Developmental shift of short-term synaptic plasticity in cortical organotypic slices.

Although short-term synaptic plasticity (STP) is ubiquitous in neocortical synapses its functional role in neural computations is not well understood. Critical to elucidating the function of STP will be to understand how STP itself changes with development and experience. Previous studies have reported developmental changes in STP using acute slices. It is not clear, however, to what extent the changes in STP are a function of local ontogenetic programs or the result of the many different sensory and experience-dependent changes that accompany development in vivo. To address this question we examined the in vitro development of STP in organotypic slices cultured for up to 4 weeks. Paired recordings were performed in L5 pyramidal neurons at different stages of in vitro development. We observed a shift in STP in the form of a decrease in the paired-pulse ratio (PPR) (less depression) from the second to fourth week in vitro. This shift in STP was not accompanied by a change in initial excitatory postsynaptic potential (EPSP) amplitude. Fitting STP to a quantitative model indicated that the developmental shift is consistent with presynaptic changes. Importantly, despite the change in the PPR we did not observe changes in the time constant governing STP. Since these experiments were conducted in vitro our results indicate that the shift in STP does not depend on in vivo sensory experience. Although sensory experience may shape STP, we suggest that developmental shifts in STP are at least in part ontogenetically determined.

Decoding temporal information: A model based on short-term synaptic plasticity.

In the current paper it is proposed that short-term plasticity and dynamic changes in the balance of excitatory-inhibitory interactions may underlie the decoding of temporal information, that is, the generation of temporally selective neurons. Our initial approach was to simulate excitatory-inhibitory disynaptic circuits. Such circuits were composed of a single excitatory and inhibitory neuron and incorporated short-term plasticity of EPSPs and IPSPs and slow IPSPs. We first showed that it is possible to tune cells to respond selectively to different intervals by changing the synaptic weights of different synapses in parallel. In other words, temporal tuning can rely on long-term changes in synaptic strength and does not require changes in the time constants of the temporal properties. When the units studied in disynaptic circuits were incorporated into a larger single-layer network, the units exhibited a broad range of temporal selectivity ranging from no interval tuning to interval-selective tuning. The variability in temporal tuning relied on the variability of synaptic strengths. The network as a whole contained a robust population code for a wide range of intervals. Importantly, the same network was able to discriminate simple temporal sequences. These results argue that neural circuits are intrinsically able to process temporal information on the time scale of tens to hundreds of milliseconds and that specialized mechanisms, such as delay lines or oscillators, may not be necessary.

Distinct functional types of associative long-term potentiation in neocortical and hippocampal pyramidal neurons.

The response of a neuron to a time-varying stimulus is influenced by both short- and long-term synaptic plasticity. Both these forms of plasticity produce changes in synaptic efficacy of similar magnitude on very different time scales. A full understanding of the functional role of each form of plasticity relies on understanding how they interact. Here we examine how long-term potentiation (LTP) and short-term plasticity (STP) interact in two different cell types that exhibit NMDA-dependent LTP: neocortical L-II/III and hippocampal CA1 pyramidal cells. STP was examined using both paired pulses and trains of pulses before and after the induction of LTP. In both cell types, the same pairing protocol was used to induce LTP in the presence of an unpaired control pathway. Pairing produced a robust increase in the amplitude of the first EPSP both in the neocortex and hippocampus. However, although in CA1 neurons the same degree of potentiation was maintained throughout the duration of a brief stimulus train, in L-II/III neurons relatively less potentiation was seen in the later EPSPs of the train. Paired-pulse analyses revealed that a uniform potentiation is observed at intervals >100 msec, but at shorter intervals there is a preferential enhancement of the first pulse. Thus, in the cortex LTP may preferentially amplify stimulus onset. These results suggest that there are distinct forms of associative LTP and that the different forms may reflect the underlying computations taking place in different areas.

A neural network model of temporal code generation and position-invariant pattern recognition.

Numerous studies have suggested that the brain may encode information in the temporal firing pattern of neurons. However, little is known regarding how information may come to be temporally encoded and about the potential computational advantages of temporal coding. Here, it is shown that local inhibition may underlie the temporal encoding of spatial images. As a result of inhibition, the response of a given cell can be significantly modulated by stimulus features outside its own receptive field. Feedforward and lateral inhibition can modulate both the firing rate and temporal features, such as latency. In this article, it is shown that a simple neural network model can use local inhibition to generate temporal codes of handwritten numbers. The temporal encoding of a spatial pattern has the interesting and computationally beneficial feature of exhibiting position invariance. This work demonstrates a manner by which the nervous system may generate temporal codes and shows that temporal encoding can be used to create position-invariant codes.

