Recent studies suggest that the tetracycline antibiotic minocycline, or its cousins, hold therapeutic potential for affective and psychotic disorders. This is proposed on the basis of a direct effect on microglia‐mediated frontocortical synaptic pruning (FSP) during adolescence, perhaps in genetically susceptible individuals harboring risk alleles in the complement component cascade that is involved in this normal process of CNS circuit refinement. In reviewing this field, it is argued that minocycline is actually probing and modulating a deeply evolved and (...) intricate system wherein psychosocial stimuli sculpt the circuitry of the “social brain” underlying adult behavior and personality. Furthermore, this system can generate psychiatric morbidity that is not dependent on genetic variation. This view has important ramifications for understanding “pathologies” of human social behavior and cognition as well as providing long‐sought potential mechanistic links between social experience and susceptibility to mental and physical disease. (shrink)

No overarching hypotheses tie the basic mechanisms of mitochondrial reactive oxygen species (ROS) production to activity dependent synapse pruning—a fundamental biological process in health and disease. Neuronal activity divergently regulates mitochondrial ROS: activity decreases whereas inactivity increases their production, respectively. Placing mitochondrial ROS as innate synaptic activity sentinels informs the novel hypothesis that: (1) at an inactive synapse, increased mitochondrial ROS production initiates intrinsic apoptosis dependent pruning; and (2) at an active synapse, decreased mitochondrial ROS production masks (...) intrinsic apoptosis dependent pruning. Immature antioxidant defense may enable the developing brain to harness mitochondrial ROS to prune weak synapses. Beyond development, endogenous antioxidant defense constrains mitochondrial (ROS) to mask pruning. Unwanted age‐related synapse loss may arise when mitochondrial ROS aberrantly recapitulate developmental pruning. Placing mitochondrial ROS with their hands on the shears is beneficial in early but deleterious in later life. (shrink)

We propose that the primary cause of schizophrenia is a pathological extension of synaptic pruning involving local connectivity that unfolds ordinarily during adolescence. Computer simulations suggest that this pathology provides reasonable accounts of a range of symptoms in schizophrenia, and is consistent with recent postmortem and genetic studies. NMDA-receptors play a regulatory role in maintaining and/or eliminating cortical synapses, and therefore may play a pathophysiological role.

In order to reach a better understanding of brain function, conceptual synergies linking empirical neurobiological studies and neurocomputational studies should be pursued. I describe an example of a potential synergy based on studies of neural network pruning. Simulations demonstrate that selective elimination of connections enhances the computational capacity of networks capable of temporal processing. These findings may shed light on the functional significance of postnatal neuro-developmental pruning of cortical connections that occurs in mammals.

This chapter provides a review of the hypothesis that synesthetic-like perception is present in infants and toddlers. Infants and very young children exhibit evidence of functional hyperconnectivity between the senses, much of which is reminiscent of the cross-sensory associations observed in synaesthetic adults. As most of these cross-sensory correspondances cannot be easily explained by learning, it is likely that these represent natural associations between the senses. In average adults, these 'natural associations' are felt only intuitively rather than explicitly. These observations (...) have led to the proposal of the 'neonatal synaesthesia hypothesis', which purports that all individuals are born synaesthetic, with explicit conscious perception of these natural cross-modal associations dissipating over development in typical individuals. This dissipation is likely the result of experience-dependent synaptic pruning and/or inhibition of cross-sensory neural connections. At the same time, cross-modal associations matching those common in the environment might be assumed to be learned. This hypothesis is re-evaluated in light of recent research findings, and is examined in the context of current evolutionary models of neuronal recycling and emerging evidence of longitudinal changes in children with synaesthesia. (shrink)

