Clinical and experimental evidence suggests that hippocampal damage causes more severe disruption of episodic memories if those memories were encoded in the recent rather than the more distant past. This decrease in sensitivity to damage over time might reflect the formation of multiple traces within the hippocampus itself, or the formation of additional associative links in entorhinal and association cortices. Physiological evidence also supports a two-stage model of the encoding process in which the initial encoding occurs during active waking and (...) deeper consolidation occurs via the formation of additional memory traces during quiet waking or slow-wave sleep. In this article I will describe the changes in cholinergic tone within the hippocampus in different stages of the sleep-wake cycle and will propose that these changes modulate different stages of memory formation. In particular, I will suggest that the high levels of acetylcholine that are present during active waking might set the appropriate dynamics for encoding new information in the hippocampus, by partially suppressing excitatory feedback connections and so facilitating encoding without interference from previously stored information. By contrast, the lower levels of acetylcholine that are present during quiet waking and slow-wave sleep might release this suppression and thereby allow a stronger spread of activity within the hippocampus itself and from the hippocampus to the entorhinal cortex, thus facilitating the process of consolidation of separate memory traces. (shrink)

The structure and behaviour of the acetylcholine receptor (AChR) is described, and the evidence that it is an allosteric protein is discussed. The genes for the AChR subunits are subject to a complex set of spatio‐temporal transcriptional controls during development of the motor endplate, and these findings are reviewed here. Finally, the biotechnological prospects suggested by the new data are noted.

We consider Walker's thorough review in the context of thinking about future research on the relation between sleep and memory. We first address methodological issues including type of memory and sleep-stage dependency. We suggest a broader investigation of potential signaling molecules that may be critical to sleep-related consolidation. A brief review of the importance of the stress hormone cortisol illustrates this point.

It was, until recently, accepted that the two classes of acetylcholine (ACh) receptors are distinct in an important sense: muscarinic ACh receptors signal via heterotrimeric GTP binding proteins (G proteins), whereas nicotinic ACh receptors (nAChRs) open to allow flux of Na+, Ca2+, and K+ ions into the cell after activation. Here we present evidence of direct coupling between G proteins and nAChRs in neurons. Based on proteomic, biophysical, and functional evidence, we hypothesize that binding to G proteins modulates the (...) activity and signaling of nAChRs in cells. It is important to note that while this hypothesis is new for the nAChR, it is consistent with known interactions between G proteins and structurally related ligand‐gated ion channels. Therefore, it underscores an evolutionarily conserved metabotropic mechanism of G protein signaling via nAChR channels.Also watch the Video Abstract. (shrink)

It was, until recently, accepted that the two classes of acetylcholine (ACh) receptors are distinct in an important sense: muscarinic ACh receptors signal via heterotrimeric GTP binding proteins (G proteins), whereas nicotinic ACh receptors (nAChRs) open to allow flux of Na+, Ca2+, and K+ ions into the cell after activation. Here we present evidence of direct coupling between G proteins and nAChRs in neurons. Based on proteomic, biophysical, and functional evidence, we hypothesize that binding to G proteins modulates the (...) activity and signaling of nAChRs in cells. It is important to note that while this hypothesis is new for the nAChR, it is consistent with known interactions between G proteins and structurally related ligand‐gated ion channels. Therefore, it underscores an evolutionarily conserved metabotropic mechanism of G protein signaling via nAChR channels.Also watch the Video Abstract. (shrink)

This commentary reviews and extends the target article's treatment of the topic of the role of acetylcholine in hallucinatory experience in health and disease. Particular attention is paid to differentiating muscarinic and nicotinic effects in modulating the use of virtual reality mechanisms by the brain. Then, attention is drawn to the similarities between these aspects of brain function and certain aspects of television digital compression technology.

Toward illuminating the structure of Llewellyn's dream theory, I compare it in formal terms to Freud's dream theory. An alternative to both of these dream machines, grounded in the distribution of cholinergic activation in the central nervous system, is presented. It is suggested that neither nor dream theory is sufficient to account for the properties of dreams.

