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)

For reasons I have never understood, some students of the cerebellum have been unwilling to accept the now overwhelming evidence that the cerebellum exhibits lasting synaptic plasticity and plays an essential role in some forms of learning and memory. With a few exceptions (e.g., target article by SIMPSON et al.) this is no longer the case, as is clear in the excellent target articles on cerebellar LTD and the excellent target review by HOUK et al. [CRÉPEL et al.; (...) HOUR et al.; KANO; LINDEN; SIMPSON et al.; SMITH; VINCENT]. (shrink)

Quartz & Sejnowski's target article concentrates on the development of a number of neural parameters, especially neuronal processes, in the mammalian brain. Data on learning-related changes in spines and synapses in the developing avian brain are consistent with a constructivist interpretation. The issue of an integration of selectionist and constructivist views is discussed.

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)

Controversy surrounds several experiments that have addressed whether selective synaptic strengthening occurs during learning. To date, the evidence suggests that widespread alterations in synaptic strength, through either kindling or electroconvulsive shock, can disrupt this hypothetical process. The lack of evidence for selective modification of learning through LTP stimulation, however, provides difficulties for both the prevailing hypothesis and the hypothesis advanced by Shors & Matzel. Subsequent experiments may indicate a role for LTP in both learning and arousal.

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 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)

Advances in molecular, genetic, and cell biological techniques have allowed neuroscientists to delve into the cellular machinery of learning and memory. The calcium and calmodulin-dependent kinase type II (CaMKII) is one of the best candidates for being a molecular component of the learning and memory machinery in the mammalian brain. It is present in abundance at synapses and its enzymatic properties and responsiveness to intracellular Ca2+ fit a model whereby Ca2+ currents activate the kinase and lead to changes in (...) class='Hi'>synaptic efficacy. Indeed, such plastic properties of synapses are thought to be important for memory formation. Genetic analysis of the alpha isoform of CaMKII in mice support the hypothesis that CaMKII signaling is required to initiate the formation of new spatial memories in the hippocampus. CaMKII is also required for the correct induction of long-term potentiation (LTP) in the hippocampus, consistent with the widely held belief that LTP is a mechanism for learning and memory. Recent cell biological, genetic, and physiological analyses suggest that one of the cellular explanations for LTP and CaMKII function might be the trafficking of AMPA-type receptors to synapses in response to neural activity. BioEssays 24:223–233, 2002. © 2002 Wiley Periodicals, Inc.; DOI 10.1002/bies.10057. (shrink)

The data on the cellular mechanism of LTD that is presented in four target articles is synthesized into a new model of Purkinje cell plasticity. This model attempts to address credit assignment problems that are crucial in learning systems. Intracellular signal transduction mechanisms may provide the mechanism for a 3-factor learning rule and a trace mechanism. The latter may permit delayed information about motor error to modify the prior synaptic events that caused the error. This model may help (...) to focus future cellular studies on issues that are particularly critical for a computationally viable concept of cerebellar plasticity, [CRÉPEL et al.; HOUK et al.; KANO; LINDEN; VINCENT]. (shrink)

We criticize the synaptic theory of long-term memory and the inappropriate usage of physical notions such as in motor control theories. Motor control and motor memory hypotheses should be based on explicitly specified hypothetical control variables that are sound from both physiological and physical perspectives. [HOUK et al.; SMITH; THACH].

Although it is not their fault, Shors & Matzel's attempt to review the LTP and learning hypothesis suffers from there being no clear published statement of the idea. Their summary of relevant evidence is not without error, however, and it oversimplifies fundamental issues relating to NMDA receptor function. Their attentional hypothesis is intriguing but requires a better systems-level understanding of how attention contributes to cognitive function.

It has been suggested that type I adenylyl cyclase may play a unique role in long-term potentiation, due to both unique regulatory properties as well as a specialized distribution within the mammalian brain. This would allow an integration of the signals wrought by increased intracellular calcium with those conveyed into the cellular milieu via increased cAMP. These results are discussed in the context of changes in cellular structure, because of changing interactions between G proteins and cytoskeletal components, which might be (...) expected to accompany chronic synaptic activation. (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)

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)

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)

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)

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.

Neuromodulatory effects of non-invasive brain stimulation (NIBS) have been extensively studied in chronic pain. A hypothetic mechanism of action would be to prevent or revert the ongoing maladaptive plasticity within the pain matrix. In this review, the authors discuss the mechanisms underlying the development of an abnormal plasticity in patients with chronic pain and the putative mechanisms of NIBS in modulating synaptic plasticity in neuropathic pain conditions.

