Striatal Cholinergic Signaling in Time and Space

The cholinergic interneurons of the striatum account for a small fraction of all striatal cell types but due to their extensive axonal arborization give the striatum the highest content of acetylcholine of almost any nucleus in the brain. The prevailing theory of striatal cholinergic interneuron signaling is that the numerous varicosities on the axon produce an extrasynaptic, volume-transmitted signal rather than mediating rapid point-to-point synaptic transmission. We review the evidence for this theory and use a mathematical model to integrate the measurements reported in the literature, from which we estimate the temporospatial distribution of acetylcholine after release from a synaptic vesicle and from multiple vesicles during tonic firing and pauses. Our calculations, together with recent data from genetically encoded sensors, indicate that the temporospatial distribution of acetylcholine is both short-range and short-lived, and dominated by diffusion. These considerations suggest that acetylcholine signaling by cholinergic interneurons is consistent with point-to-point transmission within a steep concentration gradient, marked by transient peaks of acetylcholine concentration adjacent to release sites, with potential for faithful transmission of spike timing, both bursts and pauses, to the postsynaptic cell. Release from multiple sites at greater distance contributes to the ambient concentration without interference with the short-range signaling. We indicate several missing pieces of evidence that are needed for a better understanding of the nature of synaptic transmission by the cholinergic interneurons of the striatum.     

Path Length Determines the Tunneling Decay of Substituted Carbenes

Quantum mechanical tunneling of atoms allows chemical reactions to proceed through barriers too high for thermally activated processes. This causes hydroxycarbenes to decay rapidly and at a temperature‐independent rate even at 11 K. In methylhydroxycarbene, tunneling causes decay through a mechanism that reveals a high but thin barrier rather than an alternative with a lower but broader barrier. No accurate estimates of the widths of such barriers and the lengths of tunneling paths were available. Herein, such a measure is provided by calculating the length of the tunneling paths by using instanton theory. Potential energies are provided by density functional theory verified by explicitly correlated coupled cluster CCSD(T) energies. Our results explain the decay efficiency in the known cases and suggest new substitutions to tune the effects of barrier widths and heights. Fluorination and replacement of the hydroxyl group by a thiol group change the qualitative character of the decay. Methylaminocarbene is predicted to be stable for thousands of years.     

Spin-dependent transport through a magnetic carbon nanotube-molecule junction

The electronic structure and spin-dependent conductance of a magnetic junction consisting of two Fe-doped carbon nanotubes and a C60 molecule are investigated using a first-principles approach that combines the density functional theory with the nonequilibrium Greens function technique. The tunneling magnetoresistance ratio is found to be 11%. The density of states and transmission coefficient through the molecular junction are analyzed and compared to layered magnetic tunneling junctions. Our findings suggest new possibilities for experiments and for future technology.     

Amperometric Measurements and Dynamic Models Reveal a Mechanism for How Zinc Alters Neurotransmitter Release

Zinc, a suspected potentiator of learning and memory, is shown to affect exocytotic release and storage in neurotransmitter‐containing vesicles. Structural and size analysis of the vesicular dense core and halo using transmission electron microscopy was combined with single‐cell amperometry to study the vesicle size changes induced after zinc treatment and to compare these changes to theoretical predictions based on the concept of partial release as opposed to full quantal release. This powerful combined analytical approach establishes the existence of an unsuspected strong link between vesicle structure and exocytotic dynamics, which can be used to explain the mechanism of regulation of synaptic plasticity by Zn²⁺ through modulation of neurotransmitter release.     

Atom Tunneling in Chemistry

Quantum mechanical tunneling of atoms is increasingly found to play an important role in many chemical transformations. Experimentally, atom tunneling can be indirectly detected by temperature‐independent rate constants at low temperature or by enhanced kinetic isotope effects. In contrast, the influence of tunneling on the reaction rates can be monitored directly through computational investigations. The tunnel effect, for example, changes reaction paths and branching ratios, enables chemical reactions in an astrochemical environment that would be impossible by thermal transition, and influences biochemical processes.     