The cholinergic system is a good candidate for the role of determining the relative weight given in cortical information processing to new sensory information versus prior knowledge. We discuss the physiological data supporting this, and suggest that this Bayesian perspective can easily be reconciled with the dynamical framework proposed by Behrendt & Young.

Nicotinic acetylcholine receptors (nAChRs) are ligand‐gated ion channels that bring about a diversity of fast synaptic actions. Analysis of the Caenorhabditis elegans genome has revealed one of the most‐extensive and diverse nAChR gene families known, consisting of at least 27 subunits. Striking variation with possible functional implications has been observed in normally conserved motifs at the acetylcholine‐binding site and in the channel‐lining region. Some nAChR subunits are particular to neurons whilst others are present in both neurons and muscles. (...) The localization of subunits in non‐synaptic regions suggests novel roles for nAChRs. Genetic and heterologous expression studies have identified a subset of nAChR subunits that are important drug targets while the study of mutants has identified genes functionally‐linked to nAChRs. Future studies using C. elegans offer the prospect of increasing our understanding of the functional diversity of a complex nAChR gene family as well as addressing the role of nAChRs and associated proteins in human disorders. BioEssays 26:39–49, 2004.© 2003 Wiley Periodicals, Inc. (shrink)

Molecular cloning of the genes encoding the muscarinic acetylcholine receptors has shwon that receptor subtypes classified on the basis of pharmacological properties are related polypeptides encoded by distinct genes. These studies have laso revealed the existence of novel muscarinic receptor subtypes. Functional analysis of each of the subtypes expressed in mammalian cells indicates that the different subtypes activate distinct biochemical pathways, a finding that explains the tissue‐specific physiological response elicited by the neurotransmitter, acetylcholine.

The paradigmatic assumption that REM sleep is the physiological equivalent of dreaming is in need of fundamental revision. A mounting body of evidence suggests that dreaming and REM sleep are dissociable states, and that dreaming is controlled by forebrain mechanisms. Recent neuropsychological, radiological, and pharmacological findings suggest that the cholinergic brain stem mechanisms that control the REM state can only generate the psychological phenomena of dreaming through the mediation of a second, probably dopaminergic, forebrain mechanism. The latter mechanism (and thus (...) dreaming itself) can also be activated by a variety of nonREM triggers. Dreaming can be manipulated by dopamine agonists and antagonists with no concomitant change in REM frequency, duration, and density. Dreaming can also be induced by focal forebrain stimulation and by complex partial (forebrain) seizures during nonREM sleep, when the involvement of brainstem REM mechanisms is precluded. Likewise, dreaming is obliterated by focal lesions along a specific (probably dopaminergic) forebrain pathway, and these lesions do not have any appreciable effects on REM frequency, duration, and density. These findings suggest that the forebrain mechanism in question is the final common path to dreaming and that the brainstem oscillator that controls the REM state is just one of the many arousal triggers that can activate this forebrain mechanism. The “REM-on” mechanism (like its various NREM equivalents) therefore stands outside the dream process itself, which is mediated by an independent, forebrain “dream-on” mechanism. Key Words: acetylcholine; brainstem; dopamine; dreaming; forebrain; NREM; REM; sleep. (shrink)

Backgrounds: Transcranial direct current stimulation is a non-invasive brain stimulation technique for the treatment of several psychiatric disorders, e.g., mood disorders and schizophrenia. Therapeutic effects of tDCS are suggested to be produced by bi-directional changes in cortical activities, i.e., increased/decreased cortical excitability via anodal/cathodal stimulation. Although tDCS provides a promising approach for the treatment of psychiatric disorders, its neurobiological mechanisms remain to be explored.Objectives: To review recent findings from neurophysiological, chemical, and brain-network studies, and consider how tDCS ameliorates psychiatric conditions.Findings: (...) Enhancement of excitatory synaptic transmissions through anodal tDCS stimulation is likely to facilitate glutamate transmission and suppress gamma-aminobutyric acid transmission in the cortex. On the other hand, it positively or negatively modulates the activities of dopamine, serotonin, and acetylcholine transmissions in the central nervous system. These neural events by tDCS may change the balance between excitatory and inhibitory inputs. Specifically, multi-session tDCS is thought to promote/regulate information processing efficiency in the cerebral cortical circuit, which induces long-term potentiation by synthesizing various proteins.Conclusions: This review will help understand putative mechanisms underlying the clinical benefits of tDCS from the perspective of neurotransmitters, network dynamics, intracellular events, and related modalities of the brain function. (shrink)

