Conditions for Synaptic Specificity during the Maintenance Phase of Synaptic Plasticity.

Activity-dependent modifications of synaptic efficacies are a cellular substrate of learning and memory. Experimental evidence shows that these modifications are synapse specific and that the long-lasting effects are associated with the sustained increase in concentration of specific proteins like PKM However, such proteins are likely to diffuse away from their initial synaptic location and spread out to neighboring synapses, potentially compromising synapse specificity. In this article, we address the issue of synapse specificity during memory maintenance.

The Role of Multiple Neuromodulators in Reinforcement Learning That Is Based on Competition between Eligibility Traces.

The ability to maximize reward and avoid punishment is essential for animal survival. Reinforcement learning (RL) refers to the algorithms used by biological or artificial systems to learn how to maximize reward or avoid negative outcomes based on past experiences. While RL is also important in machine learning, the types of mechanistic constraints encountered by biological machinery might be different than those for artificial systems.

A Simple Network Architecture Accounts for Diverse Reward Time Responses in Primary Visual Cortex.

Unlabelled: Many actions performed by animals and humans depend on an ability to learn, estimate, and produce temporal intervals of behavioral relevance. Exemplifying such learning of cued expectancies is the observation of reward-timing activity in the primary visual cortex (V1) of rodents, wherein neural responses to visual cues come to predict the time of future reward as behaviorally experienced in the past. These reward-timing responses exhibit significant heterogeneity in at least three qualitatively distinct classes: sustained increase or sustained decrease in firing rate until the time of expected reward, and a class of cells that reach a peak in firing at the expected delay.

Visually cued action timing in the primary visual cortex.

Most behaviors are generated in three steps: sensing the external world, processing that information to instruct decision-making, and producing a motor action. Sensory areas, especially primary sensory cortices, have long been held to be involved only in the first step of this sequence. Here, we develop a visually cued interval timing task that requires rats to decide when to perform an action following a brief visual stimulus.

Pacemaker rate and depolarization block in nigral dopamine neurons: a somatic sodium channel balancing act.

Midbrain dopamine (DA) neurons are slow intrinsic pacemakers that undergo depolarization (DP) block upon moderate stimulation. Understanding DP block is important because it has been correlated with the clinical efficacy of chronic antipsychotic drug treatment. Here we describe how voltage-gated sodium (Na(V)) channels regulate DP block and pacemaker activity in DA neurons of the substantia nigra using rat brain slices.

Functional characterization of ether-à-go-go-related gene potassium channels in midbrain dopamine neurons - implications for a role in depolarization block.

Bursting activity by midbrain dopamine neurons reflects the complex interplay between their intrinsic pacemaker activity and synaptic inputs. Although the precise mechanism responsible for the generation and modulation of bursting in vivo has yet to be established, several ion channels have been implicated in the process. Previous studies with nonselective blockers suggested that ether-à-go-go-related gene (ERG) K(+) channels are functionally significant.

Ca2+ alternans in a cardiac myocyte model that uses moment equations to represent heterogeneous junctional SR Ca2+.

Multiscale whole-cell models that accurately represent local control of Ca2+-induced Ca2+ release in cardiac myocytes can reproduce high-gain Ca2+ release that is graded with changes in membrane potential. Using a recently introduced formalism that represents heterogeneous local Ca2+ using moment equations, we present a model of cardiac myocyte Ca2+ cycling that exhibits alternating sarcoplasmic reticulum (SR) Ca2+ release when periodically stimulated by depolarizing voltage pulses. The model predicts that the distribution of junctional SR [Ca2+] across a large population of Ca2+ release units is distinct on alternating cycles.

Regulation of firing frequency in a computational model of a midbrain dopaminergic neuron.

Dopaminergic (DA) neurons of the mammalian midbrain exhibit unusually low firing frequencies in vitro. Furthermore, injection of depolarizing current induces depolarization block before high frequencies are achieved. The maximum steady and transient rates are about 10 and 20 Hz, respectively, despite the ability of these neurons to generate bursts at higher frequencies in vivo.

