecretion from nonpituitary tumors. However, the genetic abnormalities of thymic neuroendocrine tumors with EAS remain largely unknown. We aim to elucidate the genetic abnormalities and identify the somatic mutations of potential tumor-related genes of thymic neuroendocrine tumors with EAS by whole exome sequencing.

Design and methods
Nine patients with thymic neuroendocrine tumors with EAS who were diagnosed at Shanghai Clinical Center for Endocrine and Metabolic Diseases in Ruijin Hospital between 2002 and 2014 were enrolled. We performed whole exome sequencing on the DNA obtained from thymic neuroendocrine tumors and matched peripheral blood using the Hiseq2000 platform.

Results
We identified a total of 137 somatic mutations (median of 15.2 per tumor; range, 1–24) with 129 single-nucleotide mutations (SNVs). The predominant substitution in these mutations was C:G > T:A transition. Approximately 80% of detected mutations resulted in amino acid changes. However, we failed to discover any recurrent mutations in these nine patients. By functional predictions, HRAS, PAK1 and MEN1, previously reported in neuroendocrine tumors, were identified as candidate tumor-related genes associated with thymic neuroendocrine tumors.

Conclusions
Using whole exome sequencing, we identified genetic abnormalities in thymic neuroendocrine tumors with EAS. Thereby, this study acts as a further supplement of the genetic features of neuroendocrine tumors. Somatic mutations of three potential tumor-related genes (HRAS, PAK1 and MEN1) might contribute to the tumorigenesis of thymic neuroendocrine tumors with EAS.
AP2S1 and GNA11 mutations – not a common cause of familial hypocalciuric hypercalcemia
Authors: Hovden Silje , Rejnmark Lars , Ladefoged Søren A , Nissen Peter H 
Published: November 2016

Objective
Familial hypocalciuric hypercalcemia (FHH) type 1 is caused by mutations in the gene encoding the calcium-sensing receptor (CASR). Recently, mutations affecting codon 15 in the gene AP2S1 have been shown to cause FHH type 3 in up to 26% of CASR-negative FHH patients. Similarly, mutations in the gene GNA11 have been shown to cause FHH type 2. We hypothesized that mutations in AP2S1 and GNA11 are causative in Danish patients with suspected FHH and that these mutations are not found in patients with primary hyperparathyroidism (PHPT), which is the main differential diagnostic disorder.

Design
Cross-sectional study.

Methods
We identified patients with unexplained hyperparathyroid hypercalcemia and a control group of verified PHPT patients through review of 421 patients tested for CASR mutations in the period 2006–2014. DNA sequencing of all amino acid coding exons including intron–exon boundaries in AP2S1 and GNA11 was performed.

Results
In 33 CASR-negative patients with suspected FHH, we found two (~6%) with a mutation in AP2S1 (p.Arg15Leu and p.Arg15His). Family screening confirmed the genotype–phenotype correlations. We did not identify any pathogenic mutations in GNA11. No pathogenic mutations were found in the PHPT control group.

Conclusions
We suggest that the best diagnostic approach to hyperparathyroid hypercalcemic patients suspected to have FHH is to screen the CASR and AP2S1 codon 15 for mutations. If the results are negative and there is still suspicion of an inherited condition (i.e. family history), then GNA11 should be examined.