With emotional motivation the organism prepares the body to obtain a goal. There is an anticipatory sensitization of the sensory systems in the body and the brain. Presynaptic facilitation of the sensory afference in the spinal cord is probably involved. In a second stage the higher centers develop an action image/plan to realize the goal, modifying the initial preparations in the body. The subject experiences the changes in the body as a feeling. Three empirical studies supporting this description are (...) summarized. This description of how feelings develop from emotion circuits is discussed from a phenomenological viewpoint. (shrink)

Twenty five years ago, Sir John Carew Eccles together with Friedrich Beck proposed a quantum mechanical model of neurotransmitter release at synapses in the human cerebral cortex. The model endorsed causal influence of human consciousness upon the functioning of synapses in the brain through quantum tunneling of unidentified quasiparticles that trigger the exocytosis of synaptic vesicles, thereby initiating the transmission of information from the presynaptic towards the postsynaptic neuron. Here, we provide a molecular upgrade of the Beck and Eccles (...) model by identifying the quantum quasiparticles as Davydov solitons that twist the protein α-helices and trigger exocytosis of synaptic vesicles through helical zipping of the SNARE protein complex. We also calculate the observable probabilities for exocytosis based on the mass of this quasiparticle, along with the characteristics of the potential energy barrier through which tunneling is necessary. We further review the current experimental evidence in support of this novel bio-molecular model as presented. (shrink)

Unlike other organs that operate continuously, such as the heart and kidneys, many of the operations of the nervous system shut down during sleep. The evolutionarily conserved unconscious state of sleep that puts animals at risk from predators indicates that it is an indispensable integral part of systems operation. A reasonable expectation is that any hypothesis for the mechanism of the nervous system functions should be able to provide an explanation for sleep. In this regard, the semblance hypothesis is examined. (...) Postsynaptic membranes are continuously being depolarized by the quantally released neurotransmitter molecules arriving from their presynaptic terminals. In this context, an incidental lateral activation of the postsynaptic membrane is expected to induce a semblance (cellular hallucination of arrival of activity from its presynaptic terminal, which forms a unit for internal sensation) of the arrival of activity from its presynaptic terminal as a systems property. This restricts induction of semblance to a context of a very high ratio of the duration of the default state of neurotransmitter-induced postsynaptic depolarization to the total duration of incidental lateral activations of the postsynaptic membrane. This requirement spans within a time-bin of a few sleep-wake cycles. Since the duration of quantal release remains maximized, the above requirement can be achieved only by ceiling the total duration of incidental lateral activations of the postsynaptic membrane, which necessitates a state of sleep. (shrink)

Nitric oxide (NO) is involved in synaptic long-term potentiation (LTP) by multiple signaling pathways. Here, we show that LTP of synaptic transmission can be explained as a feature of signal transduction—bistable behavior in a chain of biochemical reactions with positive feedback, formed by diffusion of NO to the presynaptic site and facilitating the release of glutamate (Glu). The dynamics of Glu, calcium (Ca2+) and NO is described by a system of nonlinear reaction–diffusion equations with modified Michaelis–Menten (MM) kinetics. Numerical (...) investigation reveals that the chain of biochemical reactions analyzed can exhibit a bistable behavior under physiological conditions when production of Glu is described by MM kinetics and decay of NO is modeled by means of two enzymatic pathways with different kinetic properties. Our finding extends understanding of the role of NO in LTP: a short high-intensity stimulus is “memorized” as a long-lasting elevation of NO concentration. The conclusions obtained by analysis of the chain of biochemical reactions describing LTP can be generalized to other chains of interactions or for creating the logical elements for biological computers. (shrink)