Sleep and dreaming are important daily phenomena that are receiving growing attention from both the scientific and the philosophical communities. The increasingly popular predictive brain framework within cognitive science aims to give a full account of all aspects of cognition. The aim of this paper is to critically assess the theoretical advantages of Predictive Processing (PP, as proposed by Clark 2013, Clark 2016; and Hohwy 2013) in defining sleep and dreaming. After a brief introduction, we overview the state of the (...) art at the intersection between dream research and PP (with particular reference to Hobson and Friston 2012; Hobson et al. 2014). In the following sections we focus on two theoretically promising aspects of the research program. First, we consider the explanations of phenomenal consciousness during sleep (i.e. dreaming) and how it arises from the neural work of the brain. PP provides a good picture of the peculiarity of dreaming but it can’t fully address the problem of how consciousness comes to be in the first place. We propose that Integrated Information Theory (IIT) (Oizumi et al. 2014; Tononi et al. 2016) is a good candidate for this role and we will show its advantages and points of contact with PP. After introducing IIT, we deal with the evolutionary function of sleeping and dreaming. We illustrate that PP fits with contemporary researches on the important adaptive function of sleep and we discuss why IIT can account for sleep mentation (i.e. dreaming) in evolutionary terms (Albantakis et al. 2014). In the final section, we discuss two future avenues for dream research that can fruitfully adopt the perspective offered by PP: (a) the role of bodily predictions in the constitution of the sleeping brain activity and the dreaming experience, and (b) the precise role of the difference stages of sleep (REM (Rapid eye movement), NREM (Non-rapid eye movement) in the constitution and refinement of the predictive machinery. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Hermeneutics, Neuroscience and PsychiatryMichael T. H. Wong, MBBS, MD, MA, MDiv, PhD, FRCPsych, FRANZCP, FHKAM (bio)Hermeneutic practice in mental health has been a theme in Philosophy, Psychiatry, & Psychology (PPP) since its very beginnings. In this essay I argue that hermeneutics, the theory and practice of interpretation, promotes therapeutic interaction between mental health professionals, patients and their family.Why does this patient present in such a way at this particular (...) point in time? The distressing symptoms are there. The changes in behavior are obvious. Impairments of functions are hurting. A mental illness clearly runs in the family. There were early losses of loved ones, physical abuse at home, bullying by peers and self-medication with drugs and alcohol. Three in four adults with a mental illness first experienced that before they turned 24. The brain goes through major reorganization during adolescence and early adulthood. If synaptic pruning went wrong, psychoses emerged. When stresses activated the hypothalamic–pituitary–adrenal axis the elevated cortisol level impacted the size and function of the hippocampus and amygdala in the genetically vulnerable; anxiety, depression, bipolar, and personality disorders developed. The patient needs a voice/language to describe all these experiences and events and the psychiatrist needs a discourse to make sense of them.Eisenberg laments the swings between "brainlessness" and "mindlessness" in psychiatry. Engel argues for a "biopsychosocial" discourse. The major challenge for psychiatry is how to organize clinical information of different nature (categories, dimensions, narratives; i.e., objective vs. subjective, personal vs. interpersonal) into a coherent and comprehensible account for us all. Mental illnesses are not only neuropsychiatric spectrum disorders but also dysfunctions of social relationship and environmental/ecological adaptation. Psychiatry as a clinical neuroscience per se lacks the semantics to address the rich interactions between the physical, psychological, social, cultural, and spiritual in the illness experience of our patients. Explanation in the diagnostic formulation (objective scientific discourse on cause and effect) and understanding in the patient narrative (subjective ordinary everyday discourse on significance and meaning) are irreducible to each other (Wong, 2018). They instead interact with one another to achieve an integrative formulation, not through merging different discourses into a single assertion/monologue but via the dialectic/dialogue of "explaining more in order to understand better," as Ricoeur puts it, and between "the whole and the parts," as Schleiermacher highlights.This "therapeutic hermeneutic circle" of "explanation vs understanding" and "the whole vs the parts" includes symptoms behavior function and life events. It correlates between bio-psychosociocultural-spiritual dimensions/perspectives and does not reduce them to any particular/single [End Page 13] stance. The whole integrates the parts and the parts enrich the whole. It explains but does not explain away. It understands through an articulation of meaning and significance. This discourse is a multilayered (bio-psycho-social-cultural-spiritual) personal narrative that formulates diagnosis and care in a correlative (linking different voices/discourses) and non-reductive (no particular voice/discourse is prejudiced against) manner that is comprehensible to us all (Wong, 2021).PPP will be an excellent forum for discussing clinical hermeneutics in the future. In this digital era of social media and virtual reality, hermeneutics has the never-ending task to tackle the unprecedented challenges to meaning illness and health posed by polarizing discourses.Michael T. H. Wong Michael T.H. Wong, MBBS, MD, MA, MDiv, PhD, FRCPsych, FRANZCP, FHKAM, is Hon Clinical Professor, Department of Psychiatry, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, HKSAR, China. Michael is Chair, Section of Philosophy & Humanities in Psychiatry, World Psychiatric Association. He is an Organizational Partner & International Lead with The Collaborating Centre for Values-Based Practice in Health and Social Care, St Catherine's College Oxford. He is Advisor to the Chinese Health Foundation of Australia.ReferencesWong M. T. H. (2018). Ricoeur and the third discourse of the person: From philosophy and neuroscience to psychiatry and theology. London: Lexington Books. Google ScholarWong, M. T. H. (2021). Values, meanings, hermeneutics and mental health. In Stoyanov, D., Fulford, K. M. W. F., Stanghellini, G., Van Staden, W., & Wong, M. TH. (Eds.), International perspectives in values-based mental health practice: Case studies and commentaries (pp. 341–349... (shrink)

