Dependent Synaptic Plasticity Research Articles

A CMOS circuit for STDP with a symmetric time window

In some spiking neuron models, analog information is expressed by the timing of neuronal spike firing events, and synaptic weights change depending on the relative timing between asynchronous spikes, which is called spike-timing dependent synaptic plasticity (STDP). In this paper, we propose an analog CMOS circuit for STDP with a symmetric time window and a Hopfield-type VLSI neural network using the synapse circuit. We have confirmed by circuit simulations that the network can perform autocorrelation learning from input spike patterns.

A synaptic circuit of a pulse-type hardware neuron model with STDP

A number of recent studies of neural networks have been conducted with the purpose of applying engineering to the brain. We have been attempting to construct artificial neural networks. In the present study, we focus on STDP (spike timing dependent synaptic plasticity) and construct a neural network from a pulse-type hardware neuron model (P-HNM) with STDP. In addition, we propose a simple synaptic circuit of the P-HNM with STDP, which is composed of MOSFETs, and construct a simple neural network in order to verify the robustness with respect to phase fluctuation. We show that a pulse-type hardware neural network with STDP synapses has a learning function that has robustness with respect to phase fluctuation.

Computational consequences of experimentally derived spike-time and weight dependent plasticity rules

We present two weight- and spike-time dependent synaptic plasticity rules consistent with the physiological data of Bi and Poo (J Neurosci 18:10464-10472, 1998). One rule assumes synaptic saturation, while the other is scale free. We extend previous analyses of the asymptotic consequences of weight-dependent STDP to the case of strongly correlated pre- and post-synaptic spiking, more closely resembling associative learning. We further provide a general formula for the contribution of any number of spikes to synaptic drift. Asymptotic weights are shown to principally depend on the correlation and rate of pre- and post-synaptic activity, decreasing with increasing rate under correlated activity, and increasing with rate under uncorrelated activity. Spike train statistics reveal a quantitative effect only in the pre-asymptotic regime, and we provide a new interpretation of the relation between BCM and STDP data.

D-serine relieves chronic lead exposure-impaired long-term potentiation in the CA1 region of the rat hippocampus in vitro

Chronic lead-exposure produces long-lasting astroglial morphological and functional changes, which disturb the neuronal functions in the hippocampus. It has been shown that glia-derived d-serine is an essential signal for N-methyl- d-aspartate receptor (NMDAR)-dependent synaptic plasticity in the hippocampal CA1 region. However, the relationship between d-serine and the chronic lead exposure-induced deficit of synaptic plasticity is not clear. In the present study, the properties of d-serine on the chronic lead exposure-impaired synaptic plasticity in the rat hippocampal CA1 region were investigated with electrophysiological recording techniques in vitro. We found that 50 μM d-serine rescued the chronic lead exposure-induced deficit of long-term potentiation (LTP). However, this effect could be abolished by 7-chlorokynurenic acid (7-ClKY), which is a specific antagonist of the glycine-binding site of NMDARs. In contrast, d-serine had no effect on the NMDAR-independent LTP, which was induced in the mossy-CA3 synapses. In addition, we found that d-serine rescued the acute Pb 2+-impaired NMDAR-mediated excitatory postsynaptic currents (EPSCs) partially. These findings demonstrate that d-serine relieves the chronic lead exposure-induced deficit of synaptic plasticity via NMDAR activation suggesting that administration of d-serine may be a potential therapeutic intervention to treat chronic lead exposure-impaired cognitive functions or affective disorders.

The relation between spike-timing dependent plasticity and Ca2+ dynamics in the hippocampal CA1 network

In our previous study, spike timing dependent synaptic plasticity (STDP) was investigated in the CA1 area of rat hippocampal slices using optical imaging. It was revealed that the profiles of STDP could be classified into two types depending upon layer specific location along the dendrite. The first was characterized by a symmetric time window observed in the proximal region of the stratum radiatum (SR), and the second by an asymmetric time window in the distal region of the SR. Our methods involved the bath-application of bicuculline (GABAA receptor antagonist) to hippocampal slices, which revealed that GABAergic interneuron projections were responsible for the symmetry of a time window. In this study, the intracellular Ca2+ increase of hippocampal CA1 neurons, induced by the protocol of timing between pre- and post-synaptic excitation (i.e. STDP protocol), was measured spatially by using optical imaging to investigate how the triggering of STDP is dependant on intracellular calcium concentration. We found that the magnitude of STDP was closely related to the rate of Ca2+ increase (“velocity”) of calcium transient during application of induction stimuli. Location dependency was also analyzed in terms of Ca2+ influx. Furthermore, it was shown that decay time constant of Ca2+ dynamics during the application of STDP-inducing stimuli was also significantly correlated with STDP.