The use of upper limb vibration during exercise and rehabilitation continues to gain popularity as a modality to improve function and performance. Currently, a lack of knowledge of the pathways being altered during ULV limits its effective implementation. Therefore, the aim of this study was to investigate whether indirect ULV modulates transmission along spinal and corticospinal pathways that control the human forearm. All measures were assessed under CONTROL and ULV conditions while participants maintained a small contraction of the right flexor (...) carpi radialis muscle. To assess spinal pathways, Hoffmann reflexes elicited by stimulation of the median nerve were recorded from FCR with motor response amplitudes matched between conditions. An H-reflex conditioning paradigm was also used to assess changes in presynaptic inhibition by stimulating the superficial radial nerve 37 ms prior to median nerve stimulation. Cutaneous reflexes in FCR elicited by stimulation of the SR nerve at the wrist were also recorded. To assess corticospinal pathways, motor evoked potentials elicited by transcranial magnetic stimulation of the contralateral motor cortex were recorded from the right FCR and biceps brachii. ULV significantly reduced H-reflex amplitude by 15.7% for both conditioned and unconditioned reflexes. Therefore, ULV inhibits cutaneous and H-reflex transmission without influencing corticospinal excitability of the forearm flexors suggesting increased presynaptic inhibition of afferent transmission as a likely mechanism. A general increase in inhibition of spinal pathways with ULV may have important implications for improving rehabilitation for individuals with spasticity. (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)

Neuromuscular synapses are highly dynamic structures that respond to both intercellular and intracellular cues to manipulate synaptic form. A variety of post‐translational modifications of synaptic proteins are used to regulate synaptic plasticity. A recent report by DiAntonio et al.(1) shows that two ubiquitin pathway proteins, Highwire and Fat facets, may be mutually antagonistic regulators of presynaptic growth at the Drosophila neuromuscular junction. This work adds support to the emerging idea that ubiquitin, a polypeptide that targets proteins for proteasomal degradation, (...) regulates synaptic development. BioEssays 24:13–16, 2002. © 2002 John Wiley & Sons, Inc. (shrink)

Synaptic ribbons, the organelles identified in electron micrographs of the sensory synapses involved in vision, hearing, and balance, have long been hypothesized to play an important role in regulating presynaptic function because they associate with synaptic vesicles at the active zone. Their physiology and molecular composition have, however, remained largely unknown. Recently, a series of elegant studies spurred by technical innovation have finally begun to shed light on the ultrastructure and function of ribbon synapses. Electrical capacitance measurements have provided (...) sub‐millisecond resolution of exocytosis, evanescent‐wave microscopy has filmed the fusion of single 30 nm synaptic vesicles, electron tomography has revealed the 3D architecture of the synapse, and molecular cloning has begun to identify the proteins that make up ribbons. These results are consistent with the ribbon serving as a vesicle “conveyor belt” to resupply the active zone, and with the suggestion that ribbon and conventional chemical synapses have much in common. BioEssays 23:831–840, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

There is probably only one information system in living nature — the macromolecular system including DNA, RNA and protein. Its unity for the genetic and nervous activity can be followed in the storage of information (heredity, memory) and in its processing (recombination and selection of both genetic and mental information). According to the hypothesis of the code of nerve impulses, nucleotide triplets of the nucleus, or more likely amino acids of the surface protein of the impulse generating area of a (...) neuron, generate a limited variety of interspike intervals so that each amino acid corresponds to a certain interspike interval and this particular interval initiates by means of a specific neurotransmitter, the synthesis of the same amino acid (or nucleotide triplet) in the postsynaptic neuron. Thus, a series of impulses produces in the postsynaptic neuron a sequence of amino acids in a form of a polypeptide identical to the polypeptide of the presynaptic neuron. (shrink)

