1,014 research outputs found
Differential Role of Nicotinic Acetylcholine Receptor Subunits in Physical and Affective Nicotine Withdrawal Signs
Crucial role of α4 and α6 nicotinic acetylcholine receptor subunits from ventral tegmental area in systemic nicotine self-administration
The identification of the molecular mechanisms involved in nicotine addiction and its cognitive consequences is a worldwide priority for public health. Novel in vivo paradigms were developed to match this aim. Although the beta2 subunit of the neuronal nicotinic acetylcholine receptor (nAChR) has been shown to play a crucial role in mediating the reinforcement properties of nicotine, little is known about the contribution of the different alpha subunit partners of beta2 (i.e., alpha4 and alpha6), the homo-pentameric alpha7, and the brain areas other than the ventral tegmental area (VTA) involved in nicotine reinforcement. In this study, nicotine (8.7-52.6 microg free base/kg/inf) self-administration was investigated with drug-naive mice deleted (KO) for the beta2, alpha4, alpha6 and alpha7 subunit genes, their wild-type (WT) controls, and KO mice in which the corresponding nAChR subunit was selectively re-expressed using a lentiviral vector (VEC mice). We show that WT mice, beta2-VEC mice with the beta2 subunit re-expressed exclusively in the VTA, alpha4-VEC mice with selective alpha4 re-expression in the VTA, alpha6-VEC mice with selective alpha6 re-expression in the VTA, and alpha7-KO mice promptly self-administer nicotine intravenously, whereas beta2-KO, beta2-VEC in the substantia nigra, alpha4-KO and alpha6-KO mice do not respond to nicotine. We thus define the necessary and sufficient role of alpha4beta2- and alpha6beta2-subunit containing nicotinic receptors (alpha4beta2*- and alpha6beta2*-nAChRs), but not alpha7*-nAChRs, present in cell bodies of the VTA, and their axons, for systemic nicotine reinforcement in drug-naive mic
Cooperative Binding
Molecular binding is an interaction between molecules that results in a stable association between those molecules. Cooperative binding occurs if the number of binding sites of a macromolecule that are occupied by a specific type of ligand is a nonlinear function of this ligandâs concentration. This can be due, for instance, to an affinity for the ligand that depends on the amount of ligand bound. Cooperativity can be positive (supralinear) or negative (infralinear). Cooperative binding is most often observed in proteins, but nucleic acids can also exhibit cooperative binding, for instance of transcription factors. Cooperative binding has been shown to be the mechanism underlying a large range of biochemical and physiological processes
Behavioral Sequence Analysis Reveals a Novel Role for Ă2* Nicotinic Receptors in Exploration
Nicotinic acetylcholine receptors (nAChRs) are widely expressed throughout the
central nervous system and modulate neuronal function in most mammalian brain
structures. The contribution of defined nAChR subunits to a specific behavior is
thus difficult to assess. Mice deleted for Ă2-containing nAChRs
(Ă2â/â) have been shown to be hyperactive in an
open-field paradigm, without determining the origin of this hyperactivity. We
here develop a quantitative description of mouse behavior in the open field
based upon first order Markov and variable length Markov chain analysis focusing
on the time-organized sequence that behaviors are composed of. This description
reveals that this hyperactivity is the consequence of the absence of specific
inactive states or âstopsâ. These stops are associated with
a scanning of the environment in wild-type mice (WT), and they affect the way
that animals organize their sequence of behaviors when compared with stops
without scanning. They characterize a specific âdecision
momentâ that is reduced in Ă2â/â mutant
mice, suggesting an important role of Ă2-nAChRs in the strategy used
by animals to explore an environment and collect information in order to
organize their behavior. This integrated analysis of the displacement of an
animal in a simple environment offers new insights, specifically into the
contribution of nAChRs to higher brain functions and more generally into the
principles that organize sequences of behaviors in animals
Moralizing biology: the appeal and limits of the new compassionate view of nature
In recent years, a proliferation of books about empathy, cooperation and pro-social behaviors (Brooks, 2011a) has significantly influenced the discourse of the life-sciences and reversed consolidated views of nature as a place only for competition and aggression. In this article I describe the recent contribution of three disciplines â moral psychology (Jonathan Haidt), primatology (Frans de Waal) and the neuroscience of morality â to the present transformation of biology and evolution into direct sources of moral phenomena, a process here named the âmoralization of biologyâ. I conclude by addressing the ambivalent status of this constellation of authors, for whom today âmorality comes naturallyâ: I explore both the attractiveness of their message, and the problematic epistemological assumptions of their research-programs in the light of new discoveries in developmental and molecular biology
Endogenous cholinergic inputs and local circuit mechanisms govern the phasic mesolimbic dopamine response to nicotine