Huge Tunneling Magnetoresistance in Magnetic Tunnel Junction with Heusler Alloy Co2MnSi Electrodes

Magnetic tunnel junction with a large tunneling magnetoresistance has attracted great attention due to its importance in the spintronics applications. By performing extensive density functional theory calculations combined with the nonequilibrium Green's function method, we explore the spin-dependent transport properties of a magnetic tunnel junction, in which a non-polar SrTiO$_{3}$ barrier layer is sandwiched between two Heusler alloy Co$_{2}$MnSi electrodes. Theoretical results clearly reveal that the near perfect spin-filtering effect appears in the parallel magnetization configuration. The transmission coefficient in the parallel magnetization configuration at the Fermi level is several orders of magnitude larger than that in the antiparallel magnetization configuration, resulting in a huge tunneling magnetoresistance (i.e. $>10^6$), which originates from the coherent spin-polarized tunneling, due to the half-metallic nature of Co$_{2}$MnSi electrodes and the significant spin-polarization of the interfacial Ti 3d orbital.     

Simultaneous nanoindentation and electron tunneling through alkanethiol self-assembled monolayers

Electrical tunnel junctions consisting of alkanethiol molecules self-assembled on Au-coated Si substrates and contacted with Au-coated atomic force microscopy tips were characterized under varying junction loads in a conducting-probe atomic force microscopy configuration. Junction load was cycled in the fashion of a standard nanoindentation experiment; however, junction conductance rather than probe depth was measured directly. The junction conductance data have been analyzed with typical contact mechanics (Derjaguin-Müller-Toporov) and tunneling equations to extract the monolayer modulus (approximately 50 GPa), the contact transmission (approximately 2 x 10(-6)), contact area, and probe depth as a function of load. The monolayers are shown to undergo significant plastic deformation under compression, yielding indentations approximately 7 Angstroms deep for maximum junction loads of approximately 50 nN. Comparison of mechanical properties for different chain lengths was also performed. The film modulus decreased with the number of carbons in the molecular chain for shorter-chain films. This trend abruptly reversed once 12 carbons were present along the backbone.     

Cholesterol effects on vesicle pools in chromaffin cells revealed by carbon-fiber microelectrode amperometry

Cell–cell communication is often achieved via granular exocytosis, as in neurons during synaptic transmission or neuroendocrine cells during blood hormone control. Owing to its critical role in membrane properties and SNARE function, cholesterol is expected to play an important role in the highly conserved process of exocytosis. In this work, membrane cholesterol concentration is systematically varied in primary culture mouse chromaffin cells, and the change in secretion behavior of distinct vesicle pools as well as pool recovery following stimulation is measured using carbon-fiber microelectrode amperometry. Amperometric traces obtained from activation of the younger readily releasable and slowly releasable pool (RRP/SRP) vesicles at depleted cholesterol levels showed fewer sustained fusion pore features (6.1 ± 1.1% of spikes compared with 11.2 ± 1.0% for control), revealing that cholesterol content influences fusion pore formation and stability during exocytosis. Moreover, subsequent stimulation of RRP/SRP vesicles showed that cellular cholesterol level influences both the quantal recovery and kinetics of the later release events. Finally, diverging effects of cholesterol on RRP and the older reserve pool vesicle release suggest two different mechanisms for the release of these two vesicular pools.     

Analytical approaches to investigate transmitter content and release from single secretory vesicles

The vesicle serves as the primary intracellular unit for the highly efficient storage and release of chemical messengers triggered during signaling processes in the nervous system. This review highlights conventional and emerging analytical methods that have used microscopy, electrochemistry, and spectroscopy to resolve the location, time course, and quantal content characteristics of neurotransmitter release. Particular focus is on the investigation of the synaptic vesicle and its involvement in the fundamental molecular mechanisms of cell communication.     

Transformations of Strained Three-Membered Rings a Common,Yet Overlooked,Motif in Heavy-Atom Tunneling Reactions

Quantum mechanical tunneling has long been recognized as an important phenomenon when considering transformations dominated by a lightweight hydrogen atom. Tunneling of heavier atoms like carbon, initially dismissed as negligible, has seen a quickly increasing number of computationally predicted and/or experimentally confirmed examples over the last decade, thus highlighting its importance for a wide variety of reactions. However, no common structural motif has been pointed out within these seemingly unconnected examples, strongly limiting the predictability of the impact of heavy-atom tunneling on a given reaction. This Concept article will provide this perspective and showcase how the recognition of the formation and cleavage of three-membered rings as common motif can inform the prediction of and research into heavy-atom tunneling reactions.     

Multidimensional tunneling in the [1,5] shift in (Z)-1,3-pentadiene: how useful are Swain-Schaad exponents at detecting tunneling?

