Age-dependent effects of moderate chronic ethanol administration on different forms of memory expression in mice

Abstract

A large number of studies have investigated the effects of chronic ethanol administration (CEA) on performance in different types of learning and memory tasks in adult rodents. As a general rule, CEA has been reported to impair performance, although this depends both on the condition of administration (e.g. duration, presence or not of a withdrawn period) and on task demands (e.g. spatial versus non-spatial). Indeed, either no impairment or even a facilitation of performance have been reported following CEA. However, no study has directly addressed the issue as to whether the effect of CEA depends on the age of subjects. In this study, C57Bl/6 mice of two age ranges (i.e. 2–3- and 16–18-month-old) were given either a solution of ethanol (12% v/v) as their only source of fluid for 5 months (experimental groups) or were pair-fed with an isocaloric solution of dextri-maltose (control groups). Then, they were submitted to a place discrimination task in an 8-arm radial maze. Additionally, mice were tested for long-term retention following a 21-day interval. Confirming our previous findings, the results showed that, with respect to adults (7–8-month-old at the time of testing), aged mice (21–23-month-old) of the control group displayed impaired relational memory but not procedural memory performance. Further they exhibited a higher level of forgetting than adults over the 21-day interval. In the same paradigm, CEA resulted in an overall attenuation of both type of deficit in aged subjects without altering their procedural memory. Furthermore these ethanol-consuming aged mice displayed significantly less levels of forgetting than their age-matched controls. Conversely, in the adult group, CEA resulted in an overall, although, somewhat less selective impairment of relational memory with respect to procedural memory but had no effect on long-term forgetting. While confirming the deleterious effect of CEA on learning and memory processes in adults, our present findings provide evidence that CEA can selectively ameliorate certain cognitive deficits normally associated with ageing.

Introduction

It has repeatedly been shown that chronic ethanol administration (CEA) was associated with neurodegenerative mechanisms occurring in specific brain regions, known as key structures in learning and memory function [14], [36].

Given the complexity of the neuro-psychological disorders associated with alcoholism, animal models of alcohol consumption-related pathology have been developed [2], [4]. These studies have enabled a fine analysis of the behavioural deficits induced by alcohol consumption. For example, it was reported that CEA produced anterograde amnesia, faster forgetting rates and a deficit in the temporal ordering of information [2], [26]. These memory deficits have been suggested to be mainly due to ultra-structural alterations occurring at dendritic [5], [8], [19], [21] and/or synaptic levels [30]. Although there exist a consensus concerning the deleterious effects of CEA on cognition, the question still remains as to the exact role of several experimental factors such as the duration of ethanol exposure, the magnitude and mode of exposure (ingestion, inhalation …) and the presence or not of a withdrawal period before testing. In fact, it is now well established that ethanol withdrawal is critically involved in brain damage. Specifically it has been shown that granule cells loss continues in the dentate gyrus after exposure to alcohol ceases [7]. This phenomenon has been linked to the up-regulation of NMDA receptors-related seizures observed following ethanol withdrawal, leading to enhanced susceptibility to excitotoxicity [17].

Consistent with this consideration, it has recently been reported [24] that intermittent i.p. injection of ethanol for 1 month in rats, induced significant neuronal loss in CA2-CA3 hippocampal pyramidal cells as compared to continuous ethanol consumption, since the intermittent ethanol administration is associated with a cyclic high blood ethanol peaks alternated with repeated withdrawal periods. Taken together, ethanol withdrawal might be expected as a probable underlying cause for triggering the neurodegenerative mechanisms associated with learning and memory impairments. In support for a role of withdrawal episode in memory impairments, it has been shown that ethanol-treated rats non-withdrawn from ethanol consumption not only displayed no learning impairment, but perform certain task better than the controls [34]. Similarly, other studies in rat have failed to reveal any memory deficit subsequent to ethanol consumption in various behavioural tasks [13], [16], [18], [23], [35].

Although, a large number of studies have been undertaken to elucidate the behavioural effects of CEA in adult rodents, surprisingly however, to date there is no study who has directly addressed the question as to whether the effects of CEA might depend on the age of the subject. Therefore, the present experiment was designed to determine whether moderate CEA may compensate for memory decline associated with cognitive ageing. To this end, we used a behavioural paradigm that enables to distinguish between the expression of declarative/relational memory (which is impaired in senescent and hippocampal-lesioned mice) and the expression of procedural memory (which remains relatively intact in both cases) related to the same piece of learned material [11], [27]. As for amnesic patients, this dissociation between the two forms of memory is also noted in human senescence and the specific impairment of declarative memory is believed to stem from a dysfunction of the hippocampal region [15]. Because the hippocampal region is also thought to play a crucial role in the formation of long-term (declarative/relational) memory [32], we further assessed long-term retention (21-day interval) of the material learned across the first three stages.