A calcium-based plasticity model for predicting long-term potentiation and depression in the neocortex.

Pyramidal cells (PCs) form the backbone of the layered structure of the neocortex, and plasticity of their synapses is thought to underlie learning in the brain. However, such long-term synaptic changes have been experimentally characterized between only a few types of PCs, posing a significant barrier for studying neocortical learning mechanisms. Here we introduce a model of synaptic plasticity based on data-constrained postsynaptic calcium dynamics, and show in a neocortical microcircuit model that a single parameter set is sufficient to unify the available experimental findings on long-term potentiation (LTP) and long-term depression (LTD) of PC connections.

Effect of phone call distraction on the performance of medical students in an OSCE.

Background: The usage of smartphones in the daily clinical routine is an essential aspect however it seems that they also present an important distractor that needs to be evaluated. The aim of this prospective study was the evaluation of the influence of phone calls as distractors on the performance levels of medical students during an objective structured clinical examination (OSCE), simulating the normal clinical practice.

Methods: As the goal of an OSCE presents the examination of clinical skills of medical students in a realistic setting, more than 100 students recruited from the university hospital of Cologne participated in either OSCE I or II.

Short-term depression and long-term plasticity together tune sensitive range of synaptic plasticity.

Synaptic efficacy is subjected to activity-dependent changes on short- and long time scales. While short-term changes decay over minutes, long-term modifications last from hours up to a lifetime and are thought to constitute the basis of learning and memory. Both plasticity mechanisms have been studied extensively but how their interaction shapes synaptic dynamics is little known.

Beyond Freezing: Temporal Expectancy of an Aversive Event Engages the Amygdalo-Prefronto-Dorsostriatal Network.

During Pavlovian aversive conditioning, a neutral conditioned stimulus (CS) becomes predictive of the time of arrival of an aversive unconditioned stimulus (US). Using a paradigm where animals had to discriminate between a CS+ (associated with a footshock) and a CS- (never associated with a footshock), we show that, early in training, dynamics of neuronal oscillations in an amygdalo-prefronto-striatal network are modified during the CS+ in a manner related to the CS-US time interval (30 or 10 s). This is the case despite a generalized high level of freezing to both CS+ and CS-.

Synergism of type 1 metabotropic and ionotropic glutamate receptors in cerebellar molecular layer interneurons in vivo.

Type 1 metabotropic glutamate receptors (mGluR1s) are key elements in neuronal signaling. While their function is well documented in slices, requirements for their activation in vivo are poorly understood. We examine this question in adult mice in vivo using 2-photon imaging of cerebellar molecular layer interneurons (MLIs) expressing GCaMP.

Updating temporal expectancy of an aversive event engages striatal plasticity under amygdala control.

Pavlovian aversive conditioning requires learning of the association between a conditioned stimulus (CS) and an unconditioned, aversive stimulus (US) but also involves encoding the time interval between the two stimuli. The neurobiological bases of this time interval learning are unknown. Here, we show that in rats, the dorsal striatum and basal amygdala belong to a common functional network underlying temporal expectancy and learning of a CS-US interval.

Natural Firing Patterns Imply Low Sensitivity of Synaptic Plasticity to Spike Timing Compared with Firing Rate.

Unlabelled: Synaptic plasticity is sensitive to the rate and the timing of presynaptic and postsynaptic action potentials. In experimental protocols inducing plasticity, the imposed spike trains are typically regular and the relative timing between every presynaptic and postsynaptic spike is fixed. This is at odds with firing patterns observed in the cortex of intact animals, where cells fire irregularly and the timing between presynaptic and postsynaptic spikes varies.

Memory maintenance in synapses with calcium-based plasticity in the presence of background activity.

Most models of learning and memory assume that memories are maintained in neuronal circuits by persistent synaptic modifications induced by specific patterns of pre- and postsynaptic activity. For this scenario to be viable, synaptic modifications must survive the ubiquitous ongoing activity present in neural circuits in vivo. In this paper, we investigate the time scales of memory maintenance in a calcium-based synaptic plasticity model that has been shown recently to be able to fit different experimental data-sets from hippocampal and neocortical preparations.

Synaptic input correlations leading to membrane potential decorrelation of spontaneous activity in cortex.

