Midazolam inhibits hippocampal long-term potentiation and learning through dual central and peripheral benzodiazepine receptor activation and neurosteroidogenesis

Benzodiazepines (BDZs) enhance GABA(A) receptor inhibition by direct actions on central BDZ receptors (CBRs). Although some BDZs also bind mitochondrial receptors [translocator protein (18 kDa) (TSPO)] and promote the synthesis of GABA-enhancing neurosteroids, the role of neurosteroids in the clinical effects of BDZs is unknown. In rat hippocampal slices, we compared midazolam, an anesthetic BDZ, with clonazepam, an anticonvulsant/anxiolytic BDZ that activates CBRs selectively. Midazolam, but not clonazepam, increased neurosteroid levels in CA1 pyramidal neurons without changing TSPO immunostaining. Midazolam, but not clonazepam, also augmented a form of spike inhibition after stimulation adjacent to the pyramidal cell layer and inhibited induction of long-term potentiation. These effects were prevented by finasteride, an inhibitor of neurosteroid synthesis, or 17PA [17-phenyl-(3α,5α)-androst-16-en-3-ol], a blocker of neurosteroid effects on GABA(A) receptors. Moreover, the synaptic effects were mimicked by a combination of clonazepam with FGIN (2-[2-(4-fluorophenyl)-1H-indol-3-yl]-N,N-dihexylacetamide), a selective TSPO agonist, or a combination of clonazepam with exogenous allopregnanolone. Consistent with these in vitro results, finasteride abolished the effects of midazolam on contextual fear learning when administrated 1 d before midazolam injection. Thus, dual activation of CBRs and TSPO appears to result in unique actions of clinically important BDZs. Furthermore, endogenous neurosteroids are shown to be important regulators of pyramidal neuron function and synaptic plasticity

Corticosterone enhances the potency of ethanol against hippocampal long-term potentiation via local neurosteroid synthesis

Corticosterone is known to accumulate in brain after various stressors including alcohol intoxication. Just as severe alcohol intoxication is typically required to impair memory formation only high concentrations of ethanol (60mM) acutely inhibit long-term potentiation (LTP), a cellular memory mechanism, in naïve hippocampal slices. This LTP inhibition involves synthesis of neurosteroids, including allopregnanolone, and appears to involve a form of cellular stress. In the CA1 region of rat hippocampal slices, we examined whether a lower concentration of ethanol (20 mM) inhibits LTP in the presence of corticosterone, a stress-related modulator, and whether corticosterone stimulates local neurosteroid synthesis. Although low micromolar corticosterone alone did not inhibit LTP induction, we found that 20 mM ethanol inhibited LTP in the presence of corticosterone. At 20 mM, ethanol alone did not stimulate neurosteroid synthesis or inhibit LTP. LTP inhibition by corticosterone plus ethanol was blocked by finasteride, an inhibitor of 5α-reductase, suggesting a role for neurosteroid synthesis. We also found that corticosterone alone enhanced neurosteroid immunostaining in CA1 pyramidal neurons and that this immunostaining was further augmented by 20 mM ethanol. The enhanced neurosteroid staining was blocked by finasteride and the N-methyl-D-aspartate antagonist, 2-amino-5-phosphonovalerate (APV). These results indicate that corticosterone promotes neurosteroid synthesis in hippocampal pyramidal neurons and can participate in ethanol-mediated synaptic dysfunction even at moderate ethanol levels. These effects may contribute to the influence of stress on alcohol-induced cognitive impairment

Metaplastic LTP inhibition after LTD induction in CA1 hippocampal slices involves NMDA receptor‐mediated neurosteroidogenesis

Long-term depression (LTD) induced by low-frequency electrical stimulation (LFS) in the CA1 region of the hippocampus is a form of synaptic plasticity thought to contribute to learning and memory and to the pathophysiology of neuropsychiatric disorders. In naïve hippocampal slices from juvenile rats, we previously found that LTD induction can impair subsequent induction of long-term potentiation (LTP) via a form of N-methyl-d-aspartate receptor (NMDAR)-dependent metaplasticity, and have recently observed that pharmacologically induced NMDAR-dependent LTP inhibition involves 5α-reduced neurosteroids that augment the actions of γ-aminobutyric acid (GABA). In this study, we found that both LFS-induced LTD and subsequent inhibition of LTP induction involve neurosteroid synthesis via NMDAR activation. Furthermore, the timing of 5α-reductase inhibition relative to LFS can dissociate effects on LTD and metaplastic LTP inhibition. These findings indicate that 5α-reduced neurosteroids play an important role in synaptic plasticity and synaptic modulation in the hippocampus

Ghosts in the self-accelerating universe

The self-accelerating universe realizes the accelerated expansion of the universe at late times by large-distance modification of general relativity without a cosmological constant. The Dvali-Gabadadze-Porrati (DGP) braneworld model provides an explicit example of the self-accelerating universe. Recently, the DGP model becomes very popular to study the observational consequences of the modified gravity models as an alternative to dark energy models in GR. However, it has been shown that the self-accelerating universe in the DGP model contains a ghost at the linearized level. The ghost carries negative energy densities and it leads to the instability of the spacetime. In this article, we review the origin of the ghost in the self-accelerating universe and explore the physical implication of the existence of the ghost.Comment: Invited topical review for Classical and Quantum Gravity, 20 pages, 4 figure

Plasticity of β-brass Single Crystals at Low Temperatures(Metallurgy)