Rates, kinetic isotope effects (KIE), and Swain-Schaad exponents (SSE) have been calculated for a variety of isotopologues for the [1,5] shift in (Z)-1,3-pentadiene using mPW1K/6-31+G(d,p). Quantum mechanical effects along the reaction coordinate were incorporated with the zero-curvature tunneling (ZCT) model and with the multidimensional small curvature tunneling (SCT) model, which allows for coupling of modes perpendicular to the reaction coordinate. The latter model gives the best agreement with experimental rates and primary KIEs. The small quasiclassical primary KIE (2.6) is rationalized in terms of a nonlinear transition state. For sp3 to sp2 rehybridization, the quasiclassical alpha-secondary KIE shows an unusual inverse effect due to compression of the nonbonding hydrogens in the suprafacial transition state. SCT transmission coefficients (kappa) increase the rates by as much as one order of magnitude. Tunneling allows the reactant to evade 1-2.5 kcal/mol of the barrier depending on the isotope. Inclusion of tunneling in the secondary KIE increases it beyond the equilibrium isotope effect and converts the inverse effect (0.95) into a normal KIE (1.12). Tunneling was found to deflate the primary y SSE but by an amount too small to distinguish it from the quasiclassical SSE. On the other hand, when a specific labeling pattern is used, the difference between the quasiclassical secondary SSE (4.1) and the tunneling secondary SSE (2.3) may be sufficiently large to detect tunneling. The mixed secondary SSE shows even larger differences.     

Sequence modulation of tunneling barrier and charge transport across histidine doped oligo-alanine molecular junctions

Series tunneling across peptides composed of various amino acids is one of the main charge transport mechanisms for realizing the function of protein. Histidine, more frequently found in redox active proteins, has been proved to be efficient tunneling mediator. While how it exactly modulates charge transport in a long peptide sequence remains poorly explored. In this work, we studied charge transport of a model peptide junction, where oligo-alanine peptide was doped by histidine at different position, and the series of peptides were self-assembled into a monolayer on gold electrode with soft EGaIn as top electrode to form molecular junction. It was found that histidine increased the overall conductance of the peptide, meanwhile, its position modulated the conductance as well. Quantitative analysis by transport model and ultraviolet photoelectron spectroscopy (UPS) indicated a sequence dependent energy landscape of the tunneling barrier of the junction. Density-functional theory (DFT) calculation on the electronic structure of histidine doped oligo-alanine peptides revealed localized highest occupied molecular orbital (HOMO) on imidazole group of the histidine, which decreased charge transport barrier.     

The Cytotoxic Effect of α-Synuclein Aggregates

Parkinson's disease is a neurodegenerative disorder involving a functional protein, α-synuclein, whose primary function is related to vesicle trafficking. However, α-synuclein is prone to form aggregates, and these inclusions, known as Lewy bodies, are the hallmark of Parkinson's disease. α-synuclein can alter its conformation and acquire aggregating capacity, forming aggregates containing β-sheets. This protein's pathogenic importance is based on its ability to form oligomers that impair synaptic transmission and neuronal function by increasing membrane permeability and altering homeostasis, generating a deleterious effect over cells. First, we establish that oligomers interfere with the mechanical properties of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) membrane, as demonstrated by nanoindentation curves. In contrast, nanoindentation revealed that the α-synuclein monomer's presence leads to a much more resistant lipid bilayer. Moreover, the oligomers’ interaction with cell membranes can promote lactate dehydrogenase (LDH) release, suggesting the activation of cytotoxic events.     

Altered Lipid Composition of Secretory Cells Following Exposure to Zinc Can Be Correlated to Changes in Exocytosis

A micromolar concentration of zinc has been shown to significantly change the dynamics of exocytosis as well as the vesicle contents in a model cell line, providing direct evidence that zinc regulates neurotransmitter release. To provide insight into how zinc modulates these exocytotic processes, neurotransmitter release and vesicle content were compared with single cell amperometry and intracellular impact vesicle cytometry with a range of zinc concentrations. Additionally, time-of-flight secondary ion mass spectrometry (ToF-SIMS) images of lipid distributions in the cell membrane after zinc treatment correlate to changes in exocytosis. By combining electrochemical techniques and mass spectrometry imaging, we proposed a mechanism by which zinc changes the fusion pore and the rate of neurotransmitter release by changing lipid distributions and results in the modulation of synaptic strength and plasticity.     

Quantum interference enhanced thermopower in single-molecule thiophene junctions

Quantum interference(QI) effects, which offer unique opportunities to widely manipulate the charge transport properties in the molecular junctions, will have the potential for achieving high thermopower.Here we developed a scanning tunneling microscope break junction technique to investigate the thermopower through single-molecule thiophene junctions. We observed that the thermopower of 2,4-TPSAc with destructive quantum interference(DQI) was nearly twice of 2,5-TP-SAc without DQI, while the con...     

