Daniel Béracochéa

Effects of anterior or dorsomedial thalamic ibotenic lesions on learning and memory in rats

Sprague-Dawley rats were used to study the effects of ibotenic acid lesions of the anterior (A.Th.) and the dorsomedial (MD) thalamic nuclei on learning and memory. Memory was assessed by employing a temporal alternation task in a straight alley with varying intertrial intervals. In addition, spatial orientation and response flexibility were evaluated on a radial maze and on a spatial reversal task (SSDR). The results indicated that MD rats required more trials to learn the temporal alternation task and exhibited impaired performance compared to A.Th. and control groups at the shortest delay (15 s). In contrast, compared to the control group, A.Th. subjects which required less trials to master the task and exhibited normal performance at the 15-s delay were impaired when the intertrial interval was increased to 45 s. Whatever the lesion, no impairments were found in the SSDR or the radial maze while only MD lesions were found to result in a night hyperactivity associated with greater food and water consumptions. These findings indicate that A.Th. and MD are differentially involved in learning and memory processes. It is suggested that the MD is mostly involved in registering new information while the A.Th. plays a role in the maintenance of information over time.

On the involvement of the central cholinergic system in memory deficits induced by long term ethanol consumption in mice.

Male mice of the BALB/c strain were given a solution of 12% v/v ethanol as their only source of fluid for 7 months. Memory performance was tested after ethanol was omitted from the diet for 3 to 9 weeks, and was compared with performance of control animals (no ethanol) which had been pair-fed or had received tap water. The spontaneous alternation task that was used consisted of two forced trials (acquisition) followed, at varying intervals ranging from 30 sec to 6 hr, by a free test trial (retention). Experimental subjects exhibited an accelerated rate of decay of spontaneous alternation, reaching chance level at 6 hours. All animals were then tested at this 6-hour interval following injections of either physostigmine or neostigmine that were given before both acquisition and retention (0.05 mg/kg IP). Results showed that physostigmine, but not neostigmine, dramatically improved performance of alcohol-treated subjects. Parallel neurochemical analysis showed that chronic ethanol treatment induced a slight (12%) but significant decrease in hippocampal sodium-dependent high affinity choline uptake. Though these findings suggest that the observed memory deficits (i.e., an accelerated rate of forgetting) might be related to a cholinergic dysfunction, alternative explanations are also proposed.

Impairment of spontaneous alternation behavior in sequential test procedures following mammillary body lesions in mice: Evidence for time-dependent interference-related memory deficits.

The experiments reported here examined the effects of either radio frequency or kainic acid lesions of the median mammillary nucleus (MM) on spatial spontaneous alternation (SA) in mice. Animals were tested in a T-maze with sessions of six to nine successive trials given at varying intertrial intervals (ITIs). In the first experiment, conducted with an ITI of 30 s, damaged animals exhibited normal rates of SA on the second trial of the session but were progressively impaired on subsequent trials compared with controls. This finding was interpreted as an increased vulnerability to proactive interference. The second experiment was designed to investigate the effect of the ITI, and the results indicated that the previously observed impairment was completely suppressed by reducing the ITI from 30 s to 5 s. In order to further test our interference hypothesis, a third experiment was designed to investigate whether providing the animals with an extrinsic cue on one trial (5th) would increase the rate of SA on the subsequent (6th) trial (release from interference). Unexpectedly, results from this experiment showed that performance dramatically improved as soon as the cue was provided (i.e., on the 5th trial). These results are discussed in relation to a possible role of the mammillary bodies in memory processes. Specifically, it is suggested that as for Korsakoff patients, MM damaged mice suffer from an impaired ability to make temporal order judgments. Thus changing the context serves to help the animal actively reconstruct the sequence of past events.

Memory deficits subsequent to chronic consumption of alcohol in mice: An analysis based on spontaneous alternation behavior

Male mice of the BALB/c strain were given a solution of 15% ethanol as their only source of fluid for periods varying from 5 weeks to 8 months. For behavioral testing, they were compared with control groups which had received either an isocaloric solution of sucrose or tap water. Memory was tested by using spontaneous alternation behavior in a T maze. Each test consisted of two forced trials (acquisition) followed by a free trial (test) given at different acquisition--test intervals (from 30 s to 24 h). Results from two independent experiments showed that after 25 weeks of ethanol administration there was an accelerated rate of decay of spontaneous alternation as a function of the acquisition--test interval. Such a phenomenon persisted after ethanol was omitted from the diet. A third experiment showed that when tested on two successive sessions separated by a 5 h interval, experimental subjects exhibited a decreased ability to perform normally on the second test. Our data are interpreted as showing that long-term ethanol administration results in accelerated forgetting and increased vulnerability to proactive interference and, as such, they are compared to the memory dysfunctions observed in amnesic patients.

First evidence of a delay-dependent working memory-enhancing effect of modafinil in mice.

This study investigated the effects of pretest injection of modafinil on delayed spontaneous alternation rates (SA) used to evaluate working memory in C57 Bl/6 mice. In a first experiment, systemic modafinil at 64 mg/kg, but not at 8 mg/kg or 32 mg/kg doses produced a significant increase of alternation scores (intertrial interval (ITI) 60 s) when compared with controls. In a second experiment, modafinil (64 mg/kg) en- hanced the alternation rates mainly at long (60 s and 180 s) but not at short (5 s) ITIs. Exploratory latencies and activity in a four hole-board apparatus were not modified by modafinil administration. These experiments are the first to demonstrate a delay-dependent working memory-enhancing effect of modafinil.