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)

The cellular basis of motor learning in the cerebellum has been attributed mostly to long-term depression (LTD) at excitatory parallel fiber (PF)-Purkinje cell (PC) synapses. LTD is induced when PFs are activated in conjunction with a climbing fiber (CF), the other excitatory input to PCs. Recently, by using whole-cell patch-clamp recording from PCs in cerebellar slices, a new form of synaptic plasticity was discovered. Stimulation of excitatory CFs induced a long-lasting (usually longer than 30 min) of 30 sec) (...) and the durations of RP (>30 min) strongly suggests that some intracellular biochemical machinery is involved. Pharmacological evidence suggests that protein kinases are involved in RP of inhibitory synapses and LTD of excitatory PF synapses. Besides the well-described LTD, RP could be a cellular mechanism that plays an important role in motor learning. (shrink)

Thirty years after its initial characterization and more than 1000 publications listed in PubMed describing its properties, the small (ca15 kDa) protein profilin continues to surprise us with new, recently discovered functions. Originally described as an actin‐binding protein, profilin has now been shown to interact with more than a dozen proteins in mammalian cells. Some of the more recently described and intriguing interactions are within neurons involving a neuronal profilin family member. Profilin is now regarded as a regulator of various (...) cellular processes such as cytoskeletal dynamics, membrane trafficking and nuclear transport. Profilin is a necessary element in key steps of neuronal differentiation and synaptic plasticity, and embodies properties postulated for a synaptic tag. These findings identify profilin as an important factor linking cellular and behavioural plasticity in neural circuits. BioEssays 30:994–1002, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

AbstractmRNA stability is increasingly recognized as being essential for controlling the expression of a wide variety of transcripts during neuronal development and synaptic plasticity. In this context, the role of AU‐rich elements (ARE) contained within the 3′ untranslated region (UTR) of transcripts has now emerged as key because of their high incidence in a large number of cellular mRNAs. This important regulatory element is known to significantly modulate the longevity of mRNAs by interacting with available stabilizing or destabilizing (...) RNA‐binding proteins (RBP). Thus, in parallel with the emergence of ARE, RBP are also gaining recognition for their pivotal role in regulating expression of a variety of mRNAs. In the nervous system, the member of the Hu family of ARE‐binding proteins known as HuD, has recently been implicated in multiple aspects of neuronal function including the commitment and differentiation of neuronal precursors as well as synaptic remodeling in mature neurons. Through its ability to interact with ARE and stabilize multiple transcripts, HuD has now emerged as an important regulator of mRNA expression in neurons. The present review is designed to provide a comprehensive and updated view of HuD as an RBP in the nervous system. Additionally, we highlight the role of HuD in multiple aspects of a neuron's life from early differentiation to changes in mature neurons during learning paradigms and in response to injury and regeneration. Finally, we describe the current state of knowledge concerning the molecular and cellular events regulating the expression and activity of HuD in neurons. BioEssays 28: 822–833, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

It is worthwhile to search for forms of coding, processing, and learning common to various cortical regions and cognitive functions. Local cortical processors may coordinate their activity by maximizing the transmission of information coherently related to the context in which it occurs, thus forming synchronized population codes. This coordination involves contextual field (CF) connections that link processors within and between cortical regions. The effects of CF connections are distinguished from those mediating receptive field (RF) input; it is shown how CFs (...) can guide both learning and processing without becoming confused with the transmission of RF information. Simulations explore the capabilities of networks built from local processors with both RF and CF connections. Physiological evidence for synchronization, CFs, and plasticity of the RF and CF connections is described. Coordination via CFs is related to perceptual grouping, the effects of context on contrast sensitivity, amblyopia, implicit influences of color in achromotopsia, object and word perception, and the discovery of distal environmental variables and their interactions through self-organization. Cortical computation could thus involve the flexible evaluation of relations between input signals by locally specialized but adaptive processors whose activity is dynamically associated and coordinated within and between regions through specialized contextual connections. Key Words: cell assemblies; cerebral cortex; context; coordination; dynamic binding; epistemology; functional specialization; learning; neural coding; neural computation; neuropsychology; object recognition; perception; reading; self-organization; synaptic plasticity; synchronization. (shrink)

