Heterosynaptic Changes Research Articles

Non-associative potentiation of proximal excitatory inputs to layer 2/3 pyramidal cells in rat visual cortex

Long-term changes of synaptic transmission can be induced by Hebbian-type homosynaptic mechanisms which require activation of both pre- and postsynapse and mediate associative learning, as well as by heterosynaptic mechanisms which do not require activation of the presynapse and are non-associative. The rules for induction of homosynaptic plasticity depend on the distance of the synapse from the soma. Does induction of heterosynaptic plasticity also depend on synaptic location? Here, we investigated heterosynaptic changes in pharmacologically isolated glutamatergic inputs arriving at either the proximal or the distal segments of the apical dendrite of layer 2/3 pyramidal neurons in rat visual cortex. We show that bursts of action potentials evoked without presynaptic stimulation induced potentiation of proximal inputs while having little effect on distal inputs. Such gradient of plasticity could be related to the attenuation of backpropagating action potentials along the dendrites. Thus, the location of the synapse on the dendritic tree is a determinant not only for homosynaptic but also for heterosynaptic plasticity.

Homosynaptic plasticity induction causes heterosynaptic changes at the unstimulated neighbors in an induction pattern and location-specific manner.

Dendritic spines are highly dynamic structures whose structural and functional fluctuations depend on multiple factors. Changes in synaptic strength are not limited to synapses directly involved in specific activity patterns. Unstimulated clusters of neighboring spines in and around the site of stimulation can also undergo alterations in strength. Usually, when plasticity is induced at single dendritic spines with glutamate uncaging, neighboring spines do not show any significant structural fluctuations. Here, using two-photon imaging and glutamate uncaging at single dendritic spines of hippocampal pyramidal neurons, we show that structural modifications at unstimulated neighboring spines occur and are a function of the temporal pattern of the plasticity-inducing stimulus. Further, the relative location of the unstimulated neighbors within the local dendritic segment correlates with the extent of heterosynaptic plasticity that is observed. These findings indicate that naturalistic patterns of activity at single spines can shape plasticity at nearby clusters of synapses, and may play a role in priming local inputs for further modifications.

Altered Heterosynaptic Plasticity Impairs Visual Discrimination Learning in Adenosine A1 Receptor Knock-Out Mice.

Theoretical and modeling studies demonstrate that heterosynaptic plasticity-changes at synapses inactive during induction-facilitates fine-grained discriminative learning in Hebbian-type systems, and helps to achieve a robust ability for repetitive learning. A dearth of tools for selective manipulation has hindered experimental analysis of the proposed role of heterosynaptic plasticity in behavior. Here we circumvent this obstacle by testing specific predictions about the behavioral consequences of the impairment of heterosynaptic plasticity by experimental manipulations to adenosine A1 receptors (A1Rs). Our prior work demonstrated that the blockade of adenosine A1 receptors impairs heterosynaptic plasticity in brain slices and, when implemented in computer models, selectively impairs repetitive learning on sequential tasks. Based on this work, we predict that A1R knock-out (KO) mice will express (1) impairment of heterosynaptic plasticity and (2) behavioral deficits in learning on sequential tasks. Using electrophysiological experiments in slices and behavioral testing of animals of both sexes, we show that, compared with wild-type controls, A1R KO mice have impaired synaptic plasticity in visual cortex neurons, coupled with significant deficits in visual discrimination learning. Deficits in A1R knockouts were seen specifically during relearning, becoming progressively more apparent with learning on sequential visual discrimination tasks of increasing complexity. These behavioral results confirm our model predictions and provide the first experimental evidence for a proposed role of heterosynaptic plasticity in organism-level learning. Moreover, these results identify heterosynaptic plasticity as a new potential target for interventions that may help to enhance new learning on a background of existing memories.SIGNIFICANCE STATEMENT Understanding how interacting forms of synaptic plasticity mediate learning is fundamental for neuroscience. Theory and modeling revealed that, in addition to Hebbian-type associative plasticity, heterosynaptic changes at synapses that were not active during induction are necessary for stable system operation and fine-grained discrimination learning. However, lacking tools for selective manipulation prevented behavioral analysis of heterosynaptic plasticity. Here we circumvent this barrier: from our prior experimental and computational work we predict differential behavioral consequences of the impairment of Hebbian-type versus heterosynaptic plasticity. We show that, in adenosine A1 receptor knock-out mice, impaired synaptic plasticity in visual cortex neurons is coupled with specific deficits in learning sequential, increasingly complex visual discrimination tasks. This provides the first evidence linking heterosynaptic plasticity to organism-level learning.