Anterograde and Retrograde Effects of Benzodiazepines on Memory

Benzodiazepines are known as “acquisition-impairing” molecules, and their effects on anterograde memory processes are well described. In contrast, the impact of benzodiazepines on retrograde memory and, more particularly, on retrieval processes, is only marginally studied. This mini-review provides an overlook of the main studies evidencing an effect of benzodiazepines on retrograde memory, both in humans and animals, with special emphasis on retrieval processes. The conditions for the emergence of the benzodiazepine-induced retrieval impairments are also discussed.

Build-up and release from proactive interference during chronic ethanol consumption in mice: A behavioral and neuroanatomical study

Male mice of the BALB/c strain were given a solution of 15% ethanol as their only source of fluid during either 24 or 48 weeks. They were submitted to a sequential alternation (SA) task in a T-maze (6 successive trials). It was found that 48 but not 24 weeks of alcohol administration lead to a deficit as compared to pair-fed or tap-water controls. Whereas experimental mice performed as well as controls on the first 3 choices, they exhibited a gradual decrease in the SA rate on subsequent trials. We suggest that this deficit might result from an exaggerated vulnerability to proactive interference (PI). In order to further test this hypothesis, a second experiment investigated whether a between-trials variation of context of the maze would increase performance. It was found that the SA rate improved as soon as the variation was provided (5th trial). We suggest that the deficit of experimental mice results from an impairment of retrieval processes. A neuroanatomical study was conducted to quantify cell losses resulting from 8, 24 or 48 weeks of ethanol treatment in the mammillary bodies (MM) or the hippocampus (HPC). At the time of appearance of the deficit, MM exhibited a -32% cellular loss, whereas this was only -18% in the HPC. This result emphasises the importance of MM lesion in memory deficits resulting from long-term alcohol consumption.

Rapid stress-induced corticosterone rise in the hippocampus reverses serial memory retrieval pattern

We previously showed that an acute stress (electric footshocks) induced both a rapid plasma corticosterone rise and a reversal of serial memory retrieval pattern in a contextual serial discrimination (CSD) task. This study is aimed at determining (i) if the rapid stress effects on CSD performance are mediated by the hippocampus; (ii) if hippocampal corticosterone membrane receptor activation is involved in the rapid stress effects on CSD performance. In experiment 1, microdialysis in the dorsal hippocampus (dHPC) was used to measure the stress‐induced corticosterone rise; in parallel, the effect of acute stress on CSD performance was evaluated. In addition, the functional involvement of corticosterone in the behavioral effects of stress was assessed by administering metyrapone, a corticosterone synthesis inhibitor, before stress. In experiment 2, the involvement of hippocampal corticosterone membrane receptors in the stress‐induced reversal of CSD performance was studied by injecting corticosterone‐bovine serum albumin (BSA) (a membrane‐impermeable complex) in the dHPC in non stressed mice. Results showed that (i) the acute stress induced a rapid (15 min) and transitory (90 min) corticosterone rise into the hippocampus dHPC, and a reversal of serial memory retrieval pattern; (ii) both the endocrinal and memory stress‐induced effects were blocked by metyrapone; (iii) corticosterone‐BSA injection into the dHPC in non stressed mice mimicked the effects of stress on serial retrieval pattern. Overall, our study is first to show that (i) a rapid stress‐induced corticosterone rise into the dHPC transitorily reverses serial memory retrieval pattern and (ii) hippocampal corticosterone membrane receptors activation is involved in the rapid effects of acute stress on serial memory retrieval.

Deficits of spatial and non‐spatial memory and of auditory fear conditioning following anterior thalamic lesions in mice: comparison with chronic alcohol consumption

This study was aimed at determining (i) whether or not bilateral subtotal lesions of the anterior thalamic nuclei (ATH) in rodents produced memory deficits for spatial and/or non‐spatial information and of auditory fear conditioning, and (ii) if these eventual deficits resemble those produced by chronic alcohol consumption (CAC). Working memory was assessed using both spatial (spontaneous alternation) and non‐spatial (temporal alternation) delayed response tasks. Results showed that ATH lesions induced delay‐dependent memory impairments in both spatial and non‐spatial alternation tasks, as well as a decreased level of auditory and background contextual fear conditioning compared with respective controls. CAC did not induce accelerated rate of forgetting in the spatial and non‐spatial tasks, but increased the vulnerability to interference in the spatial task. CAC impaired only background contextual fear conditioning. We conclude that ATH nuclei are involved in the maintenance of information over time, regardless of the nature (spatial vs. non‐spatial) of the information, and play a role in associative processes for both unimodal (the tone) and polymodal (contextual) information. In contrast, ATH dysfunction does not account for the memory disorders induced by the CAC treatment. Our results contribute to showing that the functional overlap between the structures comprising the hippocampo‐mamillo‐thalamic pathway is only partial.

Modafinil restores memory performance and neural activity impaired by sleep deprivation in mice.

The original aims of our study have been to investigate in sleep-deprived mice, the effects of modafinil administration on spatial working memory, in parallel with the evaluation of neural activity level, as compared to non-sleep-deprived animals. For this purpose, an original sleep deprivation apparatus was developed and validated with continuous electroencephalography recording. Memory performance was evaluated using spontaneous alternation in a T-maze, whereas the neural activity level was estimated by the quantification of the c-Fos protein in various cerebral zones. This study allowed altogether: First, to evidence that a diurnal 10-h sleep deprivation period induced an impairment of spatial working memory. Second, to observe a decrease in c-Fos expression after sleep deprivation followed by a behavioural test, as compared to non-sleep-deprived