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)

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)

We propose that sleep is linked to synaptic homeostasis. Specifically, we propose that: (1) Wakefulness is associated with synaptic potentiation in cortical circuits; (2) synaptic potentiation is tied to the homeostatic regulation of slow wave activity; (3) slow wave activity is associated with synaptic downscaling; and (4) synaptic downscaling is tied to several beneficial effects of sleep, including performance enhancement.

CB1 receptors are functionally present within brain mitochondria, although they are usually considered specifically targeted to plasma membrane. Acute activation of mtCB1 alters mitochondrial ATP generation, synaptic transmission, and memory performance. However, the detailed mechanism linking disrupted mitochondrial metabolism and synaptic transmission is still uncharacterized. CB1 receptors are among the most abundant G protein-coupled receptors in the brain and impact on several processes, including fear coping, anxiety, stress, learning, and memory. Mitochondria perform several key physiological processes for neuronal (...) homeostasis, including production of ATP and reactive oxygen species, calcium buffering, metabolism of neurotransmitters, and apoptosis. It is therefore possible that acute activation of mtCB1 impacts on these different mitochondrial functions to modulate synaptic transmission. In reviewing and integrating across the literature in this area, we describe the possible mechanisms involved in the regulation of brain physiology by mtCB1 receptors. Activation of mitochondrial CB1 but not of plasma membrane CB1 decreases brain mitochondrial activity, glutamatergic synaptic transmission, and memory performance. Several processes can be involved in this alteration of brain physiology, including mitochondrial ATP and ROS production, axonal mitochondrial transport, Ca2+ homeostasis, and/or metabolism of the neurotransmitter glutamate. (shrink)

l‐Lactate is emerging as a crucial regulatory nexus for energy metabolism in the brain and signaling transduction in synaptic plasticity, memory processes, and drug addiction instead of being merely a waste by‐product of anaerobic glycolysis. In this review, the role of lactate in various memory processes, synapse plasticity and drug addiction on the basis of recent studies is summarized and discussed. To this end, three main parts are presented: first, lactate as an energy substrate in energy metabolism of the (...) brain is described; second, lactate as a novel signaling molecule in synaptic plasticity, neural circuits, memory, and drug addiction is described; and third, in light of the above descriptions, it is plausible to speculate that lactate is predominantly a signaling molecule in specific memory processes and partly acts as an energy substrate. The future perspective in lactate signaling involving microglia and associated precise signaling pathways in the brain is highlighted. (shrink)

Pathogenesis in tauopathies involves the accumulation of tau in the brain and progressive synapse loss accompanied by cognitive decline. Pathological tau is found at synapses, and it promotes synaptic dysfunction and memory deficits. The specific role of toxic tau in disrupting the molecular networks that regulate synaptic strength has been elusive. A novel mechanistic link between tau toxicity and synaptic plasticity involves the acetylation of two lysines on tau, K274, and K281, which are associated with dementia in (...) Alzheimer's disease (AD). We propose that an increase in tau acetylated on these lysines blocks the expression of long‐term potentiation at hippocampal synapses leading to impaired memory in AD. Acetylated tau could inhibit the activity‐dependent recruitment of postsynaptic AMPA‐type glutamate receptors required for plasticity by interfering with the postsynaptic localization of KIBRA, a memory‐associated protein. Strategies that reduce the acetylation of tau may lead to effective treatments for cognitive decline in AD. (shrink)

Insights into the role of sleep in the molecular mechanisms of memory consolidation may come from studies of activity-dependent synaptic plasticity, such as long-term potentiation (LTP). This commentary posits a specific contribution of sleep to LTP stabilization, in which mRNA transported to dendrites during wakefulness is translated during sleep. Brain-derived neurotrophic factor may drive the translation of newly transported and resident mRNA.

Long-term potentiation is one of the most extensively studied forms of neuroplasticity and is considered the strongest candidate mechanism for memory and learning. The use of event-related potentials and sensory stimulation paradigms has allowed for the translation from animal studies to non-invasive studies of LTP-like synaptic plasticity in humans. Accumulating evidence suggests that synaptic plasticity as measured by stimulus-specific response modulation is reduced in neuropsychiatric disorders such as major depressive disorder, bipolar disorders and schizophrenia, suggesting that impaired (...) class='Hi'>synaptic plasticity plays a part in the underlying pathophysiology of these disorders. This is in line with the neuroplasticity hypothesis of depression, which postulate that deficits in neuroplasticity might be a common pathway underlying depressive disorders. The current study aims to replicate and confirm earlier reports that visual stimulus-specific response modulation is a viable probe into LTP-like synaptic plasticity in a large sample of healthy adults. Further, this study explores whether impairments in LTP-like synaptic plasticity is associated with self-reported subclinical depressive symptoms and stress in a healthy population. Consistent with prior research, the current study replicated and confirmed reports demonstrating significant modulation of visual evoked potentials following visual high-frequency stimulation. Current results further indicate that reduced LTP-like synaptic plasticity is associated with higher levels of self-reported symptoms of depression and perceived stress. This indicate that LTP-like plasticity is sensitive to sub-clinical levels of psychological distress, and might represent a vulnerability marker for the development of depressive symptoms. (shrink)

In this commentary, arguments are made for a dendritic code being preferable to a temporal synaptic code as a model of conscious experience. A temporal firing pattern is a product of an ongoing neural computation; hence, it is based on a neural algorithm and an algorithm may not provide the most suitable model for conscious experience. Reiteration of a temporal firing code as suggested in a preceding article (Helekar, 1999) does not necessarily improve the situation. The alternative model presented (...) here is that certain synaptic activity patterns, possibly those possessing universal features as suggested by Helekar, can become encoded in the dendritic structure. Following dendritic encoding, quantum phenomena in those specific dendrite sets could illuminate the static image of that encoded synaptic activity. It is the activation of the static image that would be equivalent to conscious experience; thus, conscious awareness would not be directly affiliated with synaptic activity. This dendrite encoding model may go farther than other models to explain the gestalt nature of consciousness, insofar as quantum entanglement could produce an interconnectedness between specific sets of dendrites-an interconnectedness that need not be based on neural computation or neural connections. (shrink)