Neuronal remodeling is a conserved mechanism that eliminates unwanted neurites and can include the loss of cell bodies. In these processes, a key role for glial cells in events from synaptic pruning to neuron elimination has been clearly identified in the last decades. Signals sent from dying neurons or neurites to be removed are received by appropriate glial cells. After receiving these signals, glial cells infiltrate degenerating sites and then, engulf and clear neuronal debris through phagocytic mechanisms. There (...) are few identified or proposed signals and receptors involved in neuron‐glia crosstalk, which induces the transformation of glial cells to phagocytes during neuronal remodeling in Drosophila. Many of these signaling pathways are conserved in mammals. Here, we particularly emphasize the role of Orion, a recently identified neuronal CX3C chemokine‐like secreted protein, which induces astrocyte infiltration and engulfment during mushroom body neuronal remodeling. Although, chemokine signaling was not described previously in insects we propose that chemokine‐like involvement in neuron/glial cell interaction is an evolutionarily ancient mechanism. (shrink)

We offer an argument for the extended mind based on considerations from brain development. We argue that our brains develop to function in partnership with cognitive resources located in our external environments. Through our cultural upbringing we are trained to use artefacts in problem solving that become factored into the cognitive routines our brains support. Our brains literally grow to work in close partnership with resources we regularly and reliably interact with. We take this argument to be in line with (...) complementarity or “second-wave” defences of the extended mind that stress the functional differences between biological elements and external, environmental resources in putative cases of extended cognition. Complementarity defences argue that many of the kinds of cognition humans excel at can only be accomplished by brains working together with a body that directly manipulates and acts on the world [Rowlands (1999); Menary (2007); Sutton (2010)]. We argue that complementarity and functionalist defences of the extended mind aren’t opposed, but that complementarity considerations can provide much needed and hitherto under exploited leverage in defending EMT. Moreover, the developmental work we will describe adds extra weight to the complementarity case for EMT. (shrink)

This paper compares the free energy neuroscience now advocated by Karl Friston and his colleagues with that hypothesised by Freud, arguing that Freud's notions of conflict and trauma can be understood in terms of computational complexity. It relates Hobson and Friston's work on dreaming and the reduction of complexity to contemporary accounts of dreaming and the consolidation of memory, and advances the hypothesis that mental disorder can be understood in terms of computational complexity and the mechanisms, including synaptic (...) class='Hi'>pruning, that have evolved to reduce it. (shrink)

The neural basis of developmental changes in transitive reasoning in parietal regions was examined, using voxel-based morphometry. Young adolescents and adults performed a transitive reasoning task, subsequent to undergoing anatomical magnetic resonance imaging brain scans. Behaviorally, adults reasoned more accurately than did the young adolescents. Neural results showed less grey matter density in superior parietal cortex in the adults than in the young adolescents, possibly due to a developmental period of synaptic pruning; improved performance in the reasoning task (...) was negatively correlated with grey matter density in superior parietal cortex in the adolescents, but not in the adult group; and the latter results were driven by the more difficult trials, requiring greater spatial manipulation. Taken together, the results support the idea that during development, regions in superior parietal cortex are fine-tuned, to support more robust spatial manipulation, resulting in gre... (shrink)

argue that natural selection does not explain the genotypic arid phenotypic properties of individuals. On this view, natural selection explains the adaptedness of individuals, not by explaining why the individuals that exist have the adaptations they do, but rather by explaining why the individuals that exist are the ones with those adaptations. This paper argues that this ‘Negative’ view of natural selection ignores the fact that natural selection is a cumulative selection process. So understood, it explains how the genetic sequences (...) that individuals inherit and that are responsible for their complex (and co-adapted) adaptations first arose in the gene-pool. (shrink)

By allowing one artificial neural network to govern the synaptic noise injected into another based upon its appraisal of patterns nucleating from such disturbances, a contemplative form of artifici...

