Faculty Bibliography

Learning a conditioned stimulus (CS)-unconditioned stimulus (US) association is accompanied by a variety of long-lasting changes in physiology and chemistry of the synapse in the dentate gyrus. To determine the time course of synaptic modification during learning, changes in the perforant path-dentate gyrus-evoked field potentials were measured in rats performing a classical conditioning (paired tone and footshock) or pseudoconditioning (unpaired tone and footshock) task. Over the course of 4 days of training, differential changes in the evoked response were observed in the two groups. In the conditioned group, there was an increase in the slope of the excitatory postsynaptic potential (EPSP) which started after five tone-shock paired trials and lasted for more than 40 min, outlasting the training session by 20 min. In contrast, a decrease in the slope of the EPSP which commenced after training and lasted for at least 1 h was observed in the pseudoconditioned group. In both groups there was a prolonged decrease in the amplitude of the population spike. The increase in the EPSP was reduced and the duration tended to shorten over days of training in the conditioned group, whereas in the pseudoconditioned group the decrease in the EPSP tended to increase. Off-line analysis of suppression of lever-pressing for food reward during the presentation of the tone, indicated that the conditioned rats had learned the tone-footshock association. Temperature was measured in the dentate gyrus of rats undergoing an identical procedure. In both groups slight temperature increases were observed, with no difference in amplitude and time-course between the groups. The differential effect of conditioning and pseudoconditioning on the evoked response and changes in temperature eliminate the possibility that effects of stress, arousal and muscular effort are the primary cause of the changes in the EPSP. The results suggest that behavioural events can exert bidirectional control of synaptic strength of entorhinal cortex inputs to the dentate gyrus and that the sign of synaptic modification is at least in part determined by the temporal relationship between these events. The data are discussed in terms of the type of neural activity that may mediate the processing of information in the dentate gyrus.

It has been proposed that the physical substrate of memory resides in alterations of the strengths or weights of modifiable synaptic connections. In recent years, the hypothesis that the mechanisms underlying a particular form of synaptic plasticity, known as long-term potentiation, or LTP, are activated during learning and may actually subserve the formation of associative memories, has gained much empirical support. This paper reviews experimental studies suggesting that changes in synapse physiology and chemistry are involved in the formation of neural associative representation in hippocampal networks during classical conditioning. Recent experiments investigating LTP and learning-induced synaptic changes at hippocampal outputs to the prefrontal cortex are reported. The results provide a working framework within which the dynamics of information storage in hippocampal and prefrontal cortical networks is profiled.

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.

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.