A number of conditioning experiments utilize food as a reward. Hunger is considered to be a critical factor governing the animal's behavior in these experiments. Despite its significance, most theories of animal conditioning fail to take hunger into consideration while analyzing the behavioral data. In this paper, we analyze the neuroscientific data supporting the hypothesis that hunger and food consumption affect the brain's dopamine system, which in turn governs the animal's behavior. According to this hypothesis, chronic hunger results in a (...) decrease in the extra-cellular dopamine levels in the animal's brain. This decrease is believed to trigger a series of reactions that increase the responsivity of the phasic dopamine system. A direct consequence of this is an increased vigor of all dopamine-dependent behaviors. The level of extra-cellular dopamine is also modulated by the process of food consumption via the neurotransmitter Acetylcholine. Food consumption raises the dopamine above the baseline level. This rise depends on the animals' hunger, which when satisfied increases the level of Acetylcholine, which causes the dopamine level to fall back to the baseline. Thus, extra-cellular dopamine governs the response vigor, with an increase in dopamine resulting in a more vigorous response. This paper makes two primary contributions. Firstly, we present an abstract mathematical model based on the above hypothesis. Our mathematical model is able to provide a simple explanation for a number of behavioral findings. Another contribution of this paper is the development of a neurocomputational Leabra model of dopamine and acetylcholine activity in the basal ganglia to incorporate hunger and satiation. The experimental results obtained from this neural model are also largely in agreement with behavioral findings. (shrink)

The developing neuromuscular junction has provided an important paradigm for studying synapse formation. An outstanding feature of neuromuscular differentiation is the aggregation of acetylcholine receptors (AChRs) at high density in the postsynaptic membrane. While AChR aggregation is generally believed to be induced by the nerve, the mechanisms underlying aggregation remain to be clarified. A 43‐kD protein (43k) normally associated with the cytoplasmic aspect of AChR clusters has long been suspected of immobilizing AChRs by linking them to the cytoskeleton. In (...) recent studies, the AChR clustering activity of 43k has, at last, been demonstrated by expressing recombinant AChR and 43k in non‐muscle cells. Mutagenesis of 43k has revealed distinct domains within the primary structure which may be responsible for plasma membrane targeting and AChR binding. Other lines of study have provided clues as to how nerve‐derived (extracellular) AChR‐cluster inducing factors such as agrin might activate 43k‐driven postsynaptic membrane specialization. (shrink)

Stimulation of airway myocytes by contractile agents such as acetylcholine (ACh) activates a Ca2+-activated Cl– current (IClCa) which may play a key role in calcium homeostasis of airway myocytes and hence in airway reactivity. The aim of the present study was to model IClCa in airway smooth muscle cells using a computerised model previously designed for simulation of cardiac myocyte functioning. Modelling was based on a simple resistor-battery permeation model combined with multiple binding site activation by calcium. In order (...) to validate the model, a combination of equations, used to mimic [Ca2+]i response to ACh stimulation, were incorporated into the model. The results indicate that the model developed in this article accounts for experimental recordings and electrophysiological characteristics of this current in airway smooth muscle cells, with parameter values consistent with those calculated from experimental data. Such a model may thus be used to predict IClCa functioning, though additional experimental data from airway myocytes would be useful to more accurately determine some parameter values of the model. (shrink)

The muscle-specific kinase MuSK is part of an agrin receptor complex which stimulates tyrosine phosphorylation and drives clustering of acetylcholine receptors (AChRs) in the postsynaptic membrane at the vertebrate neuromuscular junction. MuSK also regulates synaptic gene transcription in subsynaptic nuclei. Over the past few years decisive progress has been made in the identification of MuSK effectors, helping at understanding its function in the formation of the NMJ. Alike AChR, MuSK and several of its partners are the target of mutations (...) responsible for diseases of the NMJ, such as congenital myasthenic syndromes. This minireview will focus on the multiple MuSK effectors so far identified that place MuSK at the center of a multifunctional signaling complex involved in the organization of the NMJ and associated disorders. (shrink)