My Neighbour Hetero-deconstructing the mechanisms underlying heterosynaptic plasticity.

Synapses change in strength following patterns of activity, but in many cases seemingly inactive neighbouring synapses also undergo changes in strength. These heterosynaptic changes occur across developmental time-points in various brain circuits in different species, but their precise molecular mechanisms are not well understood. Additionally, heterosynaptic changes can mirror homosynaptic plasticity or occur in opposition to homosynaptic changes. In this review we consider what useful functionality heterosynaptic dynamics could potentially endow the circuit with, and the underlying signalling events that implement heterosynaptic changes. We discuss what unanswered questions remain, and what the future looks like for understanding the logic of synaptic plasticity.

Distinct Heterosynaptic Plasticity in Fast Spiking and Non-Fast-Spiking Inhibitory Neurons in Rat Visual Cortex

Inhibition in neuronal networks of the neocortex serves a multitude of functions, such as balancing excitation and structuring neuronal activity in space and time. Plasticity of inhibition is mediated by changes at both inhibitory synapses, as well as excitatory synapses on inhibitory neurons. Using slices from visual cortex of young male rats, we describe a novel form of plasticity of excitatory synapses on inhibitory neurons, weight-dependent heterosynaptic plasticity. Recordings from connected pyramid-to-interneuron pairs confirm that postsynaptic activity alone can induce long-term changes at synapses that were not presynaptically active during the induction, i.e., heterosynaptic plasticity. Moreover, heterosynaptic changes can accompany homosynaptic plasticity induced in inhibitory neurons by conventional spike-timing-dependent plasticity protocols. In both fast-spiking (FS) and non-FS neurons, heterosynaptic changes were weight-dependent, because they correlated with initial paired-pulse ratio (PPR), indicative of initial strength of a synapse. Synapses with initially high PPR, indicative of low release probability ("weak" synapses), had the tendency to be potentiated, while synapses with low initial PPR ("strong" synapses) tended to depress or did not change. Interestingly, the net outcome of heterosynaptic changes was different in FS and non-FS neurons. FS neurons expressed balanced changes, with gross average (n = 142) not different from control. Non-FS neurons (n = 66) exhibited net potentiation. This difference could be because of higher initial PPR in the non-FS neurons. We propose that weight-dependent heterosynaptic plasticity may counteract runaway dynamics of excitatory inputs imposed by Hebbian-type learning rules and contribute to fine-tuning of distinct aspects of inhibitory function mediated by FS and non-FS neurons in neocortical networks.SIGNIFICANCE STATEMENT Dynamic balance of excitation and inhibition is fundamental for operation of neuronal networks. Fine-tuning of such balance requires synaptic plasticity. Knowledge about diverse forms of plasticity operating in excitatory and inhibitory neurons is necessary for understanding normal function and causes of dysfunction of the nervous system. Here we show that excitatory inputs to major archetypal classes of neocortical inhibitory neurons, fast-spiking (FS) and non-fast-spiking (non-FS), express a novel type of plasticity, weight-dependent heterosynaptic plasticity, which accompanies the induction of Hebbian-type changes. This novel form of plasticity may counteract runaway dynamics at excitatory synapses to inhibitory neurons imposed by Hebbian-type learning rules and contribute to fine-tuning of diverse aspects of inhibitory function mediated by FS and non-FS neurons in neocortical networks.

AMPA receptor trafficking and its role in heterosynaptic plasticity

Historically, long-term potentiation (LTP) and long-term depression (LTD), the best-characterized forms of long-term synaptic plasticity, are viewed as experience-dependent and input-specific processes. However, cumulative experimental and theoretical data have demonstrated that LTP and LTD can promote compensatory alterations in non-stimulated synapses. In this work, we have developed a computational model of a tridimensional spiny dendritic segment to investigate the role of AMPA receptor (AMPAR) trafficking during synaptic plasticity at specific synapses and its consequences for the populations of AMPAR at nearby synapses. Our results demonstrated that the mechanisms of AMPAR trafficking involved with LTP and LTD can promote heterosynaptic plasticity at non-stimulated synapses. These alterations are compensatory and arise from molecular competition. Moreover, the heterosynaptic changes observed in our model can modulate further activity-driven inductions of synaptic plasticity.

