Biomedical subjects

S Laroche

Publications and source records attributed to S Laroche.

50 records · Page 3Linked to original sources

PubMed1992

Linear relationship between the maintenance of hippocampal long-term potentiation and retention of an associative memory.

The hypothesis that the maintenance or decay of an associative memory trace after an extended retention interval is a function of the residual strength of the synapses originally strengthened during learning was examined in a classical conditioning paradigm in which high-frequency stimulation of a hippocampal input--the medial perforant path--served as a conditioned stimulus. Rats received perforant path stimulus-foot shock pairings while engaged in a previously acquired food-motivated lever-pressing task. Conditioned suppression of lever pressing was the behavioral measure of learning and retention of the association. Stimulus trains to the perforant path at an intensity above the threshold for eliciting a population spike induced long-term potentiation of synaptic transmission in the dentate gyrus. Synaptic potentials recorded extracellularly in the dentate gyrus were subsequently monitored for 31 days to examine quantitatively the decay of synaptic potentiation, a period after which retention of the learned association was assessed. All rats learned the association to a similar extent and displayed equivalent amounts of long-term potentiation by the end of conditioning. A slowly decaying function of synaptic potentiation was observed in remembering rats, i.e., rats with high retention performance after the 31-day learning-to-retention interval, while forgetting was associated with a rapid decay of long-term potentiation. Behavioral performance at the long-term memory test was linearly correlated with the amplitude of long-term potentiation maintained just prior to the retention test. The results favor the hypothesis that long-term associative memory depends, at least in part, on the maintenance of elevated synaptic strengths in the pathway activated during learning and suggest a role for the lasting component of long-term potentiation in the maintenance of memory.

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PubMed1990

Long-term potentiation in the prefrontal cortex following stimulation of the hippocampal CA1/subicular region.

We have examined single cell activity and field potentials in the prelimbic area of the prefrontal cortex of the rat to electrical stimulation of the CA1/subicular region of the temporal hippocampus. Excitatory unit responses were found in 50 out of 120 neurons recorded in the prelimbic area. Paired-pulse facilitation was found for both single cell responses and field potentials. High-frequency, tetanic stimulation of the temporal hippocampus produced a significant and persistent potentiation of prelimbic field potentials. The evidence suggests that the direct pathway from the temporal hippocampus to the prelimbic area of the prefrontal cortex in the rat is excitatory and can undergo long-term potentiation (LTP).

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PubMed1990

Increases in glutamate release and phosphoinositide metabolism associated with long-term potentiation and classical conditioning.

Long-term potentiation (LTP) is a widely studied model of the kind of activity-dependent modulation of synaptic efficacy which is assumed to provide the physical basis for learning. Whether LTP, in the hippocampus or elsewhere in the brain, does in fact serve such a role is still a matter for debate. One approach to answering this question is to identify physiological or biochemical changes which are common to both learning and LTP; in the hippocampus, for example, one can ask whether the biochemical changes associated with LTP are also associated with learning. In this chapter we summarize the results which we have obtained in a study of glutamate release and phosphoinositide turnover in the dentate gyrus of rats trained in a classical conditioning task. The similarity between the changes occurring after classical conditioning and those associated with LTP is consistent with the hypothesis that LTP is one of the mechanisms by which a neural trace of the learned association is formed. We discuss this interpretation in the light of the observation that classical conditioning does not appear to affect synaptic responses in the hippocampus.

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PubMed1989

Linear relation between the magnitude of long-term potentiation in the dentate gyrus and associative learning in the rat. A demonstration using commissural inhibition and local infusion of an N-methyl-D-aspartate receptor antagonist.