Soman, an anticholinesterasic neurotoxic drug, induces epileptic seizures during severe intoxication. Their trigger conditions still remain unknown and a great variability between animals is observed. The butterfly model in the catastrophe theory has been used to explain these triggering conditions.We have developed a technique allowing, in freely moving rats, the « in vivo » determination of three sets of neurophysiological data, followed before and during a soman intoxication. For the same rat, we associated cortical acetylcholinesterase (AChE) activity by microdialysis with (...) both the assay of extracellular acetylcholine (ACh) concentrations and electroencephalographic (EEG) recording and power spectrum analysis (gamma band). Data have been analysed to define the critical parameters which lead to the epileptic fit. (shrink)

The role of acetylcholinesterase (AChE) in neurotransmission is well known. But long before synapses are formed in vertebrates, AChE is expressed in young postmitotic neuroblasts that are about to extend the first long tracts. AChE histochemistry can thus be used to map primary steps of brain differentiation. Preceding an possibly inducing AChE in avian brains, the closely related butyrylcholinesterase (BChE) spatially fore-shadows AChE-positive cell areas and the course of their axons. In particular, before spinal motor axons grow, their corresponding rostral (...) sclerotomes and myotomes express BChE, and both their neuronal source and myotomal target cells express AChE. Since axon growth has been found inhibited by acetylcholine, it is postulated that both cholinetsreases can attract neurite growth cones by neutralizing the inhibitor. Thus, the early expression of both cholinesterases that is at least partially independent from classical cholinergic synaptogenesis, sheds new light on the developmental and medical significance of these enzymes. (shrink)

Glycine is a major inhibitory neurotransmitter in the spinal cord and in the brain stem, where it acts by activating a chloride conductance. The postsynaptic glycine receptor has been purified and contains two transmembrane subunits of 48 kDa (α) and 58 kDa (β), and a peripheral membrane protein of 93 kDa. cDNA sequencing of the α and β subunits has revealed a common structural organization and a strong homology between these polypeptides and the nicotinic acetylcholine and GABAA receptor proteins. (...) The glycine receptor exhibits a heterogeneity resulting from the existence of several α subtypes with distinct functional properties and different developmental expressions. When present in the central nervous system in situ, as well as in primary cultures of spinal cord neurons, these receptors are localized at the postsynaptic membrane adjacent to the presynaptic release sites, thus forming functional microdomains at the neuronal surface. This distribution raises the question of the formation and the maintenance of the heterogeneity of the somato‐dendritic plasma membrane. (shrink)