Adenosine Shifts Plasticity Regimes between Associative and Homeostatic by Modulating Heterosynaptic Changes.

Endogenous extracellular adenosine level fluctuates in an activity-dependent manner and with sleep-wake cycle, modulating synaptic transmission and short-term plasticity. Hebbian-type long-term plasticity introduces intrinsic positive feedback on synaptic weight changes, making them prone to runaway dynamics. We previously demonstrated that co-occurring, weight-dependent heterosynaptic plasticity can robustly prevent runaway dynamics. Here we show that at neocortical synapses in slices from rat visual cortex, adenosine modulates the weight dependence of heterosynaptic plasticity: blockade of adenosine A1 receptors abolished weight dependence, while increased adenosine level strengthened it. Using model simulations, we found that the strength of weight dependence determines the ability of heterosynaptic plasticity to prevent runaway dynamics of synaptic weights imposed by Hebbian-type learning. Changing the weight dependence of heterosynaptic plasticity within an experimentally observed range gradually shifted the operating point of neurons between an unbalancing regime dominated by associative plasticity and a homeostatic regime of tightly constrained synaptic changes. Because adenosine tone is a natural correlate of activity level (activity increases adenosine tone) and brain state (elevated adenosine tone increases sleep pressure), modulation of heterosynaptic plasticity by adenosine represents an endogenous mechanism that translates changes of the brain state into a shift of the regime of synaptic plasticity and learning. We speculate that adenosine modulation may provide a mechanism for fine-tuning of plasticity and learning according to brain state and activity.SIGNIFICANCE STATEMENT Associative learning depends on brain state and is impaired when the subject is sleepy or tired. However, the link between changes of brain state and modulation of synaptic plasticity and learning remains elusive. Here we show that adenosine regulates weight dependence of heterosynaptic plasticity: adenosine strengthened weight dependence of heterosynaptic plasticity; blockade of adenosine A1 receptors abolished it. In model neurons, such changes of the weight dependence of heterosynaptic plasticity shifted their operating point between regimes dominated by associative plasticity or by synaptic homeostasis. Because adenosine tone is a natural correlate of activity level and brain state, modulation of plasticity by adenosine represents an endogenous mechanism for translation of brain state changes into a shift of the regime of synaptic plasticity and learning.

Partial Breakdown of Input Specificity of STDP at Individual Synapses Promotes New Learning.

Hebbian-type learning rules, which underlie learning and refinement of neuronal connectivity, postulate input specificity of synaptic changes. However, theoretical analyses have long appreciated that additional mechanisms, not restricted to activated synapses, are needed to counteract positive feedback imposed by Hebbian-type rules on synaptic weight changes and to achieve stable operation of learning systems. The biological basis of such mechanisms has remained elusive. Here we show that, in layer 2/3 pyramidal neurons from slices of visual cortex of rats, synaptic changes induced at individual synapses by spike timing-dependent plasticity do not strictly follow the input specificity rule. Spike timing-dependent plasticity is accompanied by changes in unpaired synapses: heterosynaptic plasticity. The direction of heterosynaptic changes is weight-dependent, with balanced potentiation and depression, so that the total synaptic input to a cell remains preserved despite potentiation or depression of individual synapses. Importantly, this form of heterosynaptic plasticity is induced at unpaired synapses by the same pattern of postsynaptic activity that induces homosynaptic changes at paired synapses. In computer simulations, we show that experimentally observed heterosynaptic plasticity can indeed serve the theoretically predicted role of robustly preventing runaway dynamics of synaptic weights and activity. Moreover, it endows model neurons and networks with essential computational features: enhancement of synaptic competition, facilitation of the development of specific intrinsic connectivity, and the ability for relearning. We conclude that heterosynaptic plasticity is an inherent property of plastic synapses, crucial for normal operation of learning systems. We show that spike timing-dependent plasticity in L2/L3 pyramids from rat visual cortex is accompanied by plastic changes in unpaired synapses. These heterosynaptic changes are weight-dependent and balanced: individual synapses expressed significant LTP or LTD, but the average over all synapses did not change. Thus, the rule of input specificity breaks down at individual synapses but holds for responses averaged over many inputs. In model neurons and networks, this experimentally characterized form of heterosynaptic plasticity prevents runaway dynamics of synaptic weights and activity, enhances synaptic competition, facilitates development of specific intrinsic connectivity, and enables relearning. This new form of heterosynaptic plasticity represents the cellular basis of a theoretically postulated mechanism, which is additional to Hebbian-type rules, and is necessary for stable operation of learning systems.