Correlations in the spiking activity of neurons have been found in many regions of the cortex under multiple experimental conditions and are postulated to have important consequences for neural population coding. While there is a large body of extracellular data reporting correlations of various strengths, the subthreshold events underlying the origin and magnitude of signal-independent correlations (called noise or spike count correlations) are unknown. Here we investigate, using intracellular recordings, how synaptic input correlations from shared presynaptic neurons translate into membrane potential and spike-output correlations.

Endogenous cholinergic inputs and local circuit mechanisms govern the phasic mesolimbic dopamine response to nicotine.

Nicotine exerts its reinforcing action by stimulating nicotinic acetylcholine receptors (nAChRs) and boosting dopamine (DA) output from the ventral tegmental area (VTA). Recent data have led to a debate about the principal pathway of nicotine action: direct stimulation of the DAergic cells through nAChR activation, or disinhibition mediated through desensitization of nAChRs on GABAergic interneurons. We use a computational model of the VTA circuitry and nAChR function to shed light on this issue.

Co-activation of VTA DA and GABA neurons mediates nicotine reinforcement.

Smoking is the most important preventable cause of mortality and morbidity worldwide. This nicotine addiction is mediated through the nicotinic acetylcholine receptor (nAChR), expressed on most neurons, and also many other organs in the body. Even within the ventral tegmental area (VTA), the key brain area responsible for the reinforcing properties of all drugs of abuse, nicotine acts on several different cell types and afferents.

Calcium-based plasticity model explains sensitivity of synaptic changes to spike pattern, rate, and dendritic location.

Multiple stimulation protocols have been found to be effective in changing synaptic efficacy by inducing long-term potentiation or depression. In many of those protocols, increases in postsynaptic calcium concentration have been shown to play a crucial role. However, it is still unclear whether and how the dynamics of the postsynaptic calcium alone determine the outcome of synaptic plasticity.

Mechanisms of induction and maintenance of spike-timing dependent plasticity in biophysical synapse models.

We review biophysical models of synaptic plasticity, with a focus on spike-timing dependent plasticity (STDP). The common property of the discussed models is that synaptic changes depend on the dynamics of the intracellular calcium concentration, which itself depends on pre- and postsynaptic activity. We start by discussing simple models in which plasticity changes are based directly on calcium amplitude and dynamics.

Modeling nicotinic neuromodulation from global functional and network levels to nAChR based mechanisms.

Neuromodulator action has received increasing attention in theoretical neuroscience. Yet models involving both neuronal populations dynamics at the circuit level and detailed receptor properties are only now being developed. Here we review recent computational approaches to neuromodulation, focusing specifically on acetylcholine (ACh) and nicotine.

Computational approaches to the neurobiology of drug addiction.

To increase our understanding of drug addiction--notably its pharmacological and neurobiological determinants--researchers have begun to formulate computational models of drug self-administration. Currently, one can roughly distinguish between three classes of models which all have in common to attribute to brain dopamine signaling a key role in addiction. The first class of models contains quantitative pharmacological models that describe the influence of pharmacokinetic and pharmacodynamic factors on drug self-administration.

STDP in a bistable synapse model based on CaMKII and associated signaling pathways.

The calcium/calmodulin-dependent protein kinase II (CaMKII) plays a key role in the induction of long-term postsynaptic modifications following calcium entry. Experiments suggest that these long-term synaptic changes are all-or-none switch-like events between discrete states. The biochemical network involving CaMKII and its regulating protein signaling cascade has been hypothesized to durably maintain the evoked synaptic state in the form of a bistable switch.

A theory of plasma membrane calcium pump stimulation and activity.

The ATP-driven Plasma Membrane Calcium pump or Ca(2+)-ATPase (PMCA) is characterized by a high affinity for calcium and a low transport rate compared to other transmembrane calcium transport proteins. It plays a crucial role for calcium extrusion from cells. Calmodulin is an intracellular calcium buffering protein which is capable in its Ca(2+) liganded form of stimulating the PMCA by increasing both the affinity to calcium and the maximum calcium transport rate.

CofE catalyzes the addition of two glutamates to F420-0 in F420 coenzyme biosynthesis in Methanococcus jannaschii.