Stability of complex spike timing-dependent plasticity in cerebellar learning

Dynamics of spike-timing dependent synaptic plasticity are analyzed for excitatory and inhibitory synapses onto cerebellar Purkinje cells. The purpose of this study is to place theoretical constraints on candidate synaptic learning rules that determine the changes in synaptic efficacy due to pairing complex spikes with presynaptic spikes in parallel fibers and inhibitory interneurons. Constraints are derived for the timing between complex spikes and presynaptic spikes, constraints that result from the stability of the learning dynamics of the learning rule. Potential instabilities in the parallel fiber synaptic learning rule are found to be stabilized by synaptic plasticity at inhibitory synapses if the inhibitory learning rules are stable, and conditions for stability of inhibitory plasticity are given. Combining excitatory with inhibitory plasticity provides a mechanism for minimizing the overall synaptic input. Stable learning rules are shown to be able to sculpt simple-spike patterns by regulating the excitability of neurons in the inferior olive that give rise to climbing fibers.

Self-organized criticality and scale-free properties in emergent functional neural networks

Recent studies on complex systems have shown that the synchronization of oscillators, including neuronal ones, is faster, stronger, and more efficient in small-world networks than in regular or random networks. We show that the functional structures in the brain can be self-organized to both small-world and scale-free networks by synaptic reorganization via spike timing dependent synaptic plasticity instead of conventional Hebbian learning rules. We show that the balance between the excitatory and the inhibitory synaptic inputs is critical in the formation of the functional structure, which is found to lie in a self-organized critical state.

Activity Bidirectionally Regulates AMPA Receptor mRNA Abundance in Dendrites of Hippocampal Neurons

Activity-dependent regulation of synaptic AMPA receptor (AMPAR) number is critical to NMDA receptor (NMDAR)-dependent synaptic plasticity. Using quantitative high-resolution in situ hybridization, we show that mRNAs encoding the AMPA-type glutamate receptor subunits (GluRs) 1 and 2 are localized to dendrites of hippocampal neurons and are regulated by paradigms that alter synaptic efficacy. A substantial fraction of synaptic sites contain AMPAR mRNA, consistent with strategic positioning and availability for "on-site" protein synthesis. NMDAR activation depletes dendritic levels of AMPAR mRNAs. The decrease in mRNA occurs via rise in intracellular Ca2+, activation of extracellular signal-regulated kinase/mitogen-activated protein kinase signaling, and transcriptional arrest at the level of the nucleus. The decrease in mRNA is accompanied by a long-lasting reduction in synaptic AMPAR number, consistent with reduced synaptic efficacy. In contrast, group I metabotropic GluR signaling promotes microtubule-based trafficking of existing AMPAR mRNAs from the soma to dendrites. Bidirectional regulation of dendritic mRNA abundance represents a potentially powerful means to effect long-lasting changes in synaptic strength.

Group I mGluR regulates the polarity of spike-timing dependent plasticity in substantia gelatinosa neurons

The spinal synaptic plasticity is associated with a central sensitization of nociceptive input, which accounts for the generation of hyperalgesia in chronic pain. However, how group I metabotropic glutamate receptors (mGluRs) may operate spinal plasticity remains essentially unexplored. Here, we have identified spike-timing dependent synaptic plasticity in substantia gelatinosa (SG) neurons, using perforated patch-clamp recordings of SG neuron in a spinal cord slice preparation. In the presence of bicuculline and strychnine, long-term potentiation (LTP) was blocked by AP-5 and Ca 2+ chelator BAPTA-AM. The group I mGluR antagonist AIDA, PLC inhibitor U-73122, and IP 3 receptor blocker 2-APB shifted LTP to long-term depression (LTD) without affecting acute synaptic transmission. These findings provide a link between postsynaptic group I mGluR/PLC/IP 3-gated Ca 2+ store regulating the polarity of synaptic plasticity and spinal central sensitization.