This paper argues that nonphysical souls would violate fundamental physical laws if they were able to influence brain events. Though we have no idea how nonphysical souls might operate, we know quite a bit about how brains work, so we can consider each of the ways that an external force could interrupt brain processes enough to control one’s body. It concludes that there is no way that a nonphysical soul could interact with the brain—neither by introducing new energy into the (...) physical world, nor by borrowing existing energy from it—without apparently violating one or more basic laws of physics, such as the law of conservation of energy. And despite widespread appeals to quantum mechanics to give interactionism an air of scientific respectability, the essential randomness of quantum processes prohibits the distinctly nonrandom influence that a nonphysical soul must have on brain events in order to control the body, and quantum mechanical uncertainty is not great enough to allow neurons to fire action potentials. -/- 1. Introduction -- 2. How the Brain Works -- 3. Mind-Brain Interaction Mechanisms - 3.1 Opening Sodium Channels - 3.2 Altering Voltage Gradients - 3.3 Synaptic Transmission - 3.3.1 The Presynaptic Neuron - 3.3.2 The Post-Synaptic Neuron - 3.3.3 The Beck and Eccles Models - 3.4 Neuronal Modulation - 3.5 Self-Generation of Action Potentials by Neurons -- 4. Harnessing Energy -- 5. How Many Action Potentials for a Volitional Act? -- 6. Input: From Brain to Nonphysical Mind -- 7. Discussion -- Appendix A: Opening Gates on Membrane Channels - A.1 Directly Opening Gates - A.2 Changing Voltage Across the Membrane -- Appendix B: The Biochemical Approach. (shrink)

The RecA family proteins mediate homologous recombination, a ubiquitous mechanism for repairing DNA double‐strand breaks (DSBs) and stalled replication forks. Members of this family include bacterial RecA, archaeal RadA and Rad51, and eukaryotic Rad51 and Dmc1. These proteins bind to single‐stranded DNA at a DSB site to form a presynaptic nucleoprotein filament, align this presynaptic filament with homologous sequences in another double‐stranded DNA segment, promote DNA strand exchange and then dissociate. It was generally accepted that RecA family proteins (...) function throughout their catalytic cycles as right‐handed helical filaments with six protomers per helical turn. However, we recently reported that archaeal RadA proteins can also form an extended right‐handed filament with three monomers per helical turn and a left‐handed protein filament with four monomers per helical turn. Subsequent structural and functional analyses suggest that RecA family protein filaments, similar to the F1‐ATPase rotary motor, perform ATP‐dependent clockwise axial rotation during their catalytic cycles. This new hypothesis has opened a new avenue for understanding the molecular mechanism of RecA family proteins in homologous recombination. BioEssays 30:48–56, 2008. © 2007 Wiley Periodicals, Inc. (shrink)

Elevations in brain stimulation reward (BSR) thresholds have been observed in rats undergoing nicotine withdrawal and have been proposed as a sensitive measure of the negative affective state associated with nicotine withdrawal. mGluR are presynaptic autoreceptors that decrease glutamate release when stimulated. The aim of this study was to examine the role of glutamate neurotransmission in nicotine dependence. The mGluR agonist LY314582 (2.5–7.5 mg/kg) precipitated nicotine withdrawal as measured by elevations in BSR thresholds in nicotine-treated rats but not in (...) controls. It was hypothesized that LY314582 precipitated nicotine withdrawal by decreasing glutamatergic tone at postsynaptic glutamate receptors. Therefore, the effects of MPEP (0.5–2 mg/kg), an mGluR antagonist, and MK-801 (0.01–1 mg/kg), an NMDA receptor antagonist, were examined. MPEP elevated BSR thresholds by an equal magnitude in control and nicotine-treated rats. At low doses, MK-801 (0.01–0.2 mg/kg) lowered BSR thresholds to a similar extent in control and nicotine-treated rats. At higher doses, MK-801 (0.25–1 mg/kg) disrupted performance in nicotine-treated and control rats. These data indicate that mGluR and NMDA receptors regulate BSR in opposite directions in non-dependent animals, and chronic nicotine treatment does not alter these effects. Most importantly, the data demonstrate that the mGluR is involved in nicotine dependence, but mGluR and NMDA receptors do not mediate mGluR actions in nicotine dependence. (shrink)