Induction and consolidation of calcium-based homo- and heterosynaptic potentiation and depression

Synaptic plasticity serves as the physiological foundation for learning and memory [1]. While homosynaptic plasticity is associative learning or Hebbian-type plasticity, heterosynaptic plasticity reflects the change without direct stimulation, i.e. non-associative plasticity [2]. However, heterosynaptic plasticity is an important mechanism preventing run-away dynamics and offers a potential mechanism to understand memory allocation [2,3]. Experimental results show that the induction of heterosynaptic plasticity as well as homosynaptic plasticity depends on the postsynaptic calcium concentration [4]. We propose that heterosynaptic plasticity can be induced by the postsynaptic calcium dynamics which can be triggered by the back propagation of action potentials. However, homosynaptic plasticity has an early-phase ( 8 hours) [1]. Experiments show that an early-phase change can be transferred to a late-phase by the mechanisms of synaptic tagging and (STC) [5,6]: (i) the changed synapse get tagged and (ii) a strong activation enables in the postsynaptic neuron the synthesis of plasticity-related proteins (PRP) which are transmitted back to the tagged synapse[5,6]. We propose that the same STC mechanism consolidating homosynaptic changes are also able to consolidate heterosynaptic changes. We combine a history spiking-dependent neuron [7] with calcium-based plasticity rule [8] and consolidation mechanism [9] to understand: (i) the mechanisms of inducing heterosynaptic plasticity by which the inactive synapse can change its weight through the postsynaptic calcium level triggered by the back propagation of the shared neuron; and (ii) of the consolidation of heterosynaptic changes based on the tagging and consolidation principle. For instance, a strong stimulus transmitted by a group of synapses induces and consolidates by the postsynaptic neuron heterosynaptic changes at other, unrelated synapses. Our study provides a further step of understanding how several mechanisms interact with each other to enable the formation of computational important long-term changes or memories.

Ryanodine-receptor-driven intracellular calcium dynamics underlying spatial association of synaptic plasticity.

Synaptic modifications induced at one synapse are accompanied by hetero-synaptic changes at neighboring sites. In addition, it is suggested that the mechanism of spatial association of synaptic plasticity is based on intracellular calcium signaling that is mainly regulated by two types of receptors of endoplasmic reticulum calcium store: the ryanodine receptor (RyR) and the inositol triphosphate receptor (IP3R). However, it is not clear how these types of receptors regulate intracellular calcium flux and contribute to the outcome of calcium-dependent synaptic change. To understand the relation between the synaptic association and store-regulated calcium dynamics, we focused on the function of RyR calcium regulation and simulated its behavior by using a computational neuron model. As a result, we observed that RyR-regulated calcium release depended on spike timings of pre- and postsynaptic neurons. From the induction site of calcium release, the chain activation of RyRs occurred, and spike-like calcium increase propagated along the dendrite. For calcium signaling, the propagated calcium increase did not tend to attenuate; these characteristics came from an all-or-none behavior of RyR-sensitive calcium store. Considering the role of calcium dependent synaptic plasticity, the results suggest that RyR-regulated calcium propagation induces a similar change at the synapses. However, according to the dependence of RyR calcium regulation on the model parameters, whether the chain activation of RyRs occurred, sensitively depended on spatial expression of RyR and nominal fluctuation of calcium flux. Therefore, calcium regulation of RyR helps initiate rather than relay calcium propagation.

The mechanism of hetero-synaptic interaction based on spatiotemporal intracellular calcium dynamics.

The mechanism of hetero-synaptic interaction based on spatiotemporal intracellular calcium dynamics.