Temporal correlation based learning in neuron models

We study a learning rule based upon the temporal correlation (weighted by a learning kernel) between incoming spikes and the internal state of the postsynaptic neuron, building upon previous studies of spike timing dependent synaptic plasticity (Kempter, R., Gerstner, W., van Hemmen, J.L., Wagner, H., 1998. Extracting Oscillations: Neuronal coincidence detection with noisy periodic spike input. Neural computation 10, 1987–2017; Kempter, R., Gerstner, W., van Hemmen, J.L., 1999. Hebbian learning and spiking neurons. Physical Reviewm E59, 4498–4514; van Hemmen, J.L., 2001. Theory of synaptic plasticity. In: Moss, F., Gielen, S. (Eds.), Handbook of biological physics. vol. 4, Neuro Informatics, neural modelling, Elsevier, Amsterdam, pp. 771–823. Our learning rule for the synaptic weight w ij is w ˙ ij ( t ) = ∈ ∫ - ∞ ∞ 1 T l ∫ t - T l t ∑ μ δ ( τ + s - t j , μ ) u ( τ ) d τ Γ ( s ) d s , where the t j,μ are the arrival times of spikes from the presynaptic neuron j and the function u( t) describes the state of the postsynaptic neuron i. Thus, the spike-triggered average contained in the inner integral is weighted by a kernel Γ( s), the learning window, positive for negative, negative for positive values of the time difference s between post- and presynaptic activity. An antisymmetry assumption for the learning window enables us to derive analytical expressions for a general class of neuron models and to study the changes in input–output relationships following from synaptic weight changes. This is a genuinely non-linear effect (Song, S., Miller, K., Abbott, L., 2000. Competitive Hebbian learning through spike-timing dependent synaptic plasticity. Nature Neuroscience 3, 919–926).

Firing rate modulation: A simple statistical view of memory trace reactivation

Memory trace reactivation in hippocampal ensembles during sleep has been suggested as a coordinating mechanism for consolidation of new memories. Here we propose a simple statistical scheme allowing analysis of the reactivation of firing rate modulations, with a well-defined null hypothesis. This method allowed reliable detection of ensemble reactivation across three experimental settings. Reactivation of firing rate modulations mirrors several properties of commonly studied reactivation measures: it is stronger during hippocampal sharp waves, and decays over a period of 10–20 min. Moreover, in some conditions, firing rate reactivation covaries with reactivation of cell pair cross-correlations, suggesting the two phenomena reflect similar processes. We propose an attractor network model, with pre-wired attractors, in which experience selects and primes some attractors. Priming occurs by either experience dependent synaptic plasticity or changes in neuronal excitability. Primed attractors are more likely to activate in the following sleep, inducing reactivation of both rates and cross-correlations.

NMDA receptor kinetics are tuned for spike-timing dependent synaptic plasticity

NMDA receptor kinetics are tuned for spike-timing dependent synaptic plasticity

On the paradox of ion channel blockade and its benefits in the treatment of Alzheimer disease

The surprisingly beneficial effects in Alzheimer disease (AD) of ion channel blockers (ICB) like memantine that act on NMDA- and other aminergic transmitter receptors are yet poorly understood. NMDA receptor levels and binding were shown to be significantly decreased in AD, in which highly NMDA receptor and Ca(2+) dependent synaptic plasticity and re-modelling are severely compromised. Thus, how could one expect to improve AD by further suppressing NMDA channels with antagonists. Nevertheless, clinical trials with NMDA blockers revealed in moderate to advanced AD surprisingly positive effects. The present paper tries to provides a hypothetical explanation of that paradoxical success of ICBs. Based on evidence from current data, emphasis is put on a profound impairment in the AD brain of the inhibition-excitation balance in the neuronal circuitry to the advantage of excitation. This imbalance is conceived to result from a degeneration of four modulatory aminiergic transmitter systems (serotonin, noradrenalin, acetylcholine, histamine) and related peptidergic systems, the decline of which causes a profound loss of inhibitory impact in the forebrain neuronal circuitry leading to disinhibition of principal neurones ("aminergic disinhibition"). Subsequent Ca(2+) excito-toxicity and its sequelae are suggested to be the basic promotors of the neuro-degeneration and the related mental decline in AD. Re-adjustment of the inhibition-excitation imbalance by decreasing excitation is conceived to be the mechanism that renders ion channel blockade therapeutically successful. Putatively, attempts to increase inhibition, e.g., by application of GABA mimetics that stimulate the production GABA from preserved but "lazy" GABA neurones lacking aminergic facilitation, might be an even better way to achieve the re-balance.