Net interaction between different forms of short-term synaptic plasticity and slow-IPSPs in the hippocampus and auditory cortex.

Paired-pulse plasticity is typically used to study the mechanisms underlying synaptic transmission and modulation. An important question relates to whether, under physiological conditions in which various opposing synaptic properties are acting in parallel, the net effect is facilitatory or depressive, that is, whether cells further or closer to threshold. For example, does the net sum of paired-pulse facilitation (PPF) of excitatory postsynaptic potentials (EPSPs), paired-pulse depression (PPD) of inhibitory postsynaptic potentials (IPSPs), and the hyperpolarizing slow IPSP result in depression or facilitation? Here we examine how different time-dependent properties act in parallel and examine the contribution of gamma-aminobutyric acid-B (GABAB) receptors that mediate two opposing processes, the slow IPSP and PPD of the fast IPSP. Using intracellular recordings from rat CA3 hippocampal neurons and L-II/III auditory cortex neurons, we examined the postsynaptic responses to paired-pulse stimulation (with intervals between 50 and 400 ms) of the Schaffer collaterals and white matter, respectively. Changes in the amplitude, time-to-peak (TTP), and slope of each EPSP were analyzed before and after application of the GABAB antagonist CGP-55845. In both CA3 and L-II/III neurons the peak amplitude of the second EPSP was generally depressed (further from threshold) compared with the first at the longer intervals; however, these EPSPs were generally broader and exhibited a longer TTP that could result in facilitation by enhancing temporal summation. At the short intervals CA3 neurons exhibited facilitation of the peak EPSP amplitude in the absence and presence of CGP-55845. In contrast, on average L-II/III cells did not exhibit facilitation at any interval, in the absence or presence of CGP-55845. CGP-55845 generally "erased" short-term plasticity, equalizing the peak amplitude and TTP of the first and second EPSPs at longer intervals in the hippocampus and auditory cortex. These results show that it is necessary to consider all time-dependent properties to determine whether facilitation or depression will dominate under intact pharmacological conditions. Furthermore our results suggest that GABAB-dependent properties may be the major contributor to short-term plasticity on the time scale of a few hundred milliseconds and are consistent with the hypothesis that the balance of different time-dependent processes can modulate the state of networks in a complex manner and could contribute to the generation of temporally sensitive neural responses.

Cortical plasticity: from synapses to maps.

It has been clear for almost two decades that cortical representations in adult animals are not fixed entities, but rather, are dynamic and are continuously modified by experience. The cortex can preferentially allocate area to represent the particular peripheral input sources that are proportionally most used. Alterations in cortical representations appear to underlie learning tasks dependent on the use of the behaviorally important peripheral inputs that they represent. The rules governing this cortical representational plasticity following manipulations of inputs, including learning, are increasingly well understood. In parallel with developments in the field of cortical map plasticity, studies of synaptic plasticity have characterized specific elementary forms of plasticity, including associative long-term potentiation and long-term depression of excitatory postsynaptic potentials. Investigators have made many important strides toward understanding the molecular underpinnings of these fundamental plasticity processes and toward defining the learning rules that govern their induction. The fields of cortical synaptic plasticity and cortical map plasticity have been implicitly linked by the hypothesis that synaptic plasticity underlies cortical map reorganization. Recent experimental and theoretical work has provided increasingly stronger support for this hypothesis. The goal of the current paper is to review the fields of both synaptic and cortical map plasticity with an emphasis on the work that attempts to unite both fields. A second objective is to highlight the gaps in our understanding of synaptic and cellular mechanisms underlying cortical representational plasticity.

Context-sensitive synaptic plasticity and temporal-to-spatial transformations in hippocampal slices.

