Efectes de la D-cicloserina en la memoria i la plasticitat neural en animals sans i amb déficit cognitiu

Abstract

This dissertation is inspired by the growing scientific interest in analyzing and understanding the neural mechanisms underlying memory formation. The main goal is to develop pharmacological treatments that are able to mitigate the cognitive impairment that is manifested in several neurodegenerative diseases. Due to the progressive aging of the population, such diseases have been increasing in prevalence. In this context, the experiments aim to study the effects of the drug D-cycloserine (DCS), a partial agonist of the N-methyl-D-Aspartate (NMDA) receptor that enhances glutamatergic activity. In recent years DCS has been considered as a potential cognitive enhancer that facilitates memory and is able to reverse cognitive deficits caused by cholinergic hypofunction and normal aging. DCS has been injected into various brain regions of the rat, such as the basolateral amygdala, the prelimbic cortex and the ventral hippocampus, part of the neuroanatomical circuits involved in learning and memory processes. Its effects were assessed in olfactory learning paradigms, such as odor discrimination task and social transmission of food preference, and spatial learning, such as the Morris water maze. We have also examined the possible mechanisms of action of the DCS as an enhancer of hippocampal synaptic plasticity. The main results showed that the administration of DCS in the basolateral amygdala may strengthen the association between stimuli, since it prevents the extinction process and enhances memory reconsolidation in olfactory discrimination (experiments 1 and 2). While confirming the hypothesis that the DCS can function as a memory enhancer, the results also generated some controversy about its effectiveness to facilitate the extinction learning in the treatment of phobias and anxiety disorders in humans (Davis et al. 2006). Moreover, DCS administered in the prelimbic cortex and the ventral hippocampus reverses deficits in olfactory memory derived from cholinergic hypofunction induced by the administration of the muscarinic receptor antagonist scopolamine, which is used as a pharmacological model of cognitive impairment (Klinkenberg & Blokland 2010) (experiments 3, 4 and 5). In addition, we found that one of the mechanisms of action by which DCS could offset the deficits produced by scopolamine infusion is facilitating the synaptic plasticity mechanisms in the hippocampus, in particular long-term potentiation (experiment 6). The results of these experiments also confirm the proposed interaction between cholinergic and glutamatergic transmission in modulating learning and memory. However, although it has been shown that DCS administration in the prelimbic cortex improved memory consolidation of olfactory discrimination, no significant effects have been observed in the social transmission of food preference in normal rats that were untreated with scopolamine. Neither has it produced enhancing effects when administered in the ventral hippocampus of young rats in the social transmission of food preference and the Morris water maze. These results could be explained by the fact that this drug would produce more obvious effects in implicit memory tasks than in spatial and relational memory. Finally, we observed that the administration of DCS in the ventral region of the hippocampus in aged animals produced an improvement in the recall of the olfactory relational memory and reverses cognitive rigidity in spatial learning, features that show a clear decline with age (experiment 7). Therefore, it appears that the enhancement of glutamatergic activity through the DCS may have beneficial effects to compensate the cognitive impairment associated with aging. Finally, the results suggests that DCS may act as an effective treatment for those diseases in which cholinergic transmission is altered and accompanied by cognitive impairment, such be Alzheimer's disease.

Date of Award	4 Oct 2013
Original language	Catalan
Supervisor	Margarita Marti Nicolovius (Director) & Ana Maria Vale Martinez (Director)