The purpose of this paper is to present a bio-physical basis of mathematics. The essence of the theory is that function in the nervous system is mathematical. The mathematics arises as a result of the interaction of energy (a wave with a precise curvature in space and time) and matter (a molecular or ionic structure with a precise form in space and time). In this interaction, both energy and matter play an active role. That is, the interaction results in a (...) change in form of both energy and matter. There are at least six mathematical operations in a simple synaptic region. It is believed the form of both energy and matter are specific, and their interaction is specific, that is, function in most of the nervous system is stereotyped. It is suggested that mathematics be taken out of the mind and placed where it belongs — in nature and the synaptic regions of the nervous system; it results in both places from a precise interaction between energy (in a precise form) and matter (in a precise structure). (shrink)

Phage DNA packaging occurs by DNA translocation into a prohead. Terminases are enzymes which initiate DNA packaging by cutting the DNA concatemer, and they are closely fitted structurally to the portal vertex of the prohead to form a ‘packasome’. Analysis among a number of phages supports an active role of the terminases in coupling ATP hydrolysis to DNA translocation through the portal. In phage T4 the small terminase subunit promotes a sequence‐specific terminase gene amplification within the chromosome. This link between (...) recombination and packaging suggests a DNA synapsis mechanism by the terminase to control packaging initiation, formally homologous to eukaryotic chromosome segregation. (shrink)

The quest for molecular mechanisms that guide axons or specify synaptic contacts has largely focused on molecules that intuitively relate to the idea of an “instruction.” By contrast, “permissive” factors are traditionally considered background machinery without contribution to the information content of a molecularly executed instruction. In this essay, I recast this dichotomy as a continuum from permissive to instructive actions of single factors that provide relative contributions to a necessarily collaborative effort. Individual molecules or other factors do not (...) constitute absolute instructions by themselves; they provide necessary context for each other, thereby creating a composite that defines the overall instruction. The idea of composite instructions leads to two main conclusions: first, a composite of many seemingly permissive factors can define a specific instruction even in the absence of a single dominant contributor; second, individual factors are not necessarily related intuitively to the overall instruction or phenotypic outcome. (shrink)

Despite its uniform appearance, the cerebellar cortex is highly heterogeneous in terms of structure, genetics and physiology. Purkinje cells (PCs), the principal and sole output neurons of the cerebellar cortex, can be categorized into multiple populations that differentially express molecular markers and display distinctive physiological features. Such features include action potential rate, but also their propensity for synaptic and intrinsic plasticity. However, the precise molecular and genetic factors that correlate with the differential physiological properties of PCs remain elusive. In (...) this article, we provide a detailed overview of the cellular mechanisms that regulate PC activity and plasticity. We further perform a pathway analysis to highlight how molecular characteristics of specific PC populations may influence their physiology and plasticity mechanisms. (shrink)

Freeman's pioneering work -- and neurodynamics in general -- has largely ignored specification of an anatomical framework within which features of coherent objects are represented, associated, deleted, and manipulated in computations. Recent theoretical work suggests such a framework can emerge during embryogenesis by selection of neuron ensembles and synaptic connections that maximize the magnitude of synchrony while approaching ultra-small-world connectivity. The emergent structures correspond to those of both columnar and non-columnar cortex. With initial connections thus organized, spatio-temporal information in (...) sensory inputs can generate systematic and specific patterns of synchronous oscillation, with consequent synaptic storage. The theoretical assemblies of connections resemble experimentally observed 'lego sets', while facilitation and interference among synchronous patterns, particularly when executed by fast synapses under metabolic entanglement, imply powerful parallel computation. (shrink)

This article explores the domain of legal analysis and its methodologies, emphasising the significance of generalisation in legal systems. It discusses the process of generalisation in relation to legal concepts and the development of ideal concepts that form the foundation of law. The article examines the role of logical induction and its similarities with semantic generalisation, highlighting their importance in legal decision-making. It also critiques the formal-deductive approach in legal practice and advocates for more adaptable models, incorporating fuzzy logic, non-monotonic (...) defeasible reasoning, and artificial intelligence. The potential application of neural networks, specifically deep learning algorithms, in legal theory is also discussed. The article discusses how neural networks encode legal knowledge in their synaptic connections, while the syllogistic model condenses legal information into axioms. The article also highlights how neural networks assimilate novel experiences and exhibit evolutionary progression, unlike the deductive model of law. Additionally, the article examines the historical and theoretical foundations of jurisprudence that align with the basic principles of neural networks. It delves into the statistical analysis of legal phenomena and theories that view legal development as an evolutionary process. The article then explores Friedrich Hayek’s theory of law as an autonomous self-organising system and its compatibility with neural network models. It concludes by discussing the implications of Hayek’s theory on the role of a lawyer and the precision of neural networks. (shrink)

