Cholinergic Modulation of Locomotion and Striatal Dopamine Release Is Mediated by α6α4* Nicotinic Acetylcholine Receptors

Dopamine (DA) release in striatum is governed by firing rates of midbrain DA neurons, striatal cholinergic tone, and nicotinic ACh receptors (nAChRs) on DA presynaptic terminals. DA neurons selectively express α6* nAChRs, which show high ACh and nicotine sensitivity. To help identify nAChR subtypes that control DA transmission, we studied transgenic mice expressing hypersensitive α6^(L9’S*) receptors. α6^(L9’S) mice are hyperactive, travel greater distance, exhibit increased ambulatory behaviors such as walking, turning, and rearing, and show decreased pausing, hanging, drinking, and grooming. These effects were mediated by α6 α4* pentamers, as α6^(L9’S) mice lacking α4 subunits displayed essentially normal behavior. In α6^(L9’S) mice, receptor numbers are normal, but loss of α4 subunits leads to fewer and less sensitive α6* receptors. Gain-of-function nicotine-stimulated DA release from striatal synaptosomes requires α4 subunits, implicating α6α4β2* nAChRs in α6^(L9’S) mouse behaviors. In brain slices, we applied electrochemical measurements to study control of DA release by α6^(L9’S) nAChRs. Burst stimulation of DA fibers elicited increased DA release relative to single action potentials selectively in α6^(L9’S), but not WT or α4KO/ α6^(L9’S), mice. Thus, increased nAChR activity, like decreased activity, leads to enhanced extracellular DA release during phasic firing. Bursts may directly enhance DA release from α6^(L9’S) presynaptic terminals, as there was no difference in striatal DA receptor numbers or DA transporter levels or function in vitro. These results implicate α6α4β2* nAChRs in cholinergic control of DA transmission, and strongly suggest that these receptors are candidate drug targets for disorders involving the DA system

Orbits and phase transitions in the multifractal spectrum

We consider the one dimensional classical Ising model in a symmetric dichotomous random field. The problem is reduced to a random iterated function system for an effective field. The D_q-spectrum of the invariant measure of this effective field exhibits a sharp drop of all D_q with q < 0 at some critical strength of the random field. We introduce the concept of orbits which naturally group the points of the support of the invariant measure. We then show that the pointwise dimension at all points of an orbit has the same value and calculate it for a class of periodic orbits and their so-called offshoots as well as for generic orbits in the non-overlapping case. The sharp drop in the D_q-spectrum is analytically explained by a drastic change of the scaling properties of the measure near the points of a certain periodic orbit at a critical strength of the random field which is explicitly given. A similar drastic change near the points of a special family of periodic orbits explains a second, hitherto unnoticed transition in the D_q-spectrum. As it turns out, a decisive role in this mechanism is played by a specific offshoot. We furthermore give rigorous upper and/or lower bounds on all D_q in a wide parameter range. In most cases the numerically obtained D_q coincide with either the upper or the lower bound. The results in this paper are relevant for the understanding of random iterated function systems in the case of moderate overlap in which periodic orbits with weak singularity can play a decisive role.Comment: The article has been completely rewritten; the title has changed; a section about the typical pointwise dimension as well as several references and remarks about more general systems have been added; to appear in J. Phys. A; 25 pages, 11 figures, LaTeX2

Single-molecule studies of conformational states and dynamics in the ABC importer OpuA

The current model of active transport via ABC importers is mostly based on structural, biochemical and genetic data. We here establish single-molecule Förster resonance energy transfer (smFRET) assays to monitor the conformational states and heterogeneity of the osmoregulatory type I ABC importer OpuA from Lactococcus~lactis. We present data probing both intradomain distances that elucidate conformational changes within the substrate-binding domain (SBD) OpuAC, and interdomain distances between SBDs or transmembrane domains. Using this methodology, we studied ligand-binding mechanisms, as well as ATP and glycine betaine dependences of conformational changes. Our work expands the scope of smFRET investigations towards a class of so far unstudied ABC importers, and paves the way for a full understanding of their transport cycle in the future