Hippocampal slices are used to show that, as a temporal input pattern of activity flows through a neuronal layer, a temporal-to-spatial transformation takes place. That is, neurons can respond selectively to the first or second of a pair of input pulses, thus transforming different temporal patterns of activity into the activity of different neurons. This is demonstrated using associative long-term potentiation of polysynaptic CA1 responses as an activity-dependent marker: by depolarizing a postsynaptic CA1 neuron exclusively with the first or second of a pair of pulses from the dentate gyrus, it is possible to "tag" different subpopulations of CA3 neurons. This technique allows sampling of a population of neurons without recording simultaneously from multiple neurons. Furthermore, it reflects a biologically plausible mechanism by which single neurons may develop selective responses to time-varying stimuli and permits the induction of context-sensitive synaptic plasticity. These experimental results support the view that networks of neurons are intrinsically able to process temporal information and that it is not necessary to invoke the existence of internal clocks or delay lines for temporal processing on the time scale of tens to hundreds of milliseconds.

Learning and generalization of auditory temporal-interval discrimination in humans.

The sensory encoding of the duration, interval, and order of different stimulus features provides vital information to the nervous system. The present study focuses on the influence of practice on auditory temporal-interval discrimination. The goals of the experiment were to determine (1) whether practice improved the ability to discriminate a standard interval of 100 msec bounded by brief 1 kHz tones from longer intervals, and, if so, (2) whether this improvement generalized to different tonal frequencies or temporal intervals. Learning was examined in 14 human subjects using an adaptive, two-alternative, forced-choice procedure. One hour of training per day for 10 d led to marked improvements in the ability to discriminate between the standard and longer intervals. The generalization of learning was evaluated by independently varying the spectral (tonal frequency) and temporal (interval) components of the stimuli in four conditions tested both before and after the training phase. Remarkably, there was complete generalization to the trained interval of 100 msec bounded by tones at the untrained frequency of 4 kHz, but no generalization to the untrained intervals of 50, 200, or 500 msec bounded by tones at the trained frequency of 1 kHz. Thus, these data show that (1) temporal-interval discrimination using a 100-msec standard undergoes perceptual learning, and (2) the neural mechanisms underlying this learning are temporally, but not spectrally, specific. These results are compared with those from previous investigations of learning in visual spatial tasks, and are discussed in relation to biologically plausible models of temporal processing.

Associative synaptic plasticity in hippocampal CA1 neurons is not sensitive to unpaired presynaptic activity.

1. Hebbian or associative synaptic plasticity has been proposed to play an important role in learning and memory. Whereas many behaviorally relevant stimuli are time-varying, most experimental and theoretical work on synaptic plasticity has focused on stimuli or induction protocols without temporal structure. Recent theoretical studies have suggested that associative plasticity sensitive to only the conjunction of pre- and postsynaptic activity is not an effective learning rule for networks required to learn time-varying stimuli. Our goal in the current experiment was to determine whether associative long-term potentiation (LTP) is sensitive to temporal structure. We examined whether the presentation of unpaired presynaptic pulses in addition to paired pre- and postsynaptic activity altered the induction of associative LTP. 2. By using intracellular recordings from CA1 pyramidal cells, associative long-term potentiation (LTP) was induced in a control pathway by pairing a single presynaptic pulse with postsynaptic depolarization every 5 s (50-70 x). The experimental pathway received the same training, with additional unpaired presynaptic pulses delivered in close temporal proximity, either after or before associative pairing. Five separate sets of experiments were performed with intervals of -200, -50, +50, +200, or +800 ms. Negative intervals indicate that the unpaired presynaptic pulse was presented before the depolarizing pulse. Our results showed that the presence of unpaired presynaptic pulses, occurring either before or after pairing, did not significantly alter the magnitude of LTP. 3. The experimental design permitted an analysis of whether changes in paired-pulse facilitation (PPF) occur as a result of associative LTP. The average degree of PPF was the same before and after LTP. However, there was a significant inverse correlation between the initial degree of PPF and the degree of PPF after LTP. There was no relationship between the change in PPF, and whether the first or second pulse had been paired with depolarization. 4. These results indicate that the presence of unpaired presynaptic pulses does not alter the induction of synaptic plasticity, suggesting that plasticity of the Schaffer collateral-CA1 synapse is primarily conjunctive rather than correlative.

Temporal information transformed into a spatial code by a neural network with realistic properties.

