Faculty Bibliography

The gating and tuning actions of noradrenaline (NA) at post-synaptic sites have been highly suggestive of an important role for the locus coeruleus (LC) in attention, learning and memory. By recording the activity of single units in the LC in behaving rats in a strictly controlled conditioning paradigm, direct evidence was provided that this nucleus is engaged during specific aspects of learning. The neuronal response to a discrete sensory stimulus was monitored as a function of the changing significance of the stimulus i.e., when it was novel, during habituation, associative learning, reversal and extinction. Both appetitive and aversive paradigms were used. We consistently observed differential conditioned responding with food reinforcement, while when footshock reinforcement was used, there was an increase in response to both CS+ and CS-. In both paradigms, the LC response disappeared when the conditioning was expressed at a behavioral level, to reappear vigorously as soon as the stimulus reinforcement contingencies were changed, i.e., during reversal or extinction. These results suggest that the LC does not mediate specific sensory or associative information necessary for ongoing performance but shows remarkable plasticity of sensory responding as a function of changing cognitive significance of the stimulus

The noradrenergic system was pharmacologically activated with the alpha 2 receptor antagonist, idazoxan (2 mg/kg i.p.), during the acquisition of a complex appetitive task requiring a shift in attention to stimulus dimension and in response strategy. Rats first learned a fixed path of 6 successive choices in a linear maze. The task was then changed to a visual discrimination task in which the spatial configuration of the correct path was indicated by visual cues and changed on each daily trial. During this part of the task, the rats were injected before each trial with idazoxan, a drug which increases the firing rate of neurons in the locus coeruleus and the release of noradrenaline in the cortex and hippocampus. Two control experiments showed that the drug treatment had no effect on the acquisition of either component of the task - the successive place learning or the visual discrimination. The drug was found to be effective only during the shift phase of the experiment, the idazoxan-treated rats taking fewer trials to reach criterion than the saline. A second experiment showed that idazoxan increased the amount of time spent investigating novel and unexpected objects in a familiar hole board. These results implicate the noradrenergic system in problem-solving which requires an attentional shift or a shift in responding from familiar to novel stimuli

The role of the noradrenergic system in cognitive function was studied by using the alpha-2 adrenoceptor antagonist idazoxan to increase noradrenergic activity. Rats were trained in a complex maze task for food reward. They were left undisturbed for a 4-week 'forgetting' period and were treated with idazoxan, just before the retention test. The dose of idazoxan used had previously been shown to enhance firing of units of the locus coeruleus and to increase noradrenaline (NE) turnover in the forebrain. This pharmacological treatment effectively alleviated forgetting, while control rats showed significant decrement compared to their performance at the last training trial. A control experiment showed that the facilitative effect was not on learning or on ongoing performance of the task, since there was no effect on simple acquisition. The results are taken as support for the notion that NE plays a role in memory retrieval processes

Over the past 10 years, cholinergic deficits have been strongly correlated with memory dysfunction. On the other hand the lack of efficacy of direct or indirect cholinergic drugs has led to research in other neurotransmitter systems. Several authors have found miscellaneous results in NE and metabolites levels and in monoamine enzyme activities. These discrepancies have lead to discussions about the homogeneity of the disease. Animal lesion studies point out the importance of the septo-hippocampal cholinergic pathway and the interrelations between ACh and NE in the hippocampal formation. The author performed a series of experiments in rats in which hippocampal ACh activity was reduced (fornix section or destruction of cells in the medial septum) and the NE system modified by clonidine or neurotoxic lesions. The hypothesis was that a lesion of the cholinergic pathway leads to an enhancement of NE activity which inhibits spared ACh neurons. The alpha-2 agonist clonidine would interrupt this loop by decreasing of NE release. Results provide arguments for the author's theory

After a generation of research into the biological mechanisms of memory, the essential nature of the engram remains as elusive as ever. Many investigators have reorganized their conceptual framework to emphasize the role of physiological responses elicited by a learning experience in modulating memory for that event. This approach has generated a long list of correlations between physiological functions and memory performance. The papers comprising the present section have the common theme of contributing to that list, but the remarkable fact which they emphasize is that these correlations are much greater in the aged rat than in young animals, suggesting that it is a parallel degeneration of several physiological functions which mediate deficits in memory performance

Rats were trained to run a linear maze for food reinforcement. During the 5-week retention interval, they were implanted under electrophysiological control with fine stimulating electrodes aimed at the nucleus locus coeruleus (LC). When tested 5 weeks after training, control rats showed forgetting in that they made significantly more errors at the test trial than at the last training trial. Low-level stimulation of LC immediately before the test alleviated the forgetting in that this group made significantly fewer errors than the non-stimulated group on two successive days. The results are taken as behavioral evidence of a role for noradrenergic projections from LC in memory and attention

Rats were fed a thiamine-deficient diet for 4 weeks and injected daily with pyrithiamine during the last two weeks of the diet. This regime induced severe neurological anomalies such as ataxia, loss of righting reflex and visual place reflex, and finally full tonic-clonic seizures. These symptoms are reminiscent of the clinical Wernicke-Korsakoff syndrome. Injection of thiamine dramatically reversed these symptoms within one or two hours as seen in Wernicke patients. Six weeks later these rats showed a marked deficit in habituation of exploratory behavior and of the auditory orienting response. To what extent this chronic deficit in habituation contributes to the cognitive dysfunctions seen in Wernicke-Korsakoff patients is discussed. Histological examination of the brains of 6 of the rats revealed a heterogeneous pattern of damage to the brainstem, including mamillary bodies and several thalamic nuclei, reminiscent of that seen in Korsakoff patients. In addition there were many dark abnormal cells in limited fields of hippocampus neocortex and thalamus in almost all animals

Rats were trained in a complex maze task for food reward. After a 25-day retention interval, they made more errors than at the last training trials. This forgetting was alleviated by pretest treatment with haloperidol. The same dose of haloperidol had no effect on acquisition or performance when injected during training. The results were replicated, but smaller doses were found to be inactive. The possibility that the effect might be mediated through the noradrenergic system is considered

Rats were trained in a 6 unit spatial discrimination maze for food reinforcement; they were then implanted with intracerebroventricular (i.c.v.) cannulae and tested 25 days after training. Control animals displayed significant forgetting; 10 micrograms apomorphine alleviated this forgetting, while a higher dose did not. A hole board activity study revealed that i.c.v. Apomorphine does not produce the shaped dose-response activity curve found with systemic injections. Neurochemical analysis of forebrain structures after injections showed that the dose which facilitated memory retrieval also increased cortical and hippocampal noradrenaline, while the larger dose did not