Multidisciplinary studies have led to the discovery and characterization of cysteine string proteins (csps) in both Drosophila and Torpedo. Phenotypic analysis of csp mutants in Drosophila demonstrates a crucial role for csp in synaptic transmission. Expression studies of Torpedo csp (Tcsp) in Xenopus oocytes suggests that the protein has some role in the function of presynaptic Ca2+ channels. However, biochemical purification of Tcsp indicates that is associated with synaptic vesicles rather than with the plasma membrane of presynaptic terminals (...) where Ca2+ channels reside. These results suggest a model in which csps serve as a link by which docked synaptic vesicles could modulate the activity of presynaptic Ca2+ channels. (shrink)

Bidirectional trans‐synaptic signaling is essential for the formation, maturation, and plasticity of synaptic connections. Synaptic cell adhesion molecules (CAMs) are prime drivers in shaping the identities of trans‐synaptic signaling pathways. A series of recent studies provide evidence that diverse presynaptic cell adhesion proteins dictate the regulation of specific synaptic properties in postsynaptic neurons. Focusing on mammalian synaptic CAMs, this article outlines several exemplary cases supporting this notion and highlights how these trans‐synaptic signaling pathways collectively contribute to the specificity and (...) diversity of neural circuit architecture. (shrink)

In a companion review1 we discussed the data supporting the conclusion that at least two subtypes of spectrin exist in mammalian brain. One form is found in the cell bodies, dendrites, and post‐synaptic terminals of neurons (brain spectrin(240/235E)) and the other subtype is located in the axons and presynaptic terminals (brain spectrin(240/235)). Our recent understanding of brain spectrin subtype localization suggests a possible explanation for a conundrum concerning brain 4.1 localization. Amelin, an immunoreactive analogue of red blood cell (rbc) (...) cytoskeletal protein 4.1, is localized in neuronal cell bodies and dendrites when brain sections are stained with antibody against rbc protein 4.1. However, it has recently been suggested that synapsin I, a neuron‐specific phosphoprotein associated with the cytoplasmic surface of small synaptic vesicles, is related to erythrocyte 4.1. In this review we hypothesize that there are at least two forms of brain 4.1: a cell body/dendritic form (amelin) which is detected with rbc protein 4.1 antibody, and a unique form found exclusively in the presynaptic terminal (synapsin I). The binding of synapsin I to brain spectrin(240/235), and its ability to stimulate the spectrin/F‐actin interaction in a phosphorylation‐dependent manner suggests a model for the regulation of synaptic transmission mediated by the neuronal cytoskeleton. (shrink)

Our results on hippocampal long-term potentiation are considered in the context of Xia et al.'s hypothesis. Whereas the target article proposes presynaptic PKC involvement in adenylyl cyclase activation by phosphorylation of nenromodulin, we suggest an additional postsynaptic role involving RC3/nenrogranin. Finally, we examine the possibility that the adenylyl cyclase mutant mouse may display normal learning with a selective impairment of memory.

Mammalian neural cells contain at least two forms of brain spectrin: brain spectrin (240/235) which is located primarily in the axons and presynaptic terminals of neurons, and brain spectrin (240/235E) which is found in the cell bodies, dendrites and postsynaptic terminals of neurones. Brain spectrin (240/235E) is also found in certain glial cell types. Antibodies against red blood cell spectrin detect only brain spectrin (240/235E), while antibodies against brain spectrin isolated from axonal and synaptic membranes detect brain spectrin (240/235). (...) Previous apparent discrepancies in the literature concerning brain spectrin localization at the light microscope level were undoubtedly due to different laboratories detecting distinct brain spectrin subtypes, based on the particular antibody being utilized for immunohistochemistry. In this review we (1) discuss the data supporting the presence of at least two distinct subtypes of mammalian brain spectrin, (2) explain how these results reconcile previous discrepancies concerning the localization of spectrin within neural cells, and (3) suggest the future implications of these findings. (shrink)