The plasticity of β-brass single crystals, whose tensile axes lie relatively near the [001] direction, was investigated at temperatures ranging from 77°K to room temperature. It was found that the flow stress at 0.2% strain did not continuously increase with decreasing temperature but showed a peak value at about 195°K. The behavior is different from the temperature dependence of flow stress in ordinary bcc metals and alloys. The slip systems determined from the observation of surface traces are the {112} at 77°K and the {110} at room temperature. However, at the intermediate temperatures where the flow stress showed a peak value, two sets of slip traces or the slip plane between the basic {112} and {110} planes were observed depending on deformation temperatures. Therefore, the increase in flow stress at the intermediate temperatures is interpreted as an interaction between different slip systems or an occurrence of cross slip from the {110} or {112} basic slip plane. Below 115°K, the temperature dependence and the strain rate sensitivity of the flow stress are similar to those of ordinary bcc metals and alloys

Antiferromagnetic Order in Disorder-Induced Insulating Phase of SrRu_{1-x}Mn_xO_3 (0.4<x<0.6)

We have performed the powder neutron diffraction measurements on the solid solutions of SrRu_{1-x}Mn_xO_3, and found that the itinerant ferromagnetic order observed in pure SrRuO_3 changes into the C-type antiferromagnetic (AF) order with nearly localized d electrons in the intermediate Mn concentration between x=0.4 and 0.6. With increasing x, the AF moment is strongly enhanced from 1.1 mB (x=0.4) to 2.6 mB (x=0.6), which is accompanied by the elongation of the tetragonal c/a ratio. These results suggest that the substitution of Mn for Ru suppresses the itinerant character of the d electrons, and induces the superexchange interaction through the compression in the c plane. We have also found that the magnetic and transport properties observed in our tetragonal samples are quite similar to those of recently reported orthorhombic ones.Comment: 4 pages, 4 figure

Intracellular mGluR5 can mediate synaptic plasticity in the hippocampus

Metabotropic glutamate receptor 5 (mGluR5) is widely expressed throughout the CNS and participates in regulating neuronal function and synaptic transmission. Recent work in the striatum led to the groundbreaking discovery that intracellular mGluR5 activation drives unique signaling pathways, including upregulation of ERK1/2, Elk-1 (Jong et al., 2009) and Arc (Kumar et al., 2012). To determine whether mGluR5 signals from intracellular membranes of other cell types, such as excitatory pyramidal neurons in the hippocampus, we used dissociated rat CA1 hippocampal cultures and slice preparations to localize and characterize endogenous receptors. As in the striatum, CA1 neurons exhibited an abundance of mGluR5 both on the cell surface and intracellular membranes, including the endoplasmic reticulum and the nucleus where it colocalized with the sodium-dependent excitatory amino acid transporter, EAAT3. Inhibition of EAAT3 or sodium-free buffer conditions prevented accumulations of radiolabeled agonist. Using a pharmacological approach to isolate different pools of mGluR5, both intracellular and cell surface receptors induced oscillatory Ca(2+) responses in dissociated CA1 neurons; however, only intracellular mGluR5 activation triggered sustained high amplitude Ca(2+) rises in dendrites. Consistent with the notion that mGluR5 can signal from intracellular membranes, uncaging glutamate on a CA1 dendrite led to a local Ca(2+) rise, even in the presence of ionotropic and cell surface metabotropic receptor inhibitors. Finally, activation of intracellular mGluR5 alone mediated both electrically induced and chemically induced long-term depression, but not long-term potentiation, in acute hippocampal slices. These data suggest a physiologically relevant and important role for intracellular mGluR5 in hippocampal synaptic plasticity

Magnetism and Structural Distortion in the La0.7Sr0.3MnO3 Metallic Ferromagnet

Neutron scattering studies on a single crystal of the highly-correlated electron system, La1-xSrxMnO3 with x~0.3, have been carried out elucidating both the spin and lattice dynamics of this metallic ferromagnet. We report a large measured value of the spin wave stiffness constant, which directly shows that the electron transfer energy of the d band is large. The spin dynamics, including magnetic critical scattering, demonstrate that this material behaves similar to other typical metallic ferromagnets such as Fe or Ni. The crystal structure is rhombohedral, as previously reported, for all temperatures studied (below ~425K). We have observed new superlattice peaks which show that the primary rhombohedral lattice distortion arises from oxygen octahedra rotations resulting in an R-3c structure. The superlattice reflection intensities which are very sensitive to structural changes are independent of temperature demonstrating that there is no primary lattice distortion anomaly at the magnetic transition temperature, Tc = 378.1 K, however there is a lattice contraction.Comment: Submitted to Phys. Rev. B. (03Aug95) Uuencoded gz-compressed .tar file of Postscript text (12 pages) and 6 figures. Also available by WWW from http://insti.physics.sunysb.edu/~mmartin/ under my list of publications or by e-mail reques

Rendezvous on a Line by Location-Aware Robots Despite the Presence of Byzantine Faults

A set of mobile robots is placed at points of an infinite line. The robots are equipped with GPS devices and they may communicate their positions on the line to a central authority. The collection contains an unknown subset of "spies", i.e., byzantine robots, which are indistinguishable from the non-faulty ones. The set of the non-faulty robots need to rendezvous in the shortest possible time in order to perform some task, while the byzantine robots may try to delay their rendezvous for as long as possible. The problem facing a central authority is to determine trajectories for all robots so as to minimize the time until the non-faulty robots have rendezvoused. The trajectories must be determined without knowledge of which robots are faulty. Our goal is to minimize the competitive ratio between the time required to achieve the first rendezvous of the non-faulty robots and the time required for such a rendezvous to occur under the assumption that the faulty robots are known at the start. We provide a bounded competitive ratio algorithm, where the central authority is informed only of the set of initial robot positions, without knowing which ones or how many of them are faulty. When an upper bound on the number of byzantine robots is known to the central authority, we provide algorithms with better competitive ratios. In some instances we are able to show these algorithms are optimal