Field potentials were recorded in the dentate gyrus of freely-moving rats in a classical conditioning paradigm in which high-frequency stimulation of the perforant path served as a conditioned stimulus. Paired or unpaired perforant path stimulus-footshock presentations were given to animals engaged in a previously acquired food-motivated lever-pressing task. Conditioned suppression of lever-pressing was the behavioural measure of conditioning. Perforant path stimulus trains at an intensity above spike threshold induced long-term potentiation of synaptic transmission in the dentate gyrus. In this condition, animals learned the perforant path stimulus-shock association. Three strategies were employed to block the induction or reduce the magnitude of long-term potentiation induced by the conditioned stimulus: (1) reduction of the intensity of the stimulus below the spike threshold resulted in no long-term potentiation and a failure by the animals to learn the perforant path stimulus-shock association; (2) inhibitory modulation of long-term potentiation by high-frequency activation of commissural input to the dentate gyrus resulted in learning deficits; (3) chronic infusion of DL-2-amino-5-phosphonovalerate, a selective antagonist of the N-methyl-D-aspartate subtype of glutamate receptor, blocked the induction of long-term potentiation and prevented associative learning. A highly significant linear relation emerged from a correlational analysis between the magnitude of the change in synaptic efficacy at the activated synapses and the amount the animals learned about the perforant path stimulus-shock association. The results presented in this paper are consistent with the hypothesis that associative learning depends on the development of lasting changes in synaptic function. We propose that the activation of N-methyl-D-aspartate receptors in the dentate gyrus is involved in this process and that the more change in synaptic efficacy is produced in the activated network, the more the animals learn.

2-Amino-5-phosphonovalerate↗

PubMed1987

Increase in K+-stimulated, Ca2+-dependent release of [3H]glutamate from rat dentate gyrus three days after induction of long-term potentiation.

Long-term potentiation (LTP) was induced by unilateral tetanic stimulation of the perforant path in the dentate gyrus of rats with implanted electrodes. Evoked potentials were monitored for the subsequent 3 days in one group, and for 23 days in another. The dentate gyrus was removed bilaterally and slices prepared and stored in 10% DMSO/Krebs for subsequent analysis of K+-stimulated, Ca2+-dependent release of [3H]glutamate. In the 3-day group, in which the mean increase in the population EPSP was 35% at the time of sacrifice, release from the tetanized side was significantly greater than from the unstimulated side. In the 23-day group, both the increase in the EPSP and the increase in release from the tetanized side had declined to statistically insignificant levels. These results extend to a period of several days the previously observed association between LTP and increased K+-stimulated, Ca2+-dependent release of transmitter.

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PubMed1987

Increase in [3H]glutamate release from slices of dentate gyrus and hippocampus following classical conditioning in the rat.

The release of amino acids was examined in three hippocampal areas following classical conditioning. Paired or unpaired tone(CS)-shock(US) presentations were given to animals engaged in a previously acquired food-motivated lever-pressing task. Conditioned suppression of lever-pressing was the behavioural measure of conditioning. The dentate gyrus and areas CA1 and CA3 of the hippocampus were removed bilaterally from conditioned and pseudoconditioned animals, and slices cut and stored in liquid nitrogen for subsequent in vitro analysis of the release of radiolabelled glutamate and aspartate. K+-stimulated release of radiolabelled amino acids was analysed in the presence and absence of extracellular Ca2+. Potassium-stimulated, Ca2+-dependent release of [3H]glutamate was significantly greater in slices of dentate gyrus and area CA1 prepared from conditioned animals than from pseudoconditioned animals. This finding identifies a neurochemical change associated with classical conditioning which is similar to the increase in transmitter release seen in hippocampal long-term potentiation (LTP), and which is consistent with the hypothesis that an LTP-like mechanism is involved in mnemonic processes.

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PubMed1987

Hippocampal associative cellular responses: dissociation with behavioral responses revealed by a transfer-of-control technique.

Multiunit activity was recorded in the CA3 field of the dorsal hippocampus in freely moving rats during classical conditioning and subsequent presentation of the CS on operant baselines for food reward as well as shock avoidance. Rats were first trained in a nonsignaled bar-pressing-dependent shock omission task and in a food-motivated lever-pressing task (60-s VI). Five sessions with presentations of a previously habituated tone as a CS paired with footshock as a US were then given. Testing was carried out by presenting the CS alone while behavioral responses were maintained by reinforcement in both instrumental tasks on alternate sessions. As expected, the CS induced a marked suppression of lever pressing for food reward and a marked enhancement of bar-pressing for shock avoidance. The analysis of the frequency of multiunit discharges to the CS revealed that the hippocampal cellular responses established during classical conditioning were maintained while two different behavioral responses were exhibited to the CS. The results showed that the associative response of hippocampal neurons may be dissociated from the Pavlovian conditioned responses the CS elicits. They support the hypothesis that hippocampal cellular responses represent a neural index of the acquired CS-US associative representation.