Glucocorticoid receptor activation selectively hampers N-methyl- d-aspartate receptor dependent hippocampal synaptic plasticity in vitro

Corticosterone and exposure to stressful experiences have been reported to decrease hippocampal synaptic plasticity, in particular when relatively mild stimulation paradigms—presumably activating predominantly N-methyl- d-aspartate receptors—are being used. Using various stimulation paradigms and pharmacological approaches we tested therefore the hypothesis that elevated corticosterone levels, by activating glucocorticoid receptors, predominantly hamper N-methyl- d-aspartate receptor dependent synaptic plasticity in vitro. To address this, mouse hippocampal slices were treated for 20 min with corticosterone (100nM) or vehicle and synaptic efficacy was examined 1–6 h later. First, we found that primed burst potentiation and synaptic potentiation after 10Hz stimulation are predominantly N-methyl- d-aspartate receptor dependent, and are significantly suppressed after corticosterone treatment. Second, these latter effects were prevented by treating slices with the glucocorticoid receptor antagonist mifepristone prior to and during corticosterone administration. Third, theta burst potentiation, which was shown to involve activation of both N-methyl- d-aspartate receptors, voltage-dependent calcium channels and possibly other mechanisms, was not affected by corticosterone. However, theta-burst potentiation in the presence of nifedipine—singling out primarily the N-methyl- d-aspartate receptor dependent component—was reduced by corticosterone. These results indicate that corticosterone, via glucocorticoid receptor activation, selectively hampers N-methyl- d-aspartate receptor dependent synaptic plasticity in vitro and leaves more complex forms of long term potentiation unaffected. We speculate that these effects are involved in the impairment of cognitive performance by corticosteroid hormones after exposure to stressful and traumatic experiences.

Metabotropic glutamate receptors contribute to neocortical synaptic plasticity in vivo

Metabotropic glutamate receptors (mGluRs) have been shown to be important for hippocampus-dependent memory, as well as activity-dependent synaptic plasticity in the hippocampus. In this study, we examined the role of mGluRs in the induction of two forms of activity-dependent synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD), in the neocortex of awake, freely-moving rats. The mGluR antagonist AIDA was administered during the induction of LTP or LTD in the motor cortex. There was a 50% reduction of LTP induced in the early component of the evoked response, but there was no effect on the late component and no effect on the induction of LTD. Thus, mGluRs contribute to at least one form of activity dependent synaptic plasticity in the neocortex.

Synchrony detection and amplification by silicon neurons with STDP synapses.

Spike-timing dependent synaptic plasticity (STDP) is a form of plasticity driven by precise spike-timing differences between presynaptic and postsynaptic spikes. Thus, the learning rules underlying STDP are suitable for learning neuronal temporal phenomena such as spike-timing synchrony. It is well known that weight-independent STDP creates unstable learning processes resulting in balanced bimodal weight distributions. In this paper, we present a neuromorphic analog very large scale integration (VLSI) circuit that contains a feedforward network of silicon neurons with STDP synapses. The learning rule implemented can be tuned to have a moderate level of weight dependence. This helps stabilise the learning process and still generates binary weight distributions. From on-chip learning experiments we show that the chip can detect and amplify hierarchical spike-timing synchrony structures embedded in noisy spike trains. The weight distributions of the network emerging from learning are bimodal.