Long‐term modification of synaptic strength is thought to be the basic mechanism underlying the activity‐dependent refinement of neural circuits and the formation of memories engrammed on them. Studies ranging from cell culture preparations to humans subjects indicate that the decision of whether a synapse will undergo strengthening or weakening critically depends on the temporal order of presynaptic and postsynaptic activity. At many synapses, potentiation will be induced only when the presynaptic neuron fires an action potential within milliseconds before (...) the postsynaptic neuron fires, whereas weakening will occur when it is the postsynaptic neuron that fires first. Such processes might be important for the remodeling of neural circuits by activity during development and for network functions such as sequence learning and prediction. Ultimately, this synaptic property might also be fundamental for the cognitive process by which we structure our experience through cause and effect relations. BioEssays 24:212–222, 2002. © 2002 Wiley Periodicals, Inc.; DOI 10.1002/bies.10060. (shrink)

Synapsins I and II are a family of synaptic vesicle‐associated phosphoproteins involved in the short‐term regulation of neurotransmitter release. In this review, we discuss a working model for the molecular mechanisms by which the synapsins act. We propose that synapsin I links synaptic vesicles to actin filaments in the presynaptic nerve terminal and that these interactions are modulated by the reversible phosphorylation of synapsin I through various signal transduction pathways. The high degree of homology between the synapsins suggests that (...) some of the functional properties of synapsin I are also shared by synapsin II. (shrink)

Introduction: Congenital myasthenic syndromes refer to a heterogenic group of neuromuscular transmission disorders. CMS-subtypes are diverse regarding exercise intolerance and muscular weakness, varying from mild symptoms to life-limiting forms with neonatal onset. Long-term follow-up studies on disease progression and treatment-response in pediatric patients are rare.Patients and Methods: We analyzed retrospective clinical and medication data in a cohort of 32 CMS-patients including the application of a standardized, not yet validated test to examine muscular strength and endurance in 21 patients at the (...) last follow-up. Findings obtained in our cohort were compared with long-term follow-up studies of CMS-cohorts from the literature by considering the underlying molecular mechanisms. Outcomes of CMS-ST were compared to results of normal clinical assessment.Results: Thirty-two pediatric patients with defects in eight different CMS-genes were followed by a median time of 12.8 years. Fifty-nine percentage of patients manifested with first symptoms as neonates, 35% as infants. While 53% of patients presented a reduced walking distance, 34% were wheelchair-bound. Even under adequate therapy with pyridostigmine and 3,4-diaminopyridine, CHAT-mutations led to the progression of muscular weakness partly in combination with persistent respiratory and bulbar symptoms. RAPSN, CHRND, and CHRNB1 patients with neonatal manifestation, early respiratory problems, and bulbar symptoms showed a good and maintained treatment response. CHAT and CHRNE patients required higher PS dosages, whereas RAPSN patients needed a lower mean dosage at the last follow-up. The benefits of short-term medication and long-term progression of symptoms were highly dependent on the specific genetic defect. CMS-ST was carried out in 17/21 patients, determined affected muscle groups including bulbar and ocular symptoms, some of which were not reported by the patients.Conclusions: Our findings and comparison with the literature- suggest a better treatment-response and less severe progression of symptoms present in patients suffering from mutations in CMS-genes directly associated with receptor deficiency, while patients with defects leading to synaptopathy and presynaptic defects tend to have worse outcomes. Assessment of affected muscular groups and clinical symptoms by CMS-ST may be a useful tool for optimal therapeutic management of the patients, especially for future clinical studies. (shrink)

Neurons are now known to produce a variety of types of chemical transmitters. Classical transmitters are stored within synaptic vesicles which undergo synaptic exocytosis in association with presynaptic thickenings. The larger, dense‐cored secretory granules present in most neurons contain neuropeptides and mainly discharge their contents at morphologically undifferentiated (i.e.nonsynaptic) sites. The synaptic character of vesicle discharge enables transmitters to exercise a highly focal action, whereas nonsynaptic release probably relates to the slow rate of degradation of many neuropeptides and their (...) consequent widespread diffusion and sphere of action. However, one variant of the basic pattern, involving the restriction of granule discharge to areas of the terminal plasmalemma situated adjacent to the postsynaptic cells (i.e. a parasynaptic configuration), enables a degree of targeted peptide discharge to be achieved. The diversity of patterns of neural exocytosis adds a further dimension to the complexity of nervous function. (shrink)