Heterosynaptic Plasticity Prevents Runaway Synaptic Dynamics

Spike timing-dependent plasticity (STDP) and other conventional Hebbian-type plasticity rules are prone to produce runaway dynamics of synaptic weights. Once potentiated, a synapse would have higher probability to lead to spikes and thus to be further potentiated, but once depressed, a synapse would tend to be further depressed. The runaway synaptic dynamics can be prevented by precisely balancing STDP rules for potentiation and depression; however, experimental evidence shows a great variety of potentiation and depression windows and magnitudes. Here we show that modifications of synapses to layer 2/3 pyramidal neurons from rat visual and auditory cortices in slices can be induced by intracellular tetanization: bursts of postsynaptic spikes without presynaptic stimulation. Induction of these heterosynaptic changes depended on the rise of intracellular calcium, and their direction and magnitude correlated with initial state of release mechanisms. We suggest that this type of plasticity serves as a mechanism that stabilizes the distribution of synaptic weights and prevents their runaway dynamics. To test this hypothesis, we develop a cortical neuron model implementing both homosynaptic (STDP) and heterosynaptic plasticity with properties matching the experimental data. We find that heterosynaptic plasticity effectively prevented runaway dynamics for the tested range of STDP and input parameters. Synaptic weights, although shifted from the original, remained normally distributed and nonsaturated. Our study presents a biophysically constrained model of how the interaction of different forms of plasticity--Hebbian and heterosynaptic--may prevent runaway synaptic dynamics and keep synaptic weights unsaturated and thus capable of further plastic changes and formation of new memories.

Heterosynaptic plasticity in the neocortex

Ongoing learning continuously shapes the distribution of neurons’ synaptic weights in a system with plastic synapses. Plasticity may change the weights of synapses that were active during the induction—homosynaptic changes, but also may change synapses not active during the induction—heterosynaptic changes. Here we will argue, that heterosynaptic and homosynaptic plasticity are complementary processes, and that heterosynaptic plasticity might accompany homosynaptic plasticity induced by typical pairing protocols. Synapses are not uniform in their susceptibility for plastic changes, but have predispositions to undergo potentiation or depression, or not to change. Predisposition is one of the factors determining the direction and magnitude of homo- and heterosynaptic changes. Heterosynaptic changes which take place according to predispositions for plasticity may provide a useful mechanism(s) for homeostasis of neurons’ synaptic weights and extending the lifetime of memory traces during ongoing learning in neuronal networks.

Long-term plasticity at excitatory synapses on aspinous interneurons in area CA1 lacks synaptic specificity.

The synaptic specificity of long-term potentiation (LTP) was examined at synapses formed on aspinous dendrites of interneurons whose somata were located in the pyramidal cell layer of hippocampal area CA1. Intracellular recordings from slices prepared from rats were used to monitor excitatory postsynaptic potentials (EPSPs) elicited by extracellular stimulation in stratum radiatum. Two synaptic inputs were evoked at 0.5 Hz by stimulating axons adjacent to stratum pyramidale and s. lacunosum-moleculare. After obtaining baseline recordings (>/=10 min), one of the EPSPs was conditioned. The protocol involved tetanic stimulation, sometimes combined with somatic depolarization. Low-frequency stimulation of the two pathways was then resumed and EPSPs were recorded for <30 min. We observed both homosynaptic and heterosynaptic changes in synaptic strength. LTP and long-term depression (LTD) were seen in both pathways and all possible combinations of changes in the two EPSPs were observed, including heterosynaptic LTP associated with either homosynaptic LTP or LTD. Intracellular 1,2-bis (2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid (10 mM) abolished alterations in synaptic strength. When axons in s. radiatum synapse onto a spiny pyramidal cell, synaptic specificity of LTP is preserved. However the results obtained from aspinous interneurons show that synaptic specificity of LTP is lost. These results are consistent with the hypothesis that spines provide postsynaptic mechanism(s) for conferring specificity to LTP.

Homosynaptic and heterosynaptic changes in driving of dentate gyrus interneurons after brief tetanic stimulation in vivo.

This study addressed changes in interneuron driving in the dentate gyrus (DG) of urethane-anaesthetized rats in response to tetanic stimulation of the perforant path (PP) or the converging dentate commissural pathway (CP). Using an extracellular tungsten electrode, we recorded from putative interneurons in the DG that fired to stimulation of both the PP and the CP. Conditioning trains (400 Hz, 17.5 ms) were delivered to each pathway individually and to the two pathways together. The primary measure of synaptic drive was the latency of interneuron discharge. High-intensity PP tetany, CP tetany, and paired tetany consistently reduced firing latency to CP driving (P < .05 for all three), indicating an LTP-like increase in synaptic activation through the CP. High-intensity PP tetany decreased latency to PP driving in only two of seven cases. Heterosynaptic changes occurred frequently in individual experiments. Activity-mediated adjustments in synaptic driving of inhibitory interneurons could play a role in normal physiological function.