Research in the neurosciences continues to provide evidence that sleep plays a role in the processes of learning and memory. There is less of a consensus, however, regarding the precise stages of memory development during which sleep is considered a requirement, simply favorable, or not important. This article begins with an overview of recent studies regarding sleep and learning, predominantly in the procedural memory domain, and is measured against our current understanding of the mechanisms that govern memory formation. Based on (...) these considerations, I offer a new neurocognitive framework of procedural learning, consisting first of acquisition, followed by two specific stages of consolidation, one involving a process of stabilization, the other involving enhancement, whereby delayed learning occurs. Psychophysiological evidence indicates that initial acquisition does not rely fundamentally on sleep. This also appears to be true for the stabilization phase of consolidation, with durable representations, resistant to interference, clearly developing in a successful manner during time awake (or just time, per se). In contrast, the consolidation stage, resulting in additional/enhanced learning in the absence of further rehearsal, does appear to rely on the process of sleep, with evidence for specific sleep-stage dependencies across the procedural domain. Evaluations at a molecular, cellular, and systems level currently offer several sleep specific candidates that could play a role in sleep-dependent learning. These include the upregulation of select plasticity-associated genes, increased protein synthesis, changes in neurotransmitter concentration, and specific electrical events in neuronal networks that modulate synaptic potentiation. Key Words: consolidation; enhancement; learning; memory; plasticity; sleep; stabilization. (shrink)

By reviewing most of the neurobiology of consciousness, this article highlights some major reasons why a successful emulation of the dynamics of human consciousness by artificial intelligence is unlikely. The analysis provided leads to conclude that human consciousness is epigenetically determined and experience and context-dependent at the individual level. It is subject to changes in time that are essentially unpredictable. If cracking the code to human consciousness were possible, the result would most likely have to consist of a temporal pattern (...) code simulating long-distance signal reverberation and de-correlation of all spatial signal contents from temporal signals. In the light of the massive evidence for complex interactions between implicit (non-conscious) and explicit (conscious) contents of representation, the code would have to be capable of making implicit (non-conscious) processes explicit. It would have to be capable of a progressively less and less arbitrary selection of temporal activity patterns in a continuously developing neural network structure identical to that of the human brain, from the synaptic level to that of higher cognitive functions. The code’s activation thresholds would depend on specific temporal signal coincidence probabilities, vary considerably with time and across individual experience data, and would therefore require dynamically adaptive computations capable of emulating the properties of individual human experience. No known machine or neural network learning approach has such potential. (shrink)

This paper addresses the questions concerningthe relationship between scientific andcognitive processes. The fact that both,science and cognition, aim at acquiring somekind of knowledge or representationabout the world is the key for establishing alink between these two domains. It turns outthat the constructivist frameworkrepresents an adequate epistemologicalfoundation for this undertaking, as its focusof interest is on the (constructive)relationship between the world and itsrepresentation. More specifically, it will beshown how cognitive processes and their primaryconcern to construct a representation of theenvironment and to (...) generate functionallyfitting behavior can act as the basis forembedding the activities and dynamics of theprocess of science in them by making use ofconstructivist concepts, such as functionalfitness, structure determinedness, etc.Cognitive science and artificiallife provide the conceptual framework of representational spaces and their interactionbetween each other and with the environmentenabling us to establish this link betweencognitive processes and thedevelopment/dynamics of scientific theories.The concepts of activation, synaptic weight,and genetic (representational) spaces arepowerful tools which can be used asexplanatory vehiclesfor a cognitivefoundation of science, more specifically forthe context of discovery (i.e., thedevelopment, construction, and dynamics ofscientific theories and paradigms).Representational spaces do not only offer us abetter understanding of embedding science incognition, but also show, how theconstructivist framework, both, can act as anadequate epistemological foundation for theseprocesses and can be instantiated by theserepresentational concepts from cognitivescience. The final part of this paper addresses somemore fundamental questions concerning thepositivistic and constructivist understandingof science and human cognition. Among otherthings it is asked, whether a purelyfunctionalist and quantitative view of theworld aiming almost exclusively at itsprediction and control is really satisfying forour intellect (having the goal of achieving aprofound understanding of reality). (shrink)

Many kinds of complex systems exhibit characteristic patterns of temporal correlations that emerge as the result of functional interactions within a structured network. One such complex system is the brain, composed of numerous neuronal units linked by synaptic connections. The activity of these neuronal units gives rise to dynamic states that are characterized by specific patterns of neuronal activation and co-activation. These patterns, called functional connectivity, are possible neural correlates of perceptual and cognitive processes. Which functional connectivity patterns arise (...) depends on the anatomical structure of the underlying network, which in turn is modified by a broad range of activity-dependent processes. Given this intricate relationship between structure and function, the question of how patterns of anatomical connectivity constrain or determine dynamical patterns is of considerable theoretical importance. The present study develops computational tools to analyze networks in terms of their structure and dynamics. We identify different classes of network, including networks that are characterized by high complexity. These highly complex networks have distinct structural characteristics such as clustered connectivity and short wiring length similar to those of large-scale networks of the cerebral cortex. (shrink)

This selective review explores biologically inspired learning as a model for intelligent robot control and sensing technology on the basis of specific examples. Hebbian synaptic learning is discussed as a functionally relevant model for machine learning and intelligence, as explained on the basis of examples from the highly plastic biological neural networks of invertebrates and vertebrates. Its potential for adaptive learning and control without supervision, the generation of functional complexity, and control architectures based on self-organization is brought forward. Learning (...) without prior knowledge based on excitatory and inhibitory neural mechanisms accounts for the process through which survival-relevant or task-relevant representations are either reinforced or suppressed. The basic mechanisms of unsupervised biological learning drive synaptic plasticity and adaptation for behavioral success in living brains with different levels of complexity. The insights collected here point toward the Hebbian model as a choice solution for “intelligent” robotics and sensor systems. Keywords: Hebbian learning; synaptic plasticity; neural networks; self-organization; brain; reinforcement; sensory processing; robot control . (shrink)