The vestibulo-ocular reflex (VOR) adaptation is an ideal model for investigating how the neurosteroid 17 beta-estradiol (E2) contributes to the modification of behavior by regulating synaptic activities. We hypothesized that E2 impacts VOR adaptation by affecting cerebellar synaptic plasticity at the parallel fiber–Purkinje cell (PF) synapse. To verify this hypothesis, we investigated the acute effect of blocking E2 synthesis on gain increases and decreases in adaptation of the VOR in male rats using an oral dose (2.5 mg/kg) (...) of the aromatase inhibitor letrozole. We also assessed the effect of letrozole on synaptic plasticity at the PF synapse in vitro, using cerebellar slices from male rats. We found that letrozole acutely impaired both gain increases and decreases adaptation of the VOR without altering basal ocular-motor performance. Moreover, letrozole prevented long-term potentiation at the PF synapse (PF-LTP) without affecting long-term depression (PF-LTD). Thus, in male rats neurosteroid E2 has a relevant impact on VOR adaptation and affects exclusively PF-LTP. These findings suggest that E2 might regulate changes in VOR adaptation by acting locally on cerebellar and extra-cerebellar synaptic plasticity sites. (shrink)

Do neurobiologists aim to discover natural kinds? I address this question in this chapter via a critical analysis of classification practices operative across the 43-year history of research on long-term potentiation. I suggest that this 43-year history supports the idea that the structure of scientific practice surrounding LTP research has remained an obstacle to the discovery of natural kinds as philosophers of science have traditionally conceived them.

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)

Efforts to bridge emotion theory with neurobiology can be facilitated by dynamic systems (DS) modeling. DS principles stipulate higher-order wholes emerging from lower-order constituents through bidirectional causal processes cognition relations. I then present a psychological model based on this reconceptualization, identifying trigger, self-amplification, and self-stabilization phases of emotion-appraisal states, leading to consolidating traits. The article goes on to describe neural structures and functions involved in appraisal and emotion, as well as DS mechanisms of integration by which they interact. These mechanisms (...) include nested feedback interactions, global effects of neuromodulation, vertical integration, action-monitoring, and synaptic plasticity, and they are modeled in terms of both functional integration and temporal synchronization. I end by elaborating the psychological model of emotion–appraisal states with reference to neural processes. (shrink)

A hypothesis on the physiological conditions of consciousness is presented. It is assumed that the occurrence of states of consciousness causally depends on the formation of complex representational structures. Cortical neural networks that exhibit a high representational activity develop higher-order, self-referential representations as a result of self-organizing processes. The occurrence of such states is identical with the appearance of states of consciousness. The underlying physiological processes can be identified. It is assumed that neural assemblies instantiate mental representations; hence consciousness depends (...) on the rate at which large active assemblies are generated. The formation of assemblies involves the activation of the N-methyl-D-aspartate receptor channel complex which controls different forms of synaptic plasticity including rapid changes of the connection strengths. The various causes of unconsciousness (e.g., anaesthetics or brain stem lesions) have a common denominator: they directly or indirectly inhibit the formation of assemblies. (shrink)

Long-term potentiation (LTP) is operationally defined as a long-lasting increase in synaptic efficacy following high-frequency stimulation of afferent fibers. Since the first full description of the phenomenon in 1973, exploration of the mechanisms underlying LTP induction has been one of the most active areas of research in neuroscience. Of principal interest to those who study LTP, particularly in the mammalian hippocampus, is its presumed role in the establishment of stable memories, a role consistent with descriptions of memory formation. Other (...) characteristics of LTP, including its rapid induction, persistence, and correlation with natural brain rhythms, provide circumstantial support for this connection to memory storage. Nonetheless, there is little empirical evidence that directly links LTP to the storage of memories. In this target article we review a range of cellular and behavioral characteristics of LTP and evaluate whether they are consistent with the purported role of hippocampal LTP in memory formation. We suggest that much of the present focus on LTP reflects a preconception that LTP is a learning mechanism, although the empirical evidence often suggests that LTP is unsuitable for such a role. As an alternative to serving as a memory storage device, we propose that LTP may serve as a neural equivalent to an arousal or attention device in the brain. Accordingly, LTP may increase in a nonspecific way the effective salience of discrete external stimuli and may thereby facilitate the induction of memories at distant synapses. Other hypotheses regarding the functional utility of this intensely studied mechanism are conceivable; the intent of this target article is not to promote a single hypothesis but rather to stimulate discussion about the neural mechanisms underlying memory storage and to appraise whether LTP can be considered a viable candidate for such a mechanism. (shrink)