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)

Athenian ostracism has long captured democratic imaginations because it seems to present clear evidence of a people (demos) routinely asserting collective power over tyrannical elites. In recent times, ostracism has been particularly alluring to militant democrats, who see the institution as an ancient precursor to modern militant democratic mechanisms such as social media bans, impeachment measures, and lustration procedures, which serve to protect democratic constitutions from anti-democratic threats. Such a way of conceptualizing ostracism ultimately stems from Aristotle’s “rule of proportion,” (...) or the removal of “outstanding” individuals in a polity who threaten to disturb the achievement of communal eudaimonia (Aris. Pol. 1284a). However, this way of interpreting the institution only presents a truncated view, one which is overly centered on the ultimate expulsion of an individual from the polity, rather than on its broader contextual telos—the transformation of the ostracized individual and of the community. To move past this simplified view, this paper considers all elements of ostracism with equal force, and argues that ostracism offered a shared opportunity and shared space for all members of the polis—citizens, non-citizens, and elite members alike—to reform the character of the subject individual and to instill and reaffirm democratic values in the community. (shrink)

The neuromuscular junction has been used for several decades as an excellent model system to examine the cellular and molecular events involved in the formation and maintenance of a differentiated chemical synapse. In this context, several laboratories have focused their efforts over the last 15 years on the important contribution of transcriptional mechanisms to the regulation of the development and plasticity of the postsynaptic apparatus in muscle fibers. Converging lines of evidence now indicate that post‐transcriptional events, operating at the level (...) of mRNA stability and targeting, are likely to also play key roles at the neuromuscular junction. Here, we present the recent findings highlighting the role of these additional molecular events and extend our review to include data showing that post‐transcriptional events are also important in the control of the expression of genes encoding synaptic proteins in muscle cells placed under different conditions. Finally, we discuss the possibility that mis‐regulation of post‐transcriptional events can occur in certain neuromuscular diseases and cause abnormalities of the neuromuscular junction. BioEssays 25:25–31, 2003. © 2002 Wiley Periodicals, Inc. (shrink)

Long‐term potentiation (LTP) of excitatory synapses is a leading model to explain the concept of information storage in the brain. Multiple mechanisms contribute to LTP, but central amongst them is an increased sensitivity of the postsynaptic membrane to neurotransmitter release. This sensitivity is predominantly determined by the abundance and localization of AMPA‐type glutamate receptors (AMPARs). A combination of AMPAR structural data, super‐resolution imaging of excitatory synapses, and an abundance of electrophysiological studies are providing an ever‐clearer picture of how AMPARs are (...) recruited and organized at synaptic junctions. Here, we review the latest insights into this process, and discuss how both cytoplasmic and extracellular receptor elements cooperate to tune the AMPAR response at the hippocampal CA1 synapse. (shrink)

Alpha-beta pruning is a technique for pruning trees in artificial intelligence game-playing. This note draws an analogy between the technique, which is, in essence, an application of many-valued logic to the cut-off of the evaluation of conditionals in computer programs (for efficiency).

The objective of this paper is to present a new theory of synaptic function in the nervous system. The basis for this theory is the experimental demonstration that a nerve impulse assumes five different forms as it advances through the synaptic region, and that five basic mathematical operations have been identified as being involved in the transformation of one form into another form. As a result of these data, the synaptic region is regarded as a functional unit (...) where information coming to it is unpacked, processed, stored, and retrieved for transit to another synaptic region or effector site. The data also suggests that a nerve impulse is a bolus of energy, therefore, without substance; that it contains information coded in its shape or form; that it is precisely described mathematically. Furthermore, the data suggests synaptic regions process these nerve impulses by applying mathematical operations to them; that function in the synaptic region is highly stereotyped (programmed); that chemical substances are associated with the mathematical operations. The basic approach of this theory is to regard a significant portion of the nervous system as an interface between the external universe and man himself. As an interface, the nervous system receives and processes information from both the external universe and man himself in a programmed manner. The interface functions by converting the information it receives into a bolus of energy, the nerve impulse, then processes the bolus by converting it into numbers or functions and applying mathematical operation to it. (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)

This essay presents some thoughts on schizoanalysis and visual culture around the proposition that cinema survives in the digital age as a type of image that, after the movement-image and the time-image, could be called the neuro-image. By considering clinical schizophrenia as ‘degree zero’ of schizoanalysis in a more critical sense, a reading of The Butterfly Effect unfolds the temporal dimensions of schizoanalysis as typical for a definition of ‘the neuro-image’. The argument is that the neuro-image speaks from the (always (...) speculative) future. (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)

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)

In this book, Christopher D. Rodkey asks how the brain worships and responds by engaging ideas from neurological science, philosophy, ritual theory, and religious education. The Synaptic Gospel will prove to be a useful theoretical tool for pastors, religious educators, youth ministers, church music professionals, and seminary students.