Nerve processes elongate, branch and form synaptic contacts in a highly regulated and specific manner. Long‐distance axon elongation is restricted to the main phase of axon formation during development, but can be reinduced upon lesions in the adult (regeneration). It correlates with the expression of defined genes, including proteins involved in signalling (e.g. src, NCAM, integrins), transcription factors (e.g. c‐jun) and structural proteins (e.g. actin and tubulin isoforms). Activation of an axon elongation program may require bcl‐2. The formation and (...) growth of local branches (sprouting) is controlled by mechanisms in the target region. In addition, the expression of growth‐associated proteins such as GAP‐43 and CAP‐23 in neurons lowers the threshold for nerve sprouting and potentiates its vigour. Recent studies suggest that nerve sprouting and long‐distance elongation depend on the expression of different intrinsic components in neurons. One implication of these findings is that the differential expression of genes facilitating local branching may affect structural plasticity in the intact adult nervous system. (shrink)

The highly ordered neuronal projections from the retina to the tectum mesencephali (optic tectum) in several vertebrate groups have been intensively studied. Several hypotheses so far have been proposed, suggesting mechanisms to explain the topographical and biochemical specificity of the retinotectal projections during ontogeny. In the present paper we compare the main hypotheses of retinotectal development with respect to the nature of specificity envisaged, the activity-dependence versus inheritance criterium and the strategy of argument, in casu the descriptive versus (...) interferential type of argument. Matching of the current developmental hypotheses and mechanisms for elimination or persistance of contralateral, respectively ipsilateral connections, is attempted with respect to the known neuroanatomical connectivity data in the amphibian optic tectum and with respect to the symmetry relations between ipsilateral and contralateral connection patterns described in amphibians and other vertebrate groups. Local mechanisms influencing the survival potential of synaptic contacts between retinal afferents and tectal neurons are probably essential for generating global symmetry patterns. Finally, a global topological approach is discussed with respect to its applicability in the amphibian retinotectal projection system. Basic assumptions of topological modeling appear to rely on anatomical and functional properties of the visual system like left-right symmetry, dichotomy, (absence of) convergence and segregation of fibers and neurons into columnar information units. It is concluded however, that more neuroanatomical, physiological and ultrastructural data are needed to establish a formalized operation model of the amphibian retinotectal system. (shrink)

SNAREs (soluble N‐ethylmaleimide‐sensitive factor attachment protein receptors) are a large family of proteins that are present on all organelles involved in intracellular vesicle trafficking and secretion. The interaction of complementary SNAREs found on opposing membranes presents an attractive lock‐and‐key mechanism, which may underlie the specificity of vesicle trafficking. Moreover, formation of the tight complex between a vesicle membrane SNARE and corresponding target membrane SNAREs could drive membrane fusion. In synapses, this tight complex, also referred to as the synaptic (...) core complex, is essential for neurotransmitter release. However, recent observations in knockout mice lacking major synaptic SNAREs challenge the prevailing notion on the executive role of these proteins in fusion and open up several questions about their exact role(s) in neurotransmitter release. Persistence of a form of regulated neurotransmitter release in these mutant mice also raises the possibility that other cognate or non‐cognate SNAREs may partially compensate for the loss of a particular SNARE. Future analysis of SNARE function in central synapses will also have implications for the role of these molecules in other vesicle trafficking events such as endocytosis and vesicle replenishment. Such analysis can provide a molecular basis for synaptic processes including certain forms of short‐term synaptic plasticity. BioEssays 24:926–936, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

The materialist critics argue that insuperable difficulties are encountered by the hypothesis that immaterial mental events such as thinking can act in any way on material structures such as neurons of the cerebral cortex, as is diagrammed in Fig. 8. Such a presumed action is alleged to be incompatible with the conservation laws of physics, in particular of the First Law of Thermodynamics. This objection would certainly be sustained by 19th century physicists and by neuroscientists and philosophers who are still (...) ideologically in the physics of the 19th century, not recognizing the revolution wrought by quantum physicists in the 20th century. Unfortunately it is rare for a quantum physicist to dare an intrusion into the brain-mind problem. But in a recent book the quantum physicist Margenau (1984) makes a fundamental contribution. It is a remarkable transformation from 19th century physics to be told (p. 22): "that some fields, such as the probability field of quantum mechanics carry neither energy nor matter." He goes on (p. 96) to state: "In very complicated physical systems such as the brain, the neurons and sense organs, whose constituents are small enough to be governed by probabilistic quantum laws, the physical organ is always poised for a multitude of possible changes, each with a definite probability; if one change takes place that requires energy, or more or less energy than another, the intricate organism furnishes it automatically. Hence, even if the mind has anything to do with the change, that is if there is a mind-body interaction, the mind would not be called upon to furnish energy." In summary (p. 97) Margenau states that: "The mind may be regarded as a field in the accepted physical sense of the term. But it is a nonmaterial field; its closest analogue is perhaps a probability field. It cannot be compared with the simpler nonmaterial fields that require the presence of matter (e.g. gravity) nor does it necessarily have a definite position in space. And so far as present evidence goes it is not an energy field in any physical sense, nor is it required to contain energy in order to account for all known phenomena in which mind interacts with brain". In formulating more precisely the dualist hypothesis of mind-brain interaction, the initial statement is that the whole world of mental events (World 2) has an existence as autonomous as the world of matter-energy (World I ) (Fig. 1). The present interactionist hypothesis does not relate to these ontological problems, but merely to the mode of action of mental events on neural events, that is of the nature of the downward arrows across the frontier in Fig. 8. Following Margenau (1984) the hypothesis is that mind-brain interaction is analogous to a probability field of quantum mechanics, which has neither mass nor energy, yet can cause effective action at microsites. More specifically it is proposed that the mental concentration involved in intentions (Figs. 7, 8) or attention (Fig. 4) or planned thinking (Figs. 5, 6) can cause neural events by a process analogous to the probability fields of quantum mechanics. -/- We can ask: what neural events could be appropriate recipients for mental fields that are analogous to quantal probability fields? Already we may have the answer in recent discoveries on the nature of the synaptic mechanism whereby one nerve cell communicates with another. (shrink)