Biomedical science has been remarkably successful in explaining illness by categorizing diseases and then by identifying localizable lesions such as a virus and neoplasm in the body that cause those diseases. Not surprisingly, researchers have aspired to apply this powerful paradigm to addiction. So, for example, in a review of the neuroscience of addiction literature, Hyman and Malenka (2001, p. 695) acknowledge a general consensus among addiction researchers that “[a]ddiction can appropriately be considered as a chronic medical illness.” Like other (...) diseases, “Once addiction has taken hold, it tends to follow a chronic course.” (Koob and La Moal 2006, p. ?). Working from this perspective, much effort has gone into characterizing the symptomology of addiction and the brain changes that underlie them. Evidence for involvement of dopamine transmission changes in the ventral tegmental area (VTA) and nucleus accumbens (NAc) have received the greatest attention. Kauer and Malenka (2007, p. 844) put it well: “drugs of abuse can co-opt synaptic plasticity mechanisms in brain circuits involved in reinforcement and reward processing”. Our goal in this chapter to provide an explicit description of the assumptions of medical models, the different forms they may take, and the challenges they face in providing explanations with solid evidence of addiction. <br>. (shrink)

The structuralist program has developed a useful metascientific resource: ontological reductive links (ORLs) between the constituents of the potential models of reduced and reducing theories. This resource was developed initially to overcome an objection to structuralist ``global'' accounts of the intertheoretic reduction relation. But it also illuminates the way that concepts at a higher level of scientific investigation (e.g., cognitive psychology) become ``structured through reduction'' to lower-level investigations (e.g., cellular/molecular neuroscience). After (briefly) explaining this structuralist background, I demonstrate how this (...) resource illuminates an actual, emerging scientific example: the link between the psychological concept of a ``consolidation switch'' from short-term to long-term memory and the cellular/molecular mechanisms of the transition from early- to late-phases of long-term potentiation (LTP) (an important type of synaptic plasticity in mammalian hippocampus and cortex). (shrink)

The primate brain is able to guide complex decisions that can rapidly be adapted to changing constraints. Unfortunately, the vast numbers of highly interconnected neurons that seem to be needed make it difficult to study the cellular mechanisms that underlie the flexible combination of stored and acute information during a decision. Established simpler networks, particularly with few and identified neurons, would lend themselves more readily to such a dissection. But can simple networks implement complex and flexible decisions similarly? After a (...) brief overview of complex decisions in primates and of decision‐making in simple networks, I argue that simpler systems can combine complexity with accessibility at the cellular level. Indeed, examination of a network in fish may help in dissecting key mechanisms of complex and flexible decision‐making in an established model of synaptic plasticity at the level of identified neurons. (shrink)

This article reviews models of the cerebellum and motor learning, from the landmark papers by Marr and Albus through those of the present time. The unique architecture of the cerebellar cortex is ideally suited for pattern recognition, but how is pattern recognition incorporated into motor control and learning systems? The present analysis begins with a discussion of exactly what the cerebellar cortex needs to regulate through its anatomically defined projections to premotor networks. Next, we examine various models showing how the (...) microcircuitry in the cerebellar cortex could be used to achieve its regulatory functions. Having thus defined what it is that Purkinje cells in the cerebellar cortex must learn, we then evaluate theories of motor learning. We examine current models of synaptic plasticity, credit assignment, and the generation of training information, indicating how they could function cooperatively to guide the processes of motor learning. (shrink)

Long-Term Potentiation (LTP) is a kind of synaptic plasticity that many contemporary neuroscientists believe is a component in mechanisms of memory. This essay describes the discovery of LTP and the development of the LTP research program. The story begins in the 1950's with the discovery of synaptic plasticity in the hippocampus (a medial temporal lobe structure now associated with memory), and it ends in 1973 with the publication of three papers sketching the future course of the (...) LTP research program. The making of LTP was a protracted affair. Hippocampal synaptic plasticity was initially encountered as an experimental tool, then reported as a curiosity, and finally included in the ontic store of the neurosciences. Early researchers were not investigating the hippocampus in search of a memory mechanism; rather, they saw the hippocampus as a useful experimental model or as a structure implicated in the etiology of epilepsy. The link between hippocampal synaptic plasticity and learning or memory was a separate conceptual achievement. That link was formulated in at least three different ways at different times: reductively (claiming that plasticity is identical to learning), analogically (claiming that plasticity is an example or model of learning), and mechanistically (claiming that plasticity is a component in learning or memory mechanisms). The hypothesized link with learning or memory, coupled with developments in experimental techniques and preparations, shaped how researchers understood LTP itself. By 1973, the mechanistic formulation of the link between LTP and memory provided an abstract framework around which findings from multiple perspectives could be integrated into a multifield research program. (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.