Phase diagram of the random field Ising model on the Bethe lattice

The phase diagram of the random field Ising model on the Bethe lattice with a symmetric dichotomous random field is closely investigated with respect to the transition between the ferromagnetic and paramagnetic regime. Refining arguments of Bleher, Ruiz and Zagrebnov [J. Stat. Phys. 93, 33 (1998)] an exact upper bound for the existence of a unique paramagnetic phase is found which considerably improves the earlier results. Several numerical estimates of transition lines between a ferromagnetic and a paramagnetic regime are presented. The obtained results do not coincide with a lower bound for the onset of ferromagnetism proposed by Bruinsma [Phys. Rev. B 30, 289 (1984)]. If the latter one proves correct this would hint to a region of coexistence of stable ferromagnetic phases and a stable paramagnetic phase.Comment: Article has been condensed and reorganized; Figs 3,5,6 merged; Fig 4 omitted; Some discussion added at end of Sec. III; 9 pages, 5 figs, RevTeX4, AMSTe

Convolution of multifractals and the local magnetization in a random field Ising chain

The local magnetization in the one-dimensional random-field Ising model is essentially the sum of two effective fields with multifractal probability measure. The probability measure of the local magnetization is thus the convolution of two multifractals. In this paper we prove relations between the multifractal properties of two measures and the multifractal properties of their convolution. The pointwise dimension at the boundary of the support of the convolution is the sum of the pointwise dimensions at the boundary of the support of the convoluted measures and the generalized box dimensions of the convolution are bounded from above by the sum of the generalized box dimensions of the convoluted measures. The generalized box dimensions of the convolution of Cantor sets with weights can be calculated analytically for certain parameter ranges and illustrate effects we also encounter in the case of the measure of the local magnetization. Returning to the study of this measure we apply the general inequalities and present numerical approximations of the D_q-spectrum. For the first time we are able to obtain results on multifractal properties of a physical quantity in the one-dimensional random-field Ising model which in principle could be measured experimentally. The numerically generated probability densities for the local magnetization show impressively the gradual transition from a monomodal to a bimodal distribution for growing random field strength h.Comment: An error in figure 1 was corrected, small additions were made to the introduction and the conclusions, some typos were corrected, 24 pages, LaTeX2e, 9 figure

α6* Nicotinic Acetylcholine Receptor Expression and Function in a Visual Salience Circuit

Nicotinic acetylcholine receptors (nAChRs) containing α6 subunits are expressed in only a few brain areas, including midbrain dopamine (DA) neurons, noradrenergic neurons of the locus ceruleus, and retinal ganglion cells. To better understand the regional and subcellular expression pattern of α6-containing nAChRs, we created and studied transgenic mice expressing a variant α6 subunit with green fluorescent protein (GFP) fused in-frame in the M3-M4 intracellular loop. In α6-GFP transgenic mice, α6-dependent synaptosomal DA release and radioligand binding experiments confirmed correct expression and function in vivo. In addition to strong α6* nAChR expression in glutamatergic retinal axons, which terminate in superficial superior colliculus (sSC), we also found α6 subunit expression in a subset of GABAergic cell bodies in this brain area. In patch-clamp recordings from sSC neurons in brain slices from mice expressing hypersensitive α6* nAChRs, we confirmed functional, postsynaptic α6* nAChR expression. Further, sSC GABAergic neurons expressing α6* nAChRs exhibit a tonic conductance mediated by standing activation of hypersensitive α6* nAChRs by ACh. α6* nAChRs also appear in a subpopulation of SC neurons in output layers. Finally, selective activation of α6* nAChRs in vivo induced sSC neuronal activation as measured with c-Fos expression. Together, these results demonstrate that α6* nAChRs are uniquely situated to mediate cholinergic modulation of glutamate and GABA release in SC. The SC has emerged as a potential key brain area responsible for transmitting short-latency salience signals to thalamus and midbrain DA neurons, and these results suggest that α6* nAChRs may be important for nicotinic cholinergic sensitization of this pathway