This chapter considers how dynamic brain states continuously fine-tune processing to accommodate changes in behavioural context and task goals. First, the authors review the extant literature suggesting that content-specific patterns of preparatory activity bias competitive processing in visual cortex to favour behaviourally relevant input. Next, they consider how higher-level brain areas might provide a top-down attentional signal for modulating baseline visual activity. Extensive evidence suggests that working memory representations in prefrontal cortex are especially important for generating and maintaining biases in (...) preparatory visual activity via modulatory feedback. Although it is often proposed that such working memory representations are maintained via persistent prefrontal activity, the authors review more recent evidence that rapid short-term synaptic plasticity provides a common substrate for maintaining the content of past experience and the rules for guiding future goal-directed processing. (shrink)

Where is consciousness? Neurobiological theories of consciousness look primarily to synaptic firing and “spike codes” as the physical substrate of consciousness, although the specific mechanisms of consciousness remain unknown. Synaptic firing results from electrochemical processes in neuron axons and dendrites. All neurons also produce electromagnetic (EM) fields due to various mechanisms, including the electric potential created by transmembrane ion flows, known as “local field potentials,” but there are also more meso-scale and macro-scale EM fields present in the brain. (...) The functional role of these EM fields has long been a source of debate. We suggest that these fields, in both their local and global forms, may be the primary seat of consciousness, working as a gestalt with synaptic firing and other aspects of neuroanatomy to produce the marvelous complexity of minds. We call this assertion the “electromagnetic field hypothesis.” The neuroanatomy of the brain produces the local and global EM fields but these fields are not identical with the anatomy of the brain. These fields are produced by, but not identical with, the brain, in the same manner that twigs and leaves are produced by a tree’s branches and trunk but are not the same as the branches and trunk. As such, the EM fields represent the more granular, both spatially and temporally, aspects of the brain’s structure and functioning than the neuroanatomy of the brain. The brain’s various EM fields seem to be more sensitive to small changes than the neuroanatomy of the brain. We discuss issues with the spike code approach as well as the various lines of evidence supporting our argument that the brain’s EM fields may be the primary seat of consciousness. This evidence (which occupies most of the paper) suggests that oscillating neural EM fields may make firing in neural circuits oscillate, and these oscillating circuits. may help unify and guide conscious cognition. (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)

Recent experiments have begun to decipher the molecular dialog that mediates differentiation at sites of synaptic between neurons and their targets. It had been hypothesized that the protein agrin is released by axon terminals at embryonic neuromuscular junctions and binds to a receptor on the myofiber surface to trigger postsynaptic differentiation. Now a genetic ‘Knockout’ experiment has confirmed the essential role of agrin in signaling between developing nerve and muscle(1). A second ‘knockout’ has shown that the muscle‐specific receptor tyrosine (...) kinase MuSK is a critical element in the agrin‐induced signaling cascade(2). Additional results suggest that MuSK may comprise a portion of the agrin receptor(3). (shrink)

Evidence from invertebrate systems including Aplysia and Drosophila, as well as studies carried out with mammalian brain, suggests that Ca2+-sensitive adenylyl cyclases may be important for long-term synaptic changes and learning and memory. Furthermore, some forms of long-term potentiation (LTP) in the hippocampus elevate cyclic AMP (cAMP) signals, and activation of adenylyl cyclases and cAMP-dependent protein kinase may be required for late stages of LTP. We propose that long-term changes in neurons and at synapses may require synergism between the (...) cAMP and Ca2+ signal transduction systems which regulates transcription and synthesis of specific proteins required for long-term synaptic changes. During LTP, protein kinase C is activated and intraccllular Ca2+ increases. We hypothesize that the calmodulin (CaM)-regulated adenylyl cyclases may be activated during LTP because of increases in intracellular Ca2+, release of free CaM from neuromodulin, activation by protein kinase C, release of neurotransmitters, or a combination of these events. Synergistic activation of CaM-sensitive adenylyl cyclases may produce a robust or prolonged cAMP signal required for transcriptional control. Furthermore, the coupling of the Ca2+ and cAMP systems may provide positive feedback regulation of Ca2+ channels by cAMP-dependent protein kinase. (shrink)

The strong correlation between the geometry of the dendritic tree and the specific function of motoneurons suggests that their synaptic contacts are established on a selective stochastic basis with the characteristic form of dendrites being the source of selection in the frog. A compromise is suggested according to which specific structures may have evolved on a selective stochastic basis and “constructive learning” could be the source of selection in the cortex.

Electrical signaling by neurons depends on the precisely ordered distribution of a wide variety of ion channels on the neuronal surface. The mechanisms underlying the targeting of particular classes of ion channels to specific subcellular sites are poorly understood. Recent studies have identified a new class of protein‐protein interaction mediated by PDZ domains, protein binding modules that recognize specific sequences at the C terminus of membrane proteins. The PDZ domains of a family of synaptic cytoskeleton‐associated proteins, typified by PSD‐95, (...) bind to the intracellular C‐terminal tails of NMDA receptors and Shaker‐type K+ channels. This interaction appears to be important in the clustering and localization of these ion channels at synaptic sites. Recognition of specific C‐terminal peptide sequences by different PDZ domain‐containing proteins may be a general mechanism for differential targeting of proteins to a variety of subcellular locations. (shrink)