Moment closure for local control models of calcium-induced calcium release in cardiac myocytes.

In prior work, we introduced a probability density approach to modeling local control of Ca2+-induced Ca2+ release in cardiac myocytes, where we derived coupled advection-reaction equations for the time-dependent bivariate probability density of subsarcolemmal subspace and junctional sarcoplasmic reticulum (SR) [Ca2+] conditioned on Ca2+ release unit (CaRU) state. When coupled to ordinary differential equations (ODEs) for the bulk myoplasmic and network SR [Ca2+], a realistic but minimal model of cardiac excitation-contraction coupling was produced that avoids the computationally demanding task of resolving spatial aspects of global Ca2+ signaling, while accurately representing heterogeneous local Ca2+ signals in a population of diadic subspaces and junctional SR depletion domains. Here we introduce a computationally efficient method for simulating such whole cell models when the dynamics of subspace [Ca2+] are much faster than those of junctional SR [Ca2+].

The dynamics of luminal depletion and the stochastic gating of Ca2+-activated Ca2+ channels and release sites.

Single channel models of intracellular calcium (Ca(2+)) channels such as the 1,4,5-trisphosphate receptor and ryanodine receptor often assume that Ca(2+)-dependent transitions are mediated by constant background cytosolic [Ca(2+)]. This assumption neglects the fact that Ca(2+) released by open channels may influence subsequent gating through the processes of Ca(2+)-activation or inactivation. Similarly, the influence of the dynamics of luminal depletion on the stochastic gating of intracellular Ca(2+) channels is often neglected, in spite of the fact that the sarco/endoplasmic reticulum [Ca(2+)] near the luminal face of intracellular Ca(2+) channels influences the driving force for Ca(2+), the rate of Ca(2+) release, and the magnitude and time course of the consequent increase in cytosolic domain [Ca(2+)].

A probability density approach to modeling local control of calcium-induced calcium release in cardiac myocytes.

We present a probability density approach to modeling localized Ca2+ influx via L-type Ca2+ channels and Ca2+-induced Ca2+ release mediated by clusters of ryanodine receptors during excitation-contraction coupling in cardiac myocytes. Coupled advection-reaction equations are derived relating the time-dependent probability density of subsarcolemmal subspace and junctional sarcoplasmic reticulum [Ca2+] conditioned on "Ca2+ release unit" state. When these equations are solved numerically using a high-resolution finite difference scheme and the resulting probability densities are coupled to ordinary differential equations for the bulk myoplasmic and sarcoplasmic reticulum [Ca2+], a realistic but minimal model of cardiac excitation-contraction coupling is produced.

A multivariate population density model of the dLGN/PGN relay.

Using a population density approach we study the dynamics of two interacting collections of integrate-and-fire-or-burst (IFB) neurons representing thalamocortical (TC) cells from the dorsal lateral geniculate nucleus (dLGN) and thalamic reticular (RE) cells from the perigeniculate nucleus (PGN). Each population of neurons is described by a multivariate probability density function that satisfies a conservation equation with appropriately defined probability fluxes and boundary conditions. The state variables of each neuron are the membrane potential and the inactivation gating variable of the low-threshold Ca2+ current I(T).

Feedback inhibition and throughput properties of an integrate-and-fire-or-burst network model of retinogeniculate transmission.

Computational modeling has played an important role in the dissection of the biophysical basis of rhythmic oscillations in thalamus that are associated with sleep and certain forms of epilepsy. In contrast, the dynamic filter properties of thalamic relay nuclei during states of arousal are not well understood. Here we present a modeling and simulation study of the throughput properties of the visually driven dorsal lateral geniculate nucleus (dLGN) in the presence of feedback inhibition from the perigeniculate nucleus (PGN).