Regions in the brainstem and frontal cortex where electrical stimulation elicits parotid and submandibular saliva secretion in sheep

Tau proteins are encoded by a single gene which is regulated by a unique promoter. The proximal 196 base pairs of the tau 5′ flanking region confers tau protein with neuronal specific expression and nerve growth factor inducibility. We tested tau promoter activity in neuronally differentiated embryonal carcinoma cells, the P19 mouse blastoderm cell line. In these experiments, we examined the temporal expression pattern of the tau promoter and compared it to other viral and cellular promoters. Tau promoter activity increases significantly with differentiation, specifically during neurite initiation. In addition, tau promoter activity in neuronally differentiated P19 cells was significantly greater than all five of the other neuronal or non neuronal promoters tested. All other promoters displayed low levels of promoter activity throughout retinoic acid induced neuronal differentiation of P19 cells. Taken together, our results suggest that the tau promoter is a good choice for ectopic expression of exogenous genes in P19 cells, which serves as a differentiating neuronal model system.     

Phenytoin administration reveals a differential role of pontine reticular formation and periaqueductal gray neurons in generation of the convulsive behaviors of audiogenic seizures

The ventrolateral periaqueductal gray (PAG) and pontine reticular formation (PRF) are implicated in the neuronal network for audiogenic seizures (AGS). The AGS of genetically epilepsy-prone rats (GEPR-9s) culminate in tonic hindlimb extension (TE), and elevated acoustically evoked neuronal firing and burst firing, immediately preceding TE, have been observed in PAG and PRF. This study examined changes in PAG and PRF neuronal firing and behavior in GEPR-9s, following phenytoin administration. Recordings involved 16 PAG and nine PRF neurons in GEPR-9s. Phenytoin in doses (mean, 6. 3 mg/kg) that suppressed TE selectively did not consistently alter PAG neuronal firing. However, these doses of phenytoin resulted in significant (51.6% of control) suppression of PRF neuronal firing. Doses of phenytoin (mean, 8.3 mg/kg), which completely blocked AGS, significantly reduced PAG neuronal firing (64.6% of control), and more greatly suppressed PRF firing (25.8% of control). These results are consistent with a critical role for PRF neurons in generation of TE not evident for PAG. The suppression of PAG and PRF neuronal firing induced by phenytoin with complete seizure blockade is consistent with vital roles for both structures in the seizure network. The differential effects of phenytoin on structures requisite to the seizure network indicate that this experimental approach may be able to identify the most sensitive therapeutic target for anticonvulsant drugs, which could be critical to pharmacological suppression of specific seizure behaviors manifest in various types of convulsions, potentially including human epilepsy.     

An adenoviral vector expressing the glucose transporter protects cultured striatal neurons from 3-nitropropionic acid

Considerable interest has focused on the possibility of using gene transfer techniques to introduce protective genes into neurons around the time of necrotic insults. We have previously used herpes simplex virus amplicon vectors to overexpress the rat brain glucose transporter, Glut-1 (GT), and have shown it to protect against a variety of necrotic insults both in vitro and in vivo, as well as to buffer neurons from the steps thought to mediate necrotic injury. It is critical to show the specificity of the effects of any such transgene overexpression, in order to show that protection arises from the transgene delivered, rather than from the vector delivery system itself. As such, we tested the protective potential of GT overexpression driven, in this case, by an adenoviral vector, against a novel insult, namely exposure of primary striatal cultures to the metabolic poison, 3-nitropropionic acid (3NP). We observed that GT overexpression buffered neurons from neurotoxicity induced by 3NP.     

Recovery from methamphetamine induced long-term nigrostriatal dopaminergic deficits without substantia nigra cell loss

After administration of methamphetamine (METH) (2x2 mg/kg, 6 h apart) to vervet monkeys, long term but reversible dopaminergic deficits were observed in both in vivo and post-mortem studies. Longitudinal studies using positron emission tomography (PET) with the dopamine transporter (DAT)-binding ligand, [11C]WIN 35,428 (WIN), were used to show decreases in striatal WIN binding of 80% at 1 week and only 10% at 1.5 years. A post-mortem characterization of other METH subjects at 1 month showed extensive decreases in immunoreactivity (IR) profiles of tyrosine hydroxylase (TH), DAT and vesicular monoamine transporter-2 (VMAT) in the striatum, medial forebrain bundle and the ventral midbrain dopamine (VMD) cell region. These IR deficits were not associated with a loss of VMD cell number when assessed at 1.5 years by stereological methods. Further, at 1.5 years, IR profiles of METH subjects throughout the nigrostriatal dopamine system appeared similar to controls although some regional deficits persisted. Collectively, the magnitude and extent of the dopaminergic deficits, and the subsequent recovery were not suggestive of extensive axonal degeneration followed by regeneration. Alternatively, this apparent reversibility of the METH-induced neuroadaptations may be related primarily to long-term decreases in expression of VMD-related proteins that recover over time.     