Neural organization: Structure, function, and dynamics shows how theory and experiment can supplement each other in an integrated, evolving account of the brain's structure, function, and dynamics. (1) Structure: Studies of brain function and dynamics build on and contribute to an understanding of many brain regions, the neural circuits that constitute them, and their spatial relations. We emphasize Szentágothai's modular architectonics principle, but also stress the importance of the microcomplexes of cerebellar circuitry and the lamellae of hippocampus. (2) Function: Control (...) of eye movements, reaching and grasping, cognitive maps, and the roles of vision receive a functional decomposition in terms of schemas. Hypotheses as to how each schema is implemented through the interaction of specific brain regions provide the basis for modeling the overall function by neural networks constrained by neural data. Synthetic PET integrates modeling of primate circuitry with data from human brain imaging. (3) Dynamics: Dynamic system theory analyzes spatiotemporal neural phenomena, such as oscillatory and chaotic activity in both single neurons and (often synchronized) neural networks, the self-organizing development and plasticity of ordered neural structures, and learning and memory phenomena associated with synaptic modification. Rhythm generation involves multiple levels of analysis, from intrinsic cellular processes to loops involving multiple brain regions. A variety of rhythms are related to memory functions. The Précis presents a multifaceted case study of the hippocampus. We conclude with the claim that language and other cognitive processes can be fruitfully studied within the framework of neural organization that the authors have charted with John Szentágothai. Key Words: cognitive maps; computational neuroscience; dynamics; hippocampus; memory; modular architectonics; neural modeling; neural organization; neural plasticity; rhythmogenesis; Szentágothai. (shrink)

Neural organization: Structure, function, and dynamics shows how theory and experiment can supplement each other in an integrated, evolving account of the brain's structure, function, and dynamics. Structure: Studies of brain function and dynamics build on and contribute to an understanding of many brain regions, the neural circuits that constitute them, and their spatial relations. We emphasize Szentágothai's modular architectonics principle, but also stress the importance of the microcomplexes of cerebellar circuitry and the lamellae of hippocampus. Function: Control of eye (...) movements, reaching and grasping, cognitive maps, and the roles of vision receive a functional decomposition in terms of schemas. Hypotheses as to how each schema is implemented through the interaction of specific brain regions provide the basis for modeling the overall function by neural networks constrained by neural data. Synthetic PET integrates modeling of primate circuitry with data from human brain imaging. Dynamics: Dynamic system theory analyzes spatiotemporal neural phenomena, such as oscillatory and chaotic activity in both single neurons and neural networks, the self-organizing development and plasticity of ordered neural structures, and learning and memory phenomena associated with synaptic modification. Rhythm generation involves multiple levels of analysis, from intrinsic cellular processes to loops involving multiple brain regions. A variety of rhythms are related to memory functions. The Précis presents a multifaceted case study of the hippocampus. We conclude with the claim that language and other cognitive processes can be fruitfully studied within the framework of neural organization that the authors have charted with John Szentágothai. (shrink)

Mechanistic explanation involves the attribution of functions to both mechanisms and their component parts, and function attribution plays a central role in the individuation of mechanisms. Our aim in this paper is to investigate the impact of a perspectival view of function attribution for the broader mechanist project, and specifically for realism about mechanistic hierarchies. We argue that, contrary to the claims of function perspectivalists such as Craver, one cannot endorse both function perspectivalism and mechanistic hierarchy realism: if functions are (...) perspectival, then so are the levels of a mechanistic hierarchy. We illustrate this argument with an example from recent neuroscience, where the mechanism responsible for the phenomenon of ephaptic coupling cross-cuts the more familiar mechanism for synaptic firing. Finally, we consider what kind of structure there is left to be realist about for the function perspectivalist. (shrink)

Although the precise function of utrophin at the postsynaptic membrane of the neuromuscular junction still remains unclear, despite recent genetic ‘knockout’ experiments(1,2), a separate study in a transgenic mouse model system for Duchenne muscular dystrophy (DMD) has nonetheless shown that overexpression of utrophin into extrasynaptic regions of muscle fibers can functionally compensate for the lack of dystrophin and alleviate the muscle pathology(3). In this context, the next step is to identify the mechanisms presiding over expression of utrophin at the neuromuscular (...) synapse in attempts to induce its expression throughout DMD muscle fibers. In fact, additional studies have shown that an important DNA element contained with the utrophin promoter may confer synapse‐specific expression to the utrophin gene(4,5). Identification of the events culminating in the transaction of the utrophin gene within synaptic myonuclei should provide important cues for the development of an effective therapeutic strategy for DMD. (shrink)

A key characteristic of an animal's nervous system is that it can respond to brief environmental stimuli with lasting changes in its structure and function. These changes are triggered by specific patterns of neuronal electrical activity and are manifested as changes in the strength and patterns of synaptic connectivity between activated neurons. The biochemical mechanisms that control these changes are unclear, but cytoplasmic rises in Ca2+ levels may play a critical role, especially in regulating neuronal gene expression for making (...) activity‐induced synaptic changes permanent. Recently, two reports have explored the spatial features by which activity‐induced rises in Ca2+ levels activate transcription factors and gene expression(1,2). The reports suggest that Ca2+ influx acts both locally at the synapse and distantly within the nucleus to regulate transcription factors and gene expression. The results also show that regulatory elements within genes can respond differentially, depending on spatial differences in intracellular Ca2+ rises. These reports suggest new spatial mechanisms by which Ca2+‐dependent gene expression could contribute to activity‐dependent synaptic changes. (shrink)