Parallel processing of short-term memory for sensitization in Aplysia.

How is the short-term memory for a single form of learning distributed among the various elements of a neuronal circuit? To answer this question, we examined the short-term memory for sensitization, using the siphon component of the defensive gill- and siphon-withdrawal reflex. We found that the memory for short-term sensitization is represented by at least four sites of circuit modification, each involving a different type of plasticity. These include (1) presynaptic facilitation of the sensory neuron connections onto both interneurons and motorneurons; (2) presynaptic inhibition at the connections of the L30 inhibitory neurons onto the excitatory interneuron L29; (3) posttetanic potentiation of the excitatory connections made by L29 onto a specific subclass of siphon motorneurons, the LFS cells; and (4) an increase in the tonic firing rate of the LFS siphon motor neurons, resulting in neuromuscular facilitation. Each of the heterosynaptic changes seems to involve a common modulatory transmitter and to utilize a common second messenger system. Moreover, each of these sites seems capable of encoding a different component of the short-term memory. Facilitation of the connections of sensory neurons should contribute to the increase in amplitude of the response; the disinhibition of the L29 interneurons and the posttetanic potentiation at L29 synapses should contribute to an increase in the duration of the response; and the increase in tonic firing of the LFS subclass of siphon motor neurons seems capable of contributing both to an increase in response amplitude and to changes in response topography.

Heterosynaptic changes accompany long-term but not short-term potentiation of the perforant path in the anaesthetized rat.

Brief high-frequency trains of electrical stimulation delivered to the perforant path result in long-term potentiation (l.t.p.) of field potentials recorded extracellularly from granule cells of the dentate gyrus. L.t.p. of the population spike is often disproportionately greater than l.t.p. of the population excitatory post-synaptic potential (e.p.s.p.). We have investigated the basis of this effect in rats anaesthetized with sodium pentobarbitone. A series of graded stimuli were given before and after tetanization of the perforant path. From data obtained in this way, we plotted stimulus-response curves, and the relation (E-S curve) between the slope of the population e.p.s.p. (E) and the amplitude of the population spike (S). Curves relating spike onset latency to the slope of the e.p.s.p. were also constructed. Tetanization of the combined medial and lateral components of the perforant path led to long-term changes in the relation between the e.p.s.p. and the population spike. For a given e.p.s.p., the corresponding population spike was of greater amplitude and earlier onset. This E-S potentiation was marked by a shift to the left of the E-S amplitude curve and a downward displacement of the E-S latency curve. Tetanization of the lateral component of the perforant path had two long-term effects on responses evoked by test stimuli to the untetanized medial component: (1) long-term depression of the medial e.p.s.p. and (2) long-term E-S potentiation. The net result of these two heterosynaptically induced effects was to leave unaltered information transfer across medial perforant path-granule cell synapses; for a given test volley the e.p.s.p. was smaller, but because of E-S potentiation the population spike remained relatively unaffected. Short-term potentiation, which has a time course of only a few minutes and is presumed to be mediated by presynaptic mechanisms, was not accompanied by E-S potentiation or by corresponding changes in spike latency. Possible mechanisms of long-term heterosynaptic depression of the e.p.s.p. and of homo- and heterosynaptic E-S potentiation, are discussed. We conclude that although these effects probably reflect a generalized post-synaptic change, this change is unlikely to be a prolonged reduction in the membrane potential of granule cells.

Mathematical model of synaptic plasticity: III. Heterosynaptic changes.

A mathematical model, using differential equations, of heterosynaptic plasticity is proposed. The model is based on physiological studies of invertebrates in which nonspecific conditioning, such as sensitization and heterosynaptic inhibition, starts to be elucidated and behavioral studies of classical and instrumental conditioning, which we postulate to have the same mechanisms as those found in nonspecific conditioning. The model permits us to simulate the following heterosynaptic changes: sensitization, heterosynaptic inhibition, classical and instrumental conditioning--including short- and long-term memory--extinction and recuperation--spontaneously and by stimulation.