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PubMed1985

Enhancement of long-term potentiation in the rat dentate gyrus by post-trial stimulation of the reticular formation.

The possibility that post-trial stimulation of the mesencephalic reticular formation (m.r.f.) may modulate long-term potentiation (l.t.p.) at the perforant path to dentate granule cell synapses was studied in freely moving rats. Extracellular potentials evoked in the dentate gyrus by test pulses to the perforant path were recorded before and at various delays after a series of high-frequency stimulus trains to the perforant path (ten trains of eight pulses at 400 Hz, delivered at 5 min intervals). We have compared the magnitude and duration of l.t.p. of the population spike in this control condition with that observed when a low-intensity m.r.f. stimulation was delivered 10 s after each train to the perforant path. Post-event m.r.f. stimulation enhanced the amount of l.t.p. induced by the series of high-frequency stimulus trains and prolonged its duration for several days. The size of the population spike was unaffected by repeated m.r.f. stimulation in the absence of perforant path high-frequency stimulation, or when this failed to induce significant l.t.p. The temporal gradient of efficacy of m.r.f. stimulation was investigated. M.r.f. stimulation delivered 10 s after a single high-frequency stimulation of perforant path fibres resulted in an enhanced l.t.p. of both the population excitatory post-synaptic potential (e.p.s.p.) and population spike. L.t.p. was unaffected by m.r.f. stimulation given either before, or 120 s after perforant path high-frequency stimulation. These results show that low-intensity m.r.f. stimulation enhances lasting changes in synaptic function in the dentate gyrus when delivered during a critical period following high-frequency activation of perforant path fibres. These results are discussed in the light of our previous findings on the effects of post-event m.r.f. stimulation on memory and on the development of associative changes in hippocampal multiunit activity during conditioning. It is hypothesized that l.t.p.-like mechanisms may be involved in the stabilization of neural networks by experience and that this process might be reinforced by diffuse m.r.f. activation.

Action Potentials↗

PubMed1983

Post-trial reticular facilitation of associative changes in multiunit activity; comparison between dentate gyrus and entorhinal cortex.

Multiunit activity recorded in both the dentate gyrus and the entorhinal cortex during classical conditioning was studied in freely moving rats receiving a mild post-trial stimulation of the mesencephalic reticular formation. Dentate multiunit activity progressively increased in response to an auditory signal (conditioned stimulus) after pairing the signal with a footshock (unconditioned stimulus). No such increase was seen in the entorhinal cortex of the same animals during conditioning. Post-trial reticular stimulation facilitated the development of associative changes in dentate multiunit activity, while having no effect in the entorhinal cortex. The results were interpreted as indicating a possible specificity of action of post-trial reticular stimulation on learning-induced plasticity and are discussed in relation to the concept of neural perseverance in memory consolidation.

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PubMed1981

Conditioning of hippocampal cells: its acceleration and long-term facilitation by post-trial reticular stimulation.

Neuronal activity, recorded in the dorsal hippocampus (CA3) during classical conditioning, was studied in rats receiving mild post-trial stimulation of the mesencephalic reticular formation. Hippocampal multi-unit activity increased in response to an auditory signal (conditioned stimulus) after pairing of the signal with a footshock (unconditioned stimulus), while the auditory signal alone, presented before conditioning, did not change the rate of hippocampal cell discharges. Trial-by-trial analysis of hippocampal multi-unit responses to the conditioned stimulus, both during acquisition and during a test of long-term retention, indicated that post-trial mesencephalic reticular stimulation hastened the onset of cellular conditioning and facilitated conversion to long-term storage. A study of evoked potentials recorded in the hippocampal formation to stimulation of the perforant path in awake rats, suggested that these effects could be mediated through a modulation of synaptic efficiency within hippocampal neuronal networks. These data are discussed in relation to the concept of neural perseveration in memory consolidation.

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PubMedDate not supplied

A molecular biological approach to synaptic plasticity and learning.