IntroductionCerebral visual impairment is an important cause of visual impairment in western countries. Perinatal hypoxic-ischemic damage is the most frequent cause of CVI but CVI can also be the result of a genetic disorder. The majority of children with CVI have cerebral palsy and/or developmental delay. Early diagnosis is crucial; however, there is a need for consensus on evidence based diagnostic tools and referral criteria. The aim of this study is to develop guidelines for diagnosis and referral in CVI according (...) to the grade method.Patients and MethodsWe developed the guidelines according to the GRADE method 5 searches on CVI were performed in the databases Medline, Embase, and Psychinfo, each with a distinct topic.ResultsBased on evidence articles were selected on five topics: 1. Medical history and CVI-questionnaires 23. 2. Ophthalmological and orthoptic assessment 37. 3. Neuropsychological assessment 5. 4. Neuroradiological evaluation and magnetic resonance imaging 9. 5. Genetic assessment 5.ConclusionIn medical history taking, prematurity low birth weight and APGAR Scores are important. Different questionnaires are advised for children under the age of 3 years, older children and for specific risk groups. In ophthalmological examination, eye movements, specially saccades, accommodation, crowding, contrast sensitivity and visual fields should be evaluated. OCT can show objective signs of trans-synaptic degeneration and abnormalities in fixation and saccades can be measured with eye tracking. Screening of visual perceptive functioning is recommended and can be directive for further assessment. MRI findings in CVI in Cerebral Palsy can be structured in five groups: Brain maldevelopment, white and gray matter lesions, postnatal lesions and a normal MRI. In children with CVI and periventricular leukomalacia, brain lesion severity correlates with visual function impairment. A differentiation can be made between cortical and subcortical damage and related visual function impairment. Additional assessments can be necessary to complete the diagnosis of CVI and/or to reveal the etiology. (shrink)

Recent advances in the neuroscience of episodic memory provide a framework to integrate object relations theory, a psychoanalytic model of mind development, with potential neural mechanisms. Object relations are primordial cognitive-affective units of the mind derived from survival- and safety-level experiences with caretakers during phase-sensitive periods of infancy and toddlerhood. Because these are learning experiences, their neural substrate likely involves memory, here affect-enhanced episodic memory. Inaugural object relations are encoded by the hippocampus-amygdala synaptic plasticity, and systems-consolidated by medial prefrontal (...) cortex (mPFC). Self- and object-mental representations, extracted from these early experiences, are at first dichotomized by contradictory affects evoked by frustrating and rewarding interactions (“partial object relations”). Such affective dichotomization appears to be genetically hardwired the amygdala. Intrinsic propensity of mPFC to form schematic frameworks for episodic memories may pilot non-conscious integration of dichotomized mental representations in neonates and infants. With the emergence of working memory in toddlers, an activated self- and object-representation of a particular valence can be juxtaposed with its memorized opposites creating a balanced cognitive-affective frame (conscious “integration of object relations”). Specific events of object relations are forgotten but nevertheless profoundly influence the mental future of the individual, acting (i) as implicit schema-affect templates that regulate attentional priorities, relevance, and preferential assimilation of new information based on past experience, and (ii) as basic units of experience that are, under normal circumstances, integrated as attractors or “focal points” for interactive self-organization of functional brain networks that underlie the mind. A failure to achieve integrated object relations is predictive of poor adult emotional and social outcomes, including personality disorder. Cognitive, cellular-, and systems-neuroscience of episodic memory appear to support key postulates of object relations theory and help elucidate neural mechanisms of psychodynamic psychotherapy. Derived through the dual prism of psychoanalysis and neuroscience, the gained insights may offer new directions to enhance mental health and improve treatment of multiple forms of psychopathology. (shrink)

This commentary argues that (1) arousal is not sufficient to induce LTP in the hippocampus, (2) learning can profoundly modulate synaptic plasticity in a state-dependent manner without affecting baseline synaptic efficacy, and (3) unilateral, synapse-specific LTP induction triggers an interhippocampal communication manifested as bilateral increases in gene expression at multiple sites in the hippocampal network.

Cognitive dysfunction in Alzheimer’s disease is caused by disturbances in neuronal circuits of the brain underpinned by synapse loss, neuronal dysfunction and neuronal death. Amyloid beta and tau protein cause these pathological changes and enhance neuroinflammation, which in turn modifies disease progression and severity. Vagal nerve stimulation, via activation of the locus coeruleus, results in the release of catecholamines in the hippocampus and neocortex, which can enhance synaptic plasticity and reduce inflammatory signalling. Vagal nerve stimulation has shown promise to (...) enhance cognitive ability in animal models. Research in rodents has shown that VNS can have positive effects on basal synaptic function and synaptic plasticity, tune inflammatory signalling, and limit the accumulation of amyloid plaques. Research in humans with invasive and non-invasive VNS devices has shown promise for the modulation of cognition. However, the direct stimulation of the vagus nerve afforded with the invasive procedure carries surgical risks. In contrast, non-invasive VNS has the potential to be a broadly available therapy to manage cognitive symptoms in early AD, however, the magnitude and specificity of its effects remains to be elucidated, and the non-inferiority of the effects of non-invasive VNS as compared with invasive VNS still needs to be established. Ongoing clinical trials with healthy individuals and patients with early AD will provide valuable information to clarify the potential benefits of non-invasive VNS in cognition and AD. Whether invasive or non-invasive VNS can produce a significant improvement on memory function and whether its effects can modify the progression of AD will require further investigation. (shrink)

Sleep is a fundamental property conserved across species. The homeostatic induction of sleep indicates the presence of a mechanism that is progressively activated by the awake state and that induces sleep. Several lines of evidence support that such function, namely, sleep need, lies in the neuronal assemblies rather than specific brain regions and circuits. However, the molecular mechanism underlying the dynamics of sleep need is still unclear. This review aims to summarize recent studies mainly in rodents indicating that protein phosphorylation, (...) especially at the synapses, could be the molecular entity associated with sleep need. Genetic studies in rodents have identified a set of kinases that promote sleep. The activity of sleep-promoting kinases appears to be elevated during the awake phase and in sleep deprivation. Furthermore, the proteomic analysis demonstrated that the phosphorylation status of synaptic protein is controlled by the sleep-wake cycle. Therefore, a plausible scenario may be that the awake-dependent activation of kinases modifies the phosphorylation status of synaptic proteins to promote sleep. We also discuss the possible importance of multisite phosphorylation on macromolecular protein complexes to achieve the slow dynamics and physiological functions of sleep in mammals. (shrink)