During the paradoxical dreaming sleep stage, characterized by hallucinations and delusions, as in schizophrenia, the increased subcortical release of dopamine, the presynaptic inhibition of thalamic relay nuclei, and serotonergic disinhibition are in accordance with the model for the mechanism of hallucination-induction.

Complex functions of the central nervous system such as learning and memory are believed to result from the modulation of the synaptic transmission between neurons. The sequence of events leading to the fusion of synaptic vesicles at the presynaptic active zone and the detection of this signal at the postsynaptic density involve the activity of ion channels and neurotransmitter receptors. Their accumulation and dynamic exchange at synapses are dependent on their interaction with synaptic scaffolds. These are synaptic structures composed (...) of adaptor proteins that provide binding sites for receptors and channels as well as other synaptic proteins. While in its entirety the synaptic scaffold is a relatively stable structure, individual adaptor proteins exchange at a fast time scale. These properties of scaffolds help to ensure the stability of synaptic transmission while permitting the modulation of synaptic strength. Here, we review the dynamics of the synaptic scaffold and of adaptor proteins in relation to their roles in the organisation of the synapse as well as in the clustering and trafficking of receptor proteins. BioEssays 30:1062–1074, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

> What I'm interested in is your response to Tegmark. I haven't yet looked at > the paper you sent me in your email, but one response that I thought of is > this: Tegmark's argument, if cogent, suggests that there can't be neural > indeterminacies based on macro-level superpositions that collapse due to > neural processes. But your view doesn't involve macro-level superpositions; > it involves micro-level superpositions (of presynaptic calcium ions). So > even if Tegmark's argument is (...) sound, it's irrelevant to your view. Does > this sound right to you? (shrink)

Neurotransmitter release takes place by the exocytosis of loaded synaptic vesicles. The vesicles then fuse to the presynaptic membrane and are recycled by an endocytotic mechanism. A quantitative optical assay that detects uptake and release of a fluorescent dye during presynaptic activity was recently developed and used on the frog neauromuscular junction. I discuss a report(1) that demonstrates the effective application of this method to a Drosophila preparation. The authors use the shibire mutation and a spider venom to (...) identify two intermediates in vesicle recycling. Their report, along with other recent studies, demonstrates the power and promise of the genetic approach for the understanding of mechanisms of synapse function and development. (shrink)

The RecA family proteins mediate homologous recombination, a ubiquitous mechanism for repairing DNA double‐strand breaks (DSBs) and stalled replication forks. Members of this family include bacterial RecA, archaeal RadA and Rad51, and eukaryotic Rad51 and Dmc1. These proteins bind to single‐stranded DNA at a DSB site to form a presynaptic nucleoprotein filament, align this presynaptic filament with homologous sequences in another double‐stranded DNA segment, promote DNA strand exchange and then dissociate. It was generally accepted that RecA family proteins (...) function throughout their catalytic cycles as right‐handed helical filaments with six protomers per helical turn. However, we recently reported that archaeal RadA proteins can also form an extended right‐handed filament with three monomers per helical turn and a left‐handed protein filament with four monomers per helical turn. Subsequent structural and functional analyses suggest that RecA family protein filaments, similar to the F1‐ATPase rotary motor, perform ATP‐dependent clockwise axial rotation during their catalytic cycles. This new hypothesis has opened a new avenue for understanding the molecular mechanism of RecA family proteins in homologous recombination. BioEssays 30:48–56, 2008. © 2007 Wiley Periodicals, Inc. (shrink)