In this paper we present the problem of a noisy lexical taxonomy and suggest two tasks as potential remedies. The first task is to identify and eliminate incorrect hypernymy links, and the second is to repopulate the taxonomy with new relations. The first task consists of revising the entire taxonomy and returning a Boolean for each assertion of hypernymy between two nouns (e.g. brie is a kind of cheese). The second task consists of recursively producing a chain of hypernyms for (...) a given noun, until the most general node in the taxonomy is reached (e.g. brie → cheese → food → etc.). In order to achieve these goals, we implemented a hybrid hypernym-detection algorithm that incorporates various intuitions, such as syntagmatic, paradigmatic and morphological association measures as well as lexical patterns. We evaluate these algorithms individually and collectively and report findings in Spanish, English and French. (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)

A synaptic algebra is a generalization of the self-adjoint part of a von Neumann algebra. In this article we extend to synaptic algebras the type-I/II/III decomposition of von Neumann algebras, AW∗-algebras, and JW-algebras.

The English Court of Appeal is currently faced with three analytically distinct approaches to the question of when one party owes another a duty of care in respect of her economic interests, all of which bear the authority of the House of Lords. Unable to choose between them, it has recently adopted a fourth approach combining which combines them, in the apparent belief that the combination will eradicate any individual deficiencies. Against the background of a recent case, the author argues (...) that this is a holding strategy at best and methodologically deficient. He also challenges the continuing lip-service paid by courts to models of liability based upon ‘assumptions of responsibility,’ examining and criticising the causes of their persistence in the law in the face of widespread academic criticism. Instead, the author argues, the House of Lords should now clearly endorse a single reasoning strategy to economic loss cases based on the three-stage approach in Caparo Industries v Dickman. Properly understood, this approach offers the best prospect of facilitating consistent and transparent decision-making in the longer term. (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)

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.

Interest in the role of nitric oxide (NO) in the nervous system began with the demonstration that glutamate receptor activation in cerebellar slices causes the formation of a diffusible messenger with properties similar to those of the endothelium-derived relaxing factor. It is now clear that this is due to the Ca2+/calmodulin-dependent activation of the enzyme NO synthase, which forms NO and citrulline from the amino acid L-arginine. The cerebellum has very high levels of NO synthase, and although it has low (...) levels of guanylyl cyclase, cerebellar cyclic guanosine monophosphate (cGMP) levels are an order of magnitude higher than in other brain regions. A transcellular metabolic pathway is also present in the cerebellar cortex to recycle citrulline back to arginine. The NO formed binds to and activates soluble guanylyl cyclase to elevate cGMP levels in target cells. Studies employing NADPH-diaphorase, a selective histochemical marker for NO synthase, together with immunohistochemistry, in situ hybridization and biochemical studies have indicated that NO production occurs in granule and basket cells in the cerebellar cortex, whereas cGMP formation appears to occur largely in other cells, including Purkinje cells. Given that a long-term depression of AMPA currents can be seen in isolated Purkinje cells, this anatomical localization suggests that NO cannot play an essential role in the induction of this form of synaptic plasticity. (shrink)

During sensory stimulation, visual cortical neurons undergo massive synaptic bombardment. This increases their input conductance, and action potentials mainly result from membrane potential fluctuations. To understand the response properties of neurons operating in this regime, we studied a model neuron with synaptic inputs represented by transient membrane conductance changes. We show that with a simultaneous increase of excitation and inhibition, the firing rate first increases, reaches a maximum, and then decreases at higher input rates. Comodulation of excitation and (...) inhibition, therefore, does not provide a straightforward way of controlling the neuronal firing rate, in contrast to coding mechanisms postulated previously. The synaptically induced conductance increase plays a key role in this effect: it decreases firing rate by shunting membrane potential fluctuations, and increases it by reducing the membrane time constant, allowing for faster membrane potential transients. These findings do not depend on details of the model and, hence, are relevant to cells of other cortical areas as well. (shrink)

Discussions of branching time and branching spacetime have become common in the philosophical literature. If properly understood, these conceptions can be harmless. But they are sometimes used in the service of debatable and even downright pernicious doctrines. The purpose of this chapter is to identify the pernicious branching and prune it back.