A new theory for basic function in the nervous system has recently been proposed (Dempsher, J., 1979a, 1979b; 1980, 1981). The major basic themes of the new theory are as follows: (1) There are two fundamental units of structure and function, the fibre or conducting mechanism, and the neurocentre, where nervous system function as we know it takes place. (2) The nerve impulse is regarded as a mathematical event. The mathematics is the result of a prescribed fusion of energy and (...) matter. (3) Nervous system function everywhere in the nervous system is mathematical. In the fibre, the prescribed fusion of energy and matter results in a number. In the neurocentre, the prescribed fusion of energy and matter results in a mathematical function. Basic function in the nervous system everywhere requires a transformation of a nerve impulse in the fibre into a nerve impulse in the neurocentre with opposing properties: The nerve impulse in the fibre is confined to the fibre; cannot sum with another nerve impulse; can travel long distances with constant form and velocity; curvature in space and time are not significant features; and it is regarded as a number. On the other hand, the nerve impulse in the neurocentre is confined to the neurocentre; can sum with other nerve impulses; cannot travel long distances - even in a very short distance, it changes form; curvature in space and time is a very significant feature; and it is regarded as a mathematical function.The approach to determine how one form of the nerve impulse is transformed into the other at the input region is based on two of the differences listed above: (1) The nerve impulse in the fibre cannot sum with another nerve impulse in the fibre, whereas in the neurocentre, several nerve impulses sum to form a larger nerve impulse. (2) The nerve impulse in the fibre is regarded as a number, in the neurocentre, it is regarded as a mathematical function. The commonality of (1) and (2) is that the properties defining the nerve impulse in the fibre are associated with the property ofdiscreteness, whereas, the properties defining the nerve impulse in the neurocentre are associated with the property ofcontinuousness. Thus, the basic theme of unification of function at the input region of the neurocentre is the transformation of a phenomenon with the property of discreteness into a phenomenon with the property of continuousness. The solution to this transformation is approached from two directions:biologic andmathematical. In the biologic approach, the unit element of the nerve impulse in the fibre terminations (as.u. as a wave of energy, a spike in the classical theory) fuses with a. calcium-binding protein causing the release of Ca++. The calcium ions then combine with another protein. Associated with the second reaction is a conformational change in the Ca++-protein complex and the unit element in the neurocentre, bs.u., is emitted. Individual bs.u. then fuse with acetylcholine; summation occurs andwave b is emitted. In the mathematical approach, the nerve impulse as a number, is partitioned into two numbers with a precise rule relating these two numbers. One possibility suggested is that the number can be regarded as the value of a trigonometric function. This value then gives rise to an angle with sides related in a ratio or proportionality fashion — a relationship with the property of continuousness, as contrasted with that of a single number, discreteness. Both biologic and mathematical approaches are united so as to suggest that the mathematical (trigonometric) function arose as the result of a fusion of energy (as.u. as a wave of energy) and the calcium-binding protein as matter; following this reaction, bs.u., with opposing properties, is emitted. (shrink)

This pioneering book explores in depth the role of neurotransmitters in conscious awareness. The central aim is to identify common neural denominators of conscious awareness, informed by the neurochemistry of natural, drug induced and pathological states of consciousness. Chemicals such as acetylcholine and dopamine, which bridge the synaptic gap between neurones, are the 'neurotransmitters in mind' that form the substance of the volume, which is essential reading for all who believe that unravelling mechanisms of consciousness must include these vital (...) systems of the brain.Up-to-date information is provided on: Psychological domains of attention, motivation, memory, sleep and dreaming that define normal states of consciousness. Effects of chemicals that alter or abolish consciousness, including hallucinogens and anaesthetics. Disorders of the brain such as dementia, schizophrenia and depression considered from the novel perspective of the way these affect consciousness, and how this might relate to disturbances in neurotransmission.(Series B). (shrink)

The pharmacological literature on negative dream experiences is reviewed with respect to Revonsuo's threat rehearsal theory of dreaming. Moderate support for the theory is found, although much more work is needed. Significant questions that remain include the precise role of acetylcholine in the generation of negative dream experiences and dissociations between the pharmacology of waking fear and anxiety and threatening dreams. [Revonsuo].

There are strong resemblances between the neurobiological characteristics of hallucinations occurring in the particular case of schizophrenia and the hallucinatory activity observed during the rapid-eye-movement (dreaming) sleep stage: the same prefrontal dorsolateral deactivation; forebrain disconnectivity and disinhibition; sensory deprivation; and acetylcholine, monoamine, and glutamate modifications.

The transmission of electrical impulses in nerve and muscle cells depends fundamentally on the operation of specific ion channels in their membranes. Recent technical advances in electrical recording from cell membranes have permitted the analysis of the properties of single ion channels and the measurement of gating currents. The results have revealed considerable complexities, in particular in the operation of voltage‐gated sodium channels, and in the relationships between the several open and closed states of the channels. An important new development (...) is the cloning and analysis of the structural genes for the acetylcholine receptor and sodium channel protein, which promises to yield fresh insights into the functioning of these proteins. (shrink)

The role of brain monoamines may be important for the neurobiology of the alterations of visual alertness in recurrent complex visual hallucinations (RCVH). This is evidenced by sleep research, neurophysiologic, and clinical data. Hence, the mechanisms of RCVH may not be simply explained by acetylcholine underactivity only.