Nicotine exerts its reinforcing action by stimulating nicotinic acetylcholine receptors (nAChRs) and boosting dopamine (DA) output from the ventral tegmental area (VTA). Recent data have led to a debate about the principal pathway of nicotine action: direct stimulation of the DAergic cells through nAChR activation, or disinhibition mediated through desensitization of nAChRs on GABAergic interneurons. We use a computational model of the VTA circuitry and nAChR function to shed light on this issue. Our model illustrates that the α4ÎČ2-containing nAChRs either on DA or GABA cells can mediate the acute effects of nicotine. We account for in vitro as well as in vivo data, and predict the conditions necessary for either direct stimulation or disinhibition to be at the origin of DA activity increases. We propose key experiments to disentangle the contribution of both mechanisms. We show that the rate of endogenous acetylcholine input crucially determines the evoked DA response for both mechanisms. Together our results delineate the mechanisms by which the VTA mediates the acute rewarding properties of nicotine and suggest an acetylcholine dependence hypothesis for nicotine reinforcement.Peer reviewe
A Hydrophobic Gate in an Ion Channel: The Closed State of the Nicotinic Acetylcholine Receptor
The nicotinic acetylcholine receptor (nAChR) is the prototypic member of the
`Cys-loop' superfamily of ligand-gated ion channels which mediate synaptic
neurotransmission, and whose other members include receptors for glycine,
gamma-aminobutyric acid, and serotonin. Cryo-electron microscopy has yielded a
three dimensional structure of the nAChR in its closed state. However, the
exact nature and location of the channel gate remains uncertain. Although the
transmembrane pore is constricted close to its center, it is not completely
occluded. Rather, the pore has a central hydrophobic zone of radius about 3 A.
Model calculations suggest that such a constriction may form a hydrophobic
gate, preventing movement of ions through a channel. We present a detailed and
quantitative simulation study of the hydrophobic gating model of the nicotinic
receptor, in order to fully evaluate this hypothesis. We demonstrate that the
hydrophobic constriction of the nAChR pore indeed forms a closed gate.
Potential of mean force (PMF) calculations reveal that the constriction
presents a barrier of height ca. 10 kT to the permeation of sodium ions,
placing an upper bound on the closed channel conductance of 0.3 pS. Thus, a 3 A
radius hydrophobic pore can form a functional barrier to the permeation of a 1
A radius Na+ ion. Using a united atom force field for the protein instead of an
all atom one retains the qualitative features but results in differing
conductances, showing that the PMF is sensitive to the detailed molecular
interactions.Comment: Accepted by Physical Biology; includes a supplement and a
supplementary mpeg movie can be found at
http://sbcb.bioch.ox.ac.uk/oliver/download/Movies/watergate.mp
Stratégies démographiques des poissons des riviÚres françaises : premiers résultats
International audienceThe analysis of the biological, morphological and food characteristics of 35 French species leads to distinguish two main strategies. The first one gathers 11 species with a short life span and which maximize the survival of juveniles. Within it, cold water species with a long reproduction lifetime and thermophilous species with a relatively stronger fertility can be distinguished. Their diets are essentially made of insects- plankton and insects-fishes. In the second group, no care is given to juveniles; relative fertilities are higher and inversely correlated to the number of reproduction cycles. 10 species are omnivorous with a grass-wastes tendancy, and 4 species eat strictly fishes. The canonical analysis of correspondances shows that these biological characteristics are sufficuent to understand most of the longitudinal zonation.L'analyse des caractéristiques biologiques et morpho-alimentaires de 35 espÚces françaises permet de distinguer 2 stratégies principales. La premiÚre rassemble 11 espÚces à faible longévité et maximisant la survie des jeunes. En son sein, on distingue des espÚces d'eau froide à longue durée de vie pré-reproductrice et des espÚces thermophiles à fécondité relativement plus forte. Leurs régimes alimentaires sont essentiellement du type insectivore-planctonophage et insectivore-ichtyophage. Dans le second groupe, aucun soin n'est apporté aux jeunes ; les fécondités relatives sont plus fortes et inversement corrélées avec le nombre de cycles de reproduction. 10 espÚces sont des omnivores à tendance herbivore-détritivore et 4 des ichtyophages stricts. L'analyse canonique des correspondances démontre que ces caractéristiques biologiques rendent compte de l'essentiel de la zonation longitudinale
Allostery in Its Many Disguises: From Theory to Applications.
Allosteric regulation plays an important role in many biological processes, such as signal transduction, transcriptional regulation, and metabolism. Allostery is rooted in the fundamental physical properties of macromolecular systems, but its underlying mechanisms are still poorly understood. A collection of contributions to a recent interdisciplinary CECAM (Center Européen de Calcul Atomique et Moléculaire) workshop is used here to provide an overview of the progress and remaining limitations in the understanding of the mechanistic foundations of allostery gained from computational and experimental analyses of real protein systems and model systems. The main conceptual frameworks instrumental in driving the field are discussed. We illustrate the role of these frameworks in illuminating molecular mechanisms and explaining cellular processes, and describe some of their promising practical applications in engineering molecular sensors and informing drug design efforts
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