An important role of spike timing dependent synaptic plasticity in the formation of synchronized neural ensembles

Synchronous neural activity plays an important role in the functioning of the brain. In this paper, we study the entrainment of a heterogeneous network of electrically coupled neurons by synaptically mediated periodic stimulation. We demonstrate by computer simulations that input synapses with spike timing-dependent plasticity (STDP) greatly enhance the coherence of spiking activity in the network as compared to the case of input with constant strength. We also show that synchronization in the network stimulated through STDP synapses is much more robust to the variability of network properties. The observed mechanism may play a role in synchronizing the activity of a hippocampal network.

Kinetics of Mg2+ unblock of NMDA receptors: implications for spike-timing dependent synaptic plasticity.

The time course of Mg(2+) block and unblock of NMDA receptors (NMDARs) determines the extent they are activated by depolarization. Here, we directly measure the rate of NMDAR channel opening in response to depolarizations at different times after brief (1 ms) and sustained (4.6 s) applications of glutamate to nucleated patches from neocortical pyramidal neurons. The kinetics of Mg(2+) unblock were found to be non-instantaneous and complex, consisting of a prominent fast component (time constant approximately 100 micros) and slower components (time constants 4 and approximately 300 ms), the relative amplitudes of which depended on the timing of the depolarizing pulse. Fitting a kinetic model to these data indicated that Mg(2+) not only blocks the NMDAR channel, but reduces both the open probability and affinity for glutamate, while enhancing desensitization. These effects slow the rate of NMDAR channel opening in response to depolarization in a time-dependent manner such that the slower components of Mg(2+) unblock are enhanced during depolarizations at later times after glutamate application. One physiological consequence of this is that brief depolarizations occurring earlier in time after glutamate application are better able to open NMDAR channels. This finding has important implications for spike-timing-dependent synaptic plasticity (STDP), where the precise (millisecond) timing of action potentials relative to synaptic inputs determines the magnitude and sign of changes in synaptic strength. Indeed, we find that STDP timing curves of NMDAR channel activation elicited by realistic dendritic action potential waveforms are narrower than expected assuming instantaneous Mg(2+) unblock, indicating that slow Mg(2+) unblock of NMDAR channels makes the STDP timing window more precise.

Synaptic activity-independent persistent plasticity in endogenously active mammalian motoneurons.

Potentiation and depression of glutamate receptor function in hippocampal, cerebellar, and cortical neurons are examples of persistent changes in synaptic function that underlie important behavioral adaptations such as learning and memory. Persistent changes in synaptic function relevant for motor behaviors have not been demonstrated in mammalian motoneurons. We demonstrate that adaptive changes in (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrobromide (AMPA) receptor function at endogenously active synapses occur in motoneurons in neonatal rodents. We found a form of serotonin (5-HT)-dependent synaptic plasticity in hypoglossal (XII) motoneurons, which control tongue muscles affecting upper airway function, that is metamodulated by metabotropic glutamate receptors. Episodic, but not continuous, activation of postsynaptic 5-HT type 2 (5-HT(2)) receptors on hypoglossal (XII) motoneurons leads to long-lasting increases in their AMPA receptor-mediated respiratory drive currents and associated XII nerve motor output. Antagonism of group-I metabotropic glutamate receptors blocks induction of the 5-HT-induced increase in excitability. We propose that this activity-independent postsynaptic 5-HT-mediated plasticity represents the cellular mechanism underlying long-term facilitation, i.e., persistent increases in respiratory motor output and ventilation seen in humans and rodents in response to episodic hypoxia. Loss of activity in XII motoneurons is common during sleep causing snoring and, in serious cases, airway obstruction that interrupts breathing, a condition known as obstructive sleep apnea. These results may provide the basis for rationale development of therapeutics for obstructive sleep apnea in humans.

An important role of spike timing dependent synaptic plasticity in the formation of synchronized neural ensembles

Synchronous neural activity plays an important role in the functioning of the brain. In this paper, we study the entrainment of a heterogeneous network of electrically coupled neurons by synaptically mediated periodic stimulation. We demonstrate by computer simulations that input synapses with spike timing-dependent plasticity (STDP) greatly enhance the coherence of spiking activity in the network as compared to the case of input with constant strength. We also show that synchronization in the network stimulated through STDP synapses is much more robust to the variability of network properties. The observed mechanism may play a role in synchronizing the activity of a hippocampal network.