Coulomb blockade of small Pd clusters

Single-electron tunneling through Au substrate-alkanethiol-Pd cluster-tip junctions is investigated with scanning tunneling spectroscopy. The measured I(V) curves reveal several characteristic features of the Coulomb blockade, namely, the presence of a Coulomb gap and a Coulomb staircase. By using the orthodox theory of single-electron tunneling, the capacitances and resistances of the double junction system as well as the fractional charge are extracted from the experimental data.     

Highly conducting π-conjugated molecular junctions covalently bonded to gold electrodes

We measure electronic conductance through single conjugated molecules bonded to Au metal electrodes with direct Au-C covalent bonds using the scanning tunneling microscope based break-junction technique. We start with molecules terminated with trimethyltin end groups that cleave off in situ, resulting in formation of a direct covalent σ bond between the carbon backbone and the gold metal electrodes. The molecular carbon backbone used in this study consist of a conjugated π system that has one terminal methylene group on each end, which bonds to the electrodes, achieving large electronic coupling of the electrodes to the π system. The junctions formed with the prototypical example of 1,4-dimethylenebenzene show a conductance approaching one conductance quantum (G(0) = 2e(2)/h). Junctions formed with methylene-terminated oligophenyls with two to four phenyl units show a 100-fold increase in conductance compared with junctions formed with amine-linked oligophenyls. The conduction mechanism for these longer oligophenyls is tunneling, as they exhibit an exponential dependence of conductance on oligomer length. In addition, density functional theory based calculations for the Au-xylylene-Au junction show near-resonant transmission, with a crossover to tunneling for the longer oligomers.     

Dissociation dynamics of propargyl chloride molecular ion near the reaction threshold: manifestation of quantum mechanical tunneling

The Cl loss from the propargyl chloride molecular ion has been investigated using mass-analyzed ion kinetic energy spectrometry (MIKES). The kinetic energy release distribution in the unimolecular dissociation has been determined. The potential energy surface for the mechanistic pathway has been calculated at the B3LYP/6-311G** density functional theory level. The calculated potential energy surface suggested that the threshold dissociation of the propargyl chloride molecular ion produces the C(3)H(3)(+) ion, only with the cyclopropenium structure, and with the release of a large amount of kinetic energy. This is in agreement with experimental results. Also, calculation of the rate constants with statistical rate models predicted that the reaction observed on a microsecond time scale occurs via tunneling through the rate-determining isomerization barrier for H-atom transfer. It has been found that a broad lifetime distribution is a manifestation of quantum mechanical tunneling of a precursor prepared under thermal conditions. Reinterpretation of previous photoelectron-photoion coincidence results taking into account the tunneling effect necessitated raising the critical energy to 0.64 eV from the energy of 0.34 eV reported previously. Copyright 2000 John Wiley & Sons, Ltd.     

Theoretical studies on the transport property of oligosilane with p‐n junction

The electron transport properties of a novel p‐n junction nanowire caused by boron‐doping and phosphorus‐doping are investigated using density functional theory combined with the nonequilibrium Green's functions formalism. A satisfying rectification is observed. This is a reasonable result after the analysis of the molecular‐projected self‐consistent Hamitonian (MPSH) states, transmission spectra, the frontier orbitals, and the dipole moments. In contrast, the undoped chain has no rectification character. In addition, a negative differential resistance behavior is also observed at V = 1.8 ～ 2.2 V in the doped nanowire and it could be illustrated from the MPSH states and the transmission spectra. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2011     

Real‐time Monitoring of Discrete Synaptic Release Events and Excitatory Potentials within Self‐reconstructed Neuromuscular Junctions

Chemical synaptic transmission is central to the brain functions. In this regard, real‐time monitoring of chemical synaptic transmission during neuronal communication remains a great challenge. In this work, in vivo‐like oriented neural networks between superior cervical ganglion (SCG) neurons and their effector smooth muscle cells (SMC) were assembled in a microfluidic device. This allowed amperometric detection of individual neurotransmitter release events inside functional SCG‐SMC synapse with carbon fiber nanoelectrodes as well as recording of postsynaptic potential using glass nanopipette electrodes. The high vesicular release activities essentially involved complex events arising from flickering fusion pores as quantitatively established based on simulations. This work allowed for the first time monitoring in situ chemical synaptic transmission under conditions close to those found in vivo, which may yield important and new insights into the nature of neuronal communications.