How do human infants learn the causal dependencies between events? Evidence suggests that this remarkable feat can be achieved by observation of only a handful of examples. Many computational models have been produced to explain how infants perform causal inference without explicit teaching about statistics or the scientific method. Here, we propose a spiking neuronal network implementation that can be entrained to form a dynamical model of the temporal and causal relationships between events that it observes. The network uses spike-time (...) dependent plasticity, long-term depression, and heterosynaptic competition rules to implement Rescorla–Wagner-like learning. Transmission delays between neurons allow the network to learn a forward model of the temporal relationships between events. Within this framework, biologically realistic synaptic plasticity rules account for well-known behavioral data regarding cognitive causal assumptions such as backwards blocking and screening-off. These models can then be run as emulators for state inference. Furthermore, this mechanism is capable of copying synaptic connectivity patterns between neuronal networks by observing the spontaneous spike activity from the neuronal circuit that is to be copied, and it thereby provides a powerful method for transmission of circuit functionality between brain regions. (shrink)

Various neurophysiological experiments have revealed remarkable correlations between cortical neuronal activity and subjective experiences. However, the mere presence of neuronal electrical activity does not appear to be sufficient to produce these experiences. It has been suggested that the explanation for the neural basis of consciousness might lie in understanding the reason that some types of neuronal activity possess subjective correlates and others do not. Here I propose and develop the idea that this difference may be caused by the existence of (...) an elementary nonarbitrary linkage between temporal or spatiotemporal patterns of neuronal activity and their subjective attributes. I also show how cortical neural circuits capable of generating experience-coding patterns could emerge during evolution and brain development, due to the presence of spontaneous stochastic neuronal activity and activity-dependent synaptic plasticity. This hypothesis leads to several testable predictions, principal among which is the idea that the neural correlates of consciousness are essentially innate and universal. (shrink)

In the thirty years since its discovery by Terje Lomo and Tim Bliss, Long Term Potentiation has become one of the most extensively studied topics in contemporary neuroscience. In LTP the strength of synapses between neurons is potentiated following brief but intense activation. LTP is thought to play a central role in learning and memory, though the exact nature of its role is less clear. In spite of years of research, there are many questions about LTP regarding its functional relevance (...) that remain unanswered - for example, is it a model of memory formation, or is the actual neural mechanism used by the brain to store information? This volume presents a state of the art account of LTP. It begins with lively accounts, by the scientists most closely involved, of the discovery of LTP and of the experiments that established its basic properties and induction mechanisms. Later contributions contain reviews and new research that cover the range of molecular, cellular, physiological and behavioural approaches to the study of LTP. Provocative, accessible, and authoritative, this book makes it clear why LTP continues in equal measure to puzzle and beguile neuroscientists today. Advance praise for Long Term Potentiation: 'This book provides a definitive overview of the development of ideas about synaptic plasticity and about the wide range of current research in this fascinating field.' Colin Blakemore, University of OxfordReadership: Neuroscientists from postgraduate level upwards. (shrink)

Presenilin‐1 (PS1) is thought to regulate cell differentiation and survival by modulating the Notch signaling pathway. Mutations in PS1 have been shown to cause early‐onset inherited forms of Alzheimer's disease (AD) by a gain‐of‐function mechanism that alters proteolytic processing of the amyloid precursor protein (APP) resulting in increased production of neurotoxic forms of amyloid β‐peptide. The present article considers a second pathogenic mode of action of PS1 mutations, a defect in cellular calcium signaling characterized by overfilling of endoplasmic reticulum (ER) (...) calcium stores and altered capacitive calcium entry; this abnormality may impair synaptic plasticity and sensitize neurons to apoptosis and excitotoxicity. The calcium signaling defect has also been documented in lymphocytes, suggesting a contribution of immune dysfunction to the pathogenesis of AD. A better understanding of the calcium signaling defect resulting from PS1 mutations may lead to the development of novel preventative and therapeutic strategies for disorders of the nervous and immune systems. BioEssays 23:733–744, 2001. © 2001 John Wiley & Sons, Inc. (shrink)