Neurons exhibit a wide range of properties in addition to postsynaptic potential (PSP) summation and spike generation. Although other neuronal properties such as paired-pulse facilitation (PPF) and slow PSPs are well characterized, their role in information processing remains unclear. It is possible that these properties contribute to temporal processing in the range of hundreds of milliseconds, a range relevant to most complex sensory processing. A continuous-time neural network model based on integrate-and-fire elements that incorporate PPF and slow inhibitory postsynaptic potentials (IPSPs) was developed here. The time constants of the PPF and IPSPs were estimated from empirical data and were identical and constant for all elements in the circuit. When these elements were incorporated into a circuit inspired by neocortical connectivity, the network was able to discriminate different temporal patterns. Generalization emerged spontaneously. These results demonstrate that known time-dependent neuronal properties enable a network to transform temporal information into a spatial code in a self-organizing manner--that is, with no need to assume a spectrum of time delays or to custom-design the circuit.

Inhibitory neuron produces heterosynaptic inhibition of the sensory-to-motor neuron synapse in Aplysia.

We have identified an inhibitory neuron (RPL4) in the right pleural ganglion of Aplysia, which produced hyperpolarization of the sensory and motor neurons involved in the tail withdrawal reflex. Activation of RPL4 significantly reduced the amplitude of excitatory postsynaptic potentials produced in tail motor neurons by action potentials triggered in sensory neurons. This example of heterosynaptic inhibition was due, at least in part, to an increase in membrane input conductance in the motor neuron. Since the synaptic strength of the sensory-to-motor neuron connection has been associated with the strength of the tail withdrawal reflex, RPL4 may contribute to modulation of that reflex.

Neural and molecular bases of nonassociative and associative learning in Aplysia.

A model that summarizes some of the neural and molecular mechanisms contributing to short- and long-term sensitization is shown in Figure 14. Sensitizing stimuli lead to the release of a modulatory transmitter such as 5-HT. Both serotonin and sensitizing stimuli lead to an increase in the synthesis of cAMP and the modulation of a number of K+ currents through protein phosphorylation. Closure of these K+ channels leads to membrane depolarization and the enhancement of excitability. An additional consequence of the modulation of the K+ currents is a reduction of current during the repolarization of the action potential, which leads to an increase in its duration. As a result, Ca2+ flows into the cell for a correspondingly longer period of time, and additional transmitter is released from the cell. Modulation of the pool of transmitter available for release (mobilization) also appears to occur as a result of sensitizing stimuli. Recent evidence indicates that the mobilization process can be activated by both cAMP-dependent protein kinase and protein kinase C. Thus, release of transmitter is enhanced not only because of the greater influx of Ca2+ but also because more transmitter is made available for release by mobilization. The enhanced release of transmitter leads to enhanced activation of motor neurons and an enhanced behavioral response. Just as the regulation of membrane currents is used as a read out of the memory for short-term sensitization, it also is used as a read out of the memory for long-term sensitization. But long-term sensitization differs from short-term sensitization in that morphological changes are associated with it, and long-term sensitization requires new protein synthesis. The mechanisms that induce and maintain the long-term changes are not yet fully understood (see the dashed lines in Fig. 14) although they are likely to be due to direct interactions with the translation apparatus and perhaps also to events occurring in the cell nucleus. Nevertheless, it appears that the same intracellular messenger, cAMP, that contributes to the expression of the short-term changes, also triggers cellular processes that lead to the long-term changes. One possible mechanism for the action of cAMP is through its regulation of the synthesis of membrane modulatory proteins or key effector proteins (for example, membrane channels). It is also possible that long-term changes in membrane currents could be due in part to enhanced activity of the cAMP-dependent protein kinase so that there is a persistent phosphorylation of target proteins.(ABSTRACT TRUNCATED AT 400 WORDS)

Long-term synaptic changes produced by a cellular analog of classical conditioning in Aplysia.

A change in synaptic strength arising from the activation of two neuronal pathways at approximately the same time is a form of associative plasticity and may underlie classical or Pavlovian conditioning. A cellular analog of a classical conditioning protocol produces short-term associative plasticity at the connections between sensory and motor neurons in Aplysia. A similar training protocol produced long-term (24-hour) enhancement of excitatory postsynaptic potentials (EPSPs). EPSPs produced by sensory neurons in which activity was paired with a reinforcing stimulus were significantly larger than unpaired controls 24 hours after training. Thus, associative plasticity at the sensory to motor neuron connection can occur in a long-term form in addition to the short-term form. In this system, it should be possible to analyze the molecular mechanisms underlying long-term associative plasticity and classical conditioning.