The protein product of the Methanococcus jannaschii MJ0768 gene has been expressed in Escherichia coli, purified to homogeneity, and shown to catalyze the GTP-dependent addition of two l-glutamates to the l-lactyl phosphodiester of 7,8-didemethyl-8-hydroxy-5-deazariboflavin (F(420)-0) to form F(420)-0-glutamyl-glutamate (F(420)-2). Since the reaction is the fifth step in the biosynthesis of coenzyme F(420), the enzyme has been designated as CofE, the product of the cofE gene. Gel filtration chromatography indicates CofE is a dimer.

Methanococcus jannaschii coenzyme F420 analogs contain a terminal alpha-linked glutamate.

Analyses of the F(420)s present in Methanococcus jannaschii have shown that these cells contain a series of gamma-glutamyl-linked F(420)s capped with a single, terminal alpha-linked L-glutamate. The predominant form of F(420) was designated as alpha-F(420)-3 and represented 86% of the F(420)s in these cells. Analyses of Methanosarcina thermophila, Methanosarcina barkeri, Methanobacterium thermoautotrophicum, Archaeoglobus fulgidus, and Mycobacterium smegmatis showed that they contained only gamma-glutamyl-linked F(420)s.

[Sclerochoroidal calcification--a rare disease pattern--report on two patients, differential diagnosis and review of the literature].

Background: Idiopathic sclerochoroidal calcification is a benign calcification at the level of the choroid and the sclera. Due to the location of the lesions mainly between the superior temporal vascular arcade and the equator, there is no visual disturbance. Diagnosis of idiopathic sclerochoroidal calcification is made by the typical fundus appearance in combination with ultrasonic findings.

The pyrimidine nucleotide reductase step in riboflavin and F(420) biosynthesis in archaea proceeds by the eukaryotic route to riboflavin.

The Methanococcus jannaschii gene MJ0671 was cloned and overexpressed in Escherichia coli, and its gene product was tested for its ability to catalyze the pyridine nucleotide-dependent reduction of either 2,5-diamino-6-ribosylamino-4(3H)-pyrimidinone 5'-phosphate (compound 3) to 2,5-diamino-6-ribitylamino-4(3H)-pyrimidinone 5'-phosphate (compound 4) or 5-amino-6-ribosylamino-2,4(1H,3H)-pyrimidinedione 5'-phosphate (compound 7) to 5-amino-6-ribitylamino-2,4(1H,3H)-pyrimidinedione 5'-phosphate (compound 5). Only compound 3 was found to serve as a substrate for the enzyme. NADPH and NADH functioned equally well as the reductants.

Characterization of the 2-phospho-L-lactate transferase enzyme involved in coenzyme F(420) biosynthesis in Methanococcus jannaschii.

The protein product of the Methanococcus jannaschii MJ1256 gene has been expressed in Escherichia coli, purified to homogeneity, and shown to be involved in coenzyme F(420) biosynthesis. The protein catalyzes the transfer of the 2-phospholactate moiety from lactyl (2) diphospho-(5')guanosine (LPPG) to 7,8-didemethyl-8-hydroxy-5-deazariboflavin (Fo) with the formation of the L-lactyl phosphodiester of 7,8-didemethyl-8-hydroxy-5-deazariboflavin (F(420)-0) and GMP. On the basis of the reaction catalyzed, the enzyme is named LPPG:Fo 2-phospho-L-lactate transferase.

New class of IMP cyclohydrolases in Methanococcus jannaschii.

The enzyme responsible for observed IMP cyclohydrolase activity in Methanococcus jannaschii was purified and sequenced: its genetic locus was found to correspond to gene MJ0626. The MJ0626 gene was cloned, and its protein product was expressed in Escherichia coli and shown to catalyze the cyclization of 5-formylamidoimidazole-4-carboxamide ribonucleotide to IMP. The enzyme has no sequence similarity to known enzymes, and its catalytic properties appear distinct from any characterized IMP cyclohydrolase.

Identification of coenzyme M biosynthetic 2-phosphosulfolactate phosphatase. A member of a new class of Mg(2+)-dependent acid phosphatases.

Coenzyme M (CoM; 2-mercaptoethanesulfonic acid) is the terminal methyl carrier in methanogenesis. Methanogenic archaea begin the production of this essential cofactor by sulfonating phosphoenolpyruvate to form 2-phospho-3-sulfolactate. After dephosphorylation, this precursor is oxidized, decarboxylated and then reductively thiolated to form CoM.