The goal of the present study is to explore whether the affective states of a pedagogical agent in an online multimedia lesson yields different learning processes and outcomes, and whether the effects of affective PAs depend on the learners’ emotion regulation strategies and their prior knowledge. In three experiments, undergraduates were asked to view a narrated animation about synaptic transmission that included either a happy PA or a neutral PA and subsequently took emotions, motivation, cognitive outcomes tests. Across three (...) experiments, the happy PA group reported more positive emotions and higher level of motivation than the neutral PA group. Moreover, the happy PA prompted higher germane load than a neutral PA in Experiment 3. However, adding a happy PA to the screen did not improve learning performance. In addition, in Experiment 2, learners’ usage of emotion regulation strategies moderated the effectiveness of affective PA on positive emotions in learners. Specifically, happy PAs increased the positive emotions of students who used expressive suppression strategy but not those who used cognitive reappraisal strategy. In Experiment 3, the effectiveness of affective PAs was not moderated by learners’ prior knowledge. Results support the cognitive affective theory of learning with media that students are happier and more motivated when they learn from happy PAs than from neutral PAs. (shrink)

Working memory is developed in one region of the brain called the dorsolateral prefrontal cortex. The dysfunction of this region leads to synaptic neuroplasticity impairment. It has been reported that several biochemical parameters and anthropometric measurements play a vital role in cognition and brain health. This study aimed to investigate the relationships between cognitive function, serum biochemical profile, and anthropometric measurements using DLPFC activation. A cross-sectional study was conducted among 35 older adults who experienced mild cognitive impairment. For this (...) purpose, we distributed a comprehensive interview-based questionnaire for collecting sociodemographic information from the participants and conducting cognitive tests. Anthropometric values were measured, and fasting blood specimens were collected. We investigated their brain activation using the task-based functional MRI, specifically in the DLPFC region. Positive relationships were observed between brain-derived neurotrophic factor and Mini-Mental State Examination ; however, negative relationships were observed between serum triglyceride and serum malondialdehyde with right DLPFC activation while the participants performed 1-back task after adjustments for age, gender, and years of education. In conclusion, higher serum triglycerides, higher oxidative stress, and lower neurotrophic factor were associated with lower right DLPFC activation among older adults with MCI. A further investigation needs to be carried out to understand the causal-effect mechanisms of the significant parameters and the DLPFC activation so that better intervention strategies can be developed for reducing the risk of irreversible neurodegenerative diseases among older adults with MCI. (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)

We recently described a novel form of stress‐associated bidirectional plasticity at GABA synapses onto hypothalamic parvocellular neuroendocrine cells (PNCs), the apex of the hypothalamus‐pituitary‐adrenal axis. This plasticity may contribute to neuroendocrine adaptation. However, this GABA synapse plasticity likely does not translate into a simple more and less of inhibition because the ionic driving force for Cl−, the primary charge carrier for GABAA receptors, is dynamic. Specifically, stress impairs a Cl− extrusion mechanism in PNCs. This not only renders the steady‐state GABA (...) response less hyperpolarizing but also makes PNCs susceptible to the activity‐dependent accumulation of Cl−. Accordingly, GABA synapse plasticity impacts both the robustness of GABA voltage response and dynamic Cl− loading, imposing nonlinear influences on PNC excitability during circuit activities. This theoretical consideration predicts roles for GABA transmission far more versatile than canonical inhibition. We propose potential impacts of GABA synapse plasticity on the experience‐dependent fine‐tuning of neuroendocrine stress responses. (shrink)

While issues of efficacy and specificity are crucial for the future of neurofeedback training, there may be alternative designs and control analyses to circumvent the methodological and ethical problems associated with double-blind placebo studies. Surprisingly, most NF studies do not report the most immediate result of their NF training, i.e. whether or not children with ADHD gain control over their brain activity during the training sessions. For the investigation of specificity, however, it seems essential to analyze the learning (...) and adaptation processes that take place in the course of the training and to relate improvements in self-regulated brain activity across training sessions to behavioral, neuropsychological and electrophysiological outcomes. To this aim, a review of studies on neurofeedback training with ADHD patients, which include the analysis of learning across training sessions or relate training performance to outcome, is presented. Methods on how to evaluate and quantify learning of EEG regulation over time are discussed. “Non-learning” has been reported in a small number of ADHD-studies, but has not been a focus of general methodological discussion so far. For this reason, selected results from the brain-computer interface (BCI) research on the so-called “brain-computer illiteracy”, the inability to gain control over one’s brain activity, are also included. It is concluded that in the discussion on specificity, more attention should be devoted to the analysis of EEG regulation performance in the course of the training and its impact on clinical outcome. It is necessary to improve the knowledge on characteristic cross-session and within-session learning trajectories in ADHD and to provide the best conditions for learning. (shrink)

The interventionist account provides us with several notions permitting the qualification of causal relationships. In recent years, there has been a push toward formalizing these notions using information theory. In this paper, I discuss one of them, namely causal specificity. The notion of causal specificity is ambiguous as it can refer to at least two different concepts. After having presented these, I show that current attempts to formalize causal specificity in information theoretic terms have mostly focused on (...) one of these two concepts. I then propose and apply a new information-theoretic measure which captures the other concept. (shrink)