Until the more recent advances made in molecular biology, attempts to link synaptic plasticity and learning have focused on using LTP as a marker of learning-induced synaptic plasticity, where one has expected to observe the same magnitude of change in synaptic strength as that observed with artificial stimulation. To a large extent this approach has been frustrated by the fact that it is generally assumed that the representation of the memory traces is distributed throughout widespread networks of cells. By implication it is more likely that one would observe small distributed changes within a network; a formidable task to measure. In this review we describe how the advances in molecular biology give us both the tools to investigate the mechanisms of synaptic plasticity and to apply these to investigations of the underlying mechanisms in learning and the formation of memories that have until now remained out of our grasp.

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PubMedDate not supplied

Alterations in the expression of specific glutamate receptor subunits following hippocampal LTP in vivo.

Quantitative in situ hybridization revealed that following the induction of hippocampal long-term potentiation (LTP) in the dentate gyrus of freely moving rats, specific increases in the expression of the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor and mGluR1c, a short splice variant of the metabotropic glutamate receptors that are linked intracellularly to phospholipase C (PLC) and protein kinase C (PKC), were seen in the postsynaptic dentate granule cells. There were no changes in the expression of NR2A; NR2C and NR2D NMDA receptor subunits; or mGluR1a, mGluR1b, mGluR5a, and mGluR5b PLC-associated metabotropic receptors. The elevations in NR2B and mGluR1c mRNA were delayed, occurring days after LTP induction. NR2B expression was enhanced significantly by 48 hr after LTP but was starting to decrease toward basal levels by 96 hr. The transient increase in the expression of NR2B mirrored the increase in the expression of PKC-sensitive isoforms of the NR1 subunits of the NMDA receptor we observed previously (Thomas et al. 1994a). The increase in mGluR1c expression was more persistent, showing a significant increase 96 hr after LTP. This study demonstrates that not only are there changes in the expression of individual glutamate receptor subunits but the increases in their expression occur days after the induction of LTP and may reflect so-called late-onset genes that may be important for the maintenance of LTP.

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PubMedDate not supplied

Increase in syntaxin 1B mRNA in hippocampal and cortical circuits during spatial learning reflects a mechanism of trans-synaptic plasticity involved in establishing a memory trace.

It has long been proposed that the cellular and molecular mechanisms responsible for LTP may well involve the mechanisms that lead to the type of synaptic modification that occurs during learning. However, it is also known that a single memory trace is encoded in spatially distributed networks; implying that alterations of synaptic strength occur at multiple sites along circuits of connected cells. Recent evidence suggests that regulation of the gene encoding syntaxin 1B, a presynaptic protein involved in exocytosis, plays an important role in the mediation of trans-synaptic LTP, a candidate mechanism for the propagation of plasticity in neural circuits during learning. Using in situ hybridization to measure the mRNA levels at different time points after learning a spatial working or reference memory task, we show that expression of the gene encoding this protein in the hippocampal and corticoprefrontal circuits increases linearly with performance at a critical window of learning when rats are reaching between 75% and 100% of their maximal performance. No changes were observed during the early phases of learning or when rats where overtrained. The correlational analysis indicates that coordinated increases in syntaxin 1B expression occurs in hippocampal circuits during working memory and in more widespread hippocampocortical circuits during reference memory. These results suggest that a form of trans-synaptic plasticity mediated in part by regulation of the expression of syntaxin 1B may play an active role in configuring specific spatially distributed circuits during the laying down of memories.

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PubMedDate not supplied

Cellular and molecular approaches to memory storage.

There has been nearly a century of interest in the idea that information is stored in the brain as changes in the efficacy of synaptic connections on neurons that are activated during learning. The discovery and detailed report of the phenomenon generally known as long-term potentiation opened a new chapter in the study of synaptic plasticity in the vertebrate brain, and this form of synaptic plasticity has now become the dominant model in the search for the cellular bases of learning and memory. To date, considerable progress has been made in understanding the cellular and molecular mechanisms underlying synaptic plasticity and in identifying the neural systems which express it. In parallel, the hypothesis that the mechanisms underlying synaptic plasticity are activated during learning and serve learning and memory has gained much empirical support. Accumulating evidence suggests that the rapid activation of the genetic machinery is a key mechanism underlying the enduring modification of neural networks required for the laying down of memory. These advances are reviewed below.

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