How self-organized criticality works: A unified mean-field picture

We present a unified mean-field theory, based on the single site approximation to the master-equation, for stochastic self-organized critical models. In particular, we analyze in detail the properties of sandpile and forest-fire (FF) models. In analogy with other non-equilibrium critical phenomena, we identify the order parameter with the density of ``active'' sites and the control parameters with the driving rates. Depending on the values of the control parameters, the system is shown to reach a subcritical (absorbing) or super-critical (active) stationary state. Criticality is analyzed in terms of the singularities of the zero-field susceptibility. In the limit of vanishing control parameters, the stationary state displays scaling characteristic of self-organized criticality (SOC). We show that this limit corresponds to the breakdown of space-time locality in the dynamical rules of the models. We define a complete set of critical exponents, describing the scaling of order parameter, response functions, susceptibility and correlation length in the subcritical and supercritical states. In the subcritical state, the response of the system to small perturbations takes place in avalanches. We analyze their scaling behavior in relation with branching processes. In sandpile models because of conservation laws, a critical exponents subset displays mean-field values ($\nu=1/2$ and $\gamma = 1$) in any dimensions. We treat bulk and boundary dissipation and introduce a new critical exponent relating dissipation and finite size effects. We present numerical simulations that confirm our results. In the case of the forest-fire model, our approach can distinguish between different regimes (SOC-FF and deterministic FF) studied in the literature and determine the full spectrum of critical exponents.Comment: 21 RevTex pages, 3 figures, submitted to Phys. Rev.

Nicotinic cholinergic mechanisms causing elevated dopamine release and abnormal locomotor behavior

Firing rates of dopamine (DA) neurons in substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) control DA release in target structures such as striatum and prefrontal cortex. DA neuron firing in the soma and release probability at axon terminals are tightly regulated by cholinergic transmission and nicotinic acetylcholine receptors (nAChRs). To understand the role of α6* nAChRs in DA transmission, we studied several strains of mice expressing differing levels of mutant, hypersensitive (leucine 9′ to serine [L9′S]) α6 subunits. α6 L9′S mice harboring six or more copies of the hypersensitive α6 gene exhibited spontaneous home-cage hyperactivity and novelty-induced locomotor activity, whereas mice with an equal number of WT and L9′S α6 genes had locomotor activity resembling that of control mice. α6-dependent, nicotine-stimulated locomotor activation was also more robust in high-copy α6 L9′S mice versus low-copy mice. In wheel-running experiments, results were also bi-modal; high-copy α6 L9′S animals exhibited blunted total wheel rotations during each day of a 9-day experiment, but low-copy α6 L9′S mice ran normally on the wheel. Reduced wheel running in hyperactive strains of α6 L9′S mice was attributable to a reduction in both overall running time and velocity. ACh and nicotine-stimulated DA release from striatal synaptosomes in α6 L9′S mice was well-correlated with behavioral phenotypes, supporting the hypothesis that augmented DA release mediates the altered behavior of α6 L9′S mice. This study highlights the precise control that the nicotinic cholinergic system exerts on DA transmission and provides further insights into the mechanisms and consequences of enhanced DA release

PtrWRKY19, a novel WRKY transcription factor, contributes to the regulation of pith secondary wall formation in Populus trichocarpa

WRKY proteins are one of the largest transcription factor families in higher plants and play diverse roles in various biological processes. Previous studies have shown that some WRKY members act as negative regulators of secondary cell wall formation in pith parenchyma cells. However, the regulatory mechanism of pith secondary wall formation in tree species remains largely unknown. In this study, PtrWRKY19 encoding a homolog of Arabidopsis WRKY12 was isolated from Populus trichocarpa. PtrWRKY19 was expressed in all tissues tested, with highest expression in stems, especially in pith. PtrWRKY19 was located in the nucleus and functioned as a transcriptional repressor. Ectopic expression of PtrWRKY19 in an atwrky12 mutant successfully rescued the phenotype in pith cell walls caused by the defect of AtWRKY12, suggesting that PtrWRKY19 had conserved functions for homologous AtWRKY12. Overexpression of PtrWRKY19 in poplar plants led to a significant increase in the number of pith parenchyma cells. qRT-PCR analysis showed that lignin biosynthesis-related genes were repressed in transgenic plants. In transcient reporter assays, PtrWRKY19 was identified to repress transcription from the PtoC4H2 promoter containing the conserved W-box elements. These results indicated that PtrWRKY19 may function as a negative regulator of pith secondary wall formation in poplar