Planar cell polarity genes, Celsr1-3, in neural development

flamingo is among the ’core’ planar cell-polarity genes, protein of which belongs to a unique cadherin subfamily. In contrast to the classic cadherins, composed of several extracellular cadherin repeats, one transmembrane domain and one cytoplasmic segment linked to catenin binding, Drosophila Flamingo has seven transmembrane segments and a cytoplasmic tail with no catenin-binding sequence. In Drosophila, Flamingo has pleotropic roles in controlling epithelial polarity and neuronal morphogenesis. Three mammalian orthologs of flamingo, Celsr1-3, are widely expressed in the nervous system. Recent work has shown that Celsr1-3 play important roles in neural development, such as in axon guidance, neuronal migration, and cilium polarity. Celsr1-3 single-gene knockout mice exhibit different phenotypes, but there are cooperative interactions among these genes.     

Combination of fluoxetine and extinction treatments forms a unique synaptic protein profile that correlates with long-term fear reduction in adult mice

The antidepressant fluoxetine induces synaptic plasticity in the visual and fear networks and promotes the structural remodeling of neuronal circuits, which is critical for experience-dependent plasticity in response to an environmental stimulus. We recently demonstrated that chronic fluoxetine administration together with extinction training in adult mice reduced fear in a context-independent manner. Fear conditioning and extinction alter excitatory and inhibitory transmissions within the fear circuitry. In this study, we investigated whether fluoxetine, extinction or their combination produced distinct long-lasting changes in the synaptic protein profile in the amygdala, hippocampus and prefrontal cortex of conditioned mice. We determined that extinction induced synaptophysin expression and down-regulated the GluA1:GluA2 ratio throughout the fear network in water- and fluoxetine-treated mice, suggesting a common fluoxetine-independent mechanism for increased synaptic transmission and re-arrangement of AMPA-receptors by extinction training. In contrast to common changes, the presynaptic vesicular neurotransmitter transporters VGAT and Vglut1 were upregulated after extinction in water- and fluoxetine-treated mice, respectively. The cortical levels of the GABA transporter Gat1 were reduced in high-freezing water-drinking mice, suggesting a maladaptive increase of GABA spillover at cortical inhibitory synapses. Fear conditioning decreased, and extinction induced the expression of GABA-receptor alpha1 and alpha2 subunits in water- and fluoxetine-treated mice, respectively. Only a combination of fluoxetine with extinction enhanced GluN2A expression in the amygdala and hippocampus, emphasizing the role of this NMDA-receptor subunit in the successful erasure of fear memories. Our finding provides novel data that may become helpful in developing beneficial pharmacological fear-reducing treatment strategies.     

Neuronal intranuclear inclusion disease mimicking acute cerebellitis: A case report

BACKGROUNDNeuronal intranuclear inclusion disease (NIID) is an unusual autosomal dominant, chronic progressive neurodegenerative disease. The clinical manifestations of NIID are complex and varied, complicating its clinical diagnosis. To the best of our knowledge, this report is the first to document sporadic adult-onset NIID mimicking acute cerebellitis (AC) that was finally diagnosed by imaging studies, skin biopsy, and genetic testing.CASE SUMMARYA 63-year-old man presented with fever, gait unsteadiness, dysarthria, and an episode of convulsion. His serum levels of white blood cells and C-reactive protein were significantly elevated. T2-weighted brain magnetic resonance imaging and fluid attenuation inversion recovery sequences showed bilateral high-intensity signals in the medial part of the cerebellar hemisphere beside the vermis. While we initially considered a diagnosis of AC, the patient’s symptoms improved significantly without special treatment, prompting our consideration of NIID. Diffusion-weighted imaging showed hyperintensity in the corticomedullary junction. Skin biopsy revealed eosinophilic inclusions positive for anti-p62 in epithelial sweat-gland cells. GGC repeat expansions in the Notch 2 N-terminal like C gene confirmed the diagnosis of NIID. CONCLUSIONFor patients with clinical manifestations mimicking AC, the possibility of underlying NIID should be considered along with prompt rigorous examinations.     

A Quantum Probability Perspective on Borderline Vagueness

The term “vagueness” describes a property of natural concepts, which normally have fuzzy boundaries, admit borderline cases, and are susceptible to Zeno's sorites paradox. We will discuss the psychology of vagueness, especially experiments investigating the judgment of borderline cases and contradictions. In the theoretical part, we will propose a probabilistic model that describes the quantitative characteristics of the experimental finding and extends Alxatib's and Pelletier's ( 2011 ) theoretical analysis. The model is based on a Hopfield network for predicting truth values. Powerful as this classical perspective is, we show that it falls short of providing an adequate coverage of the relevant empirical results. In the final part, we will argue that a substantial modification of the analysis put forward by Alxatib and Pelletier and its probabilistic pendant is needed. The proposed modification replaces the standard notion of probabilities by quantum probabilities. The crucial phenomenon of borderline contradictions can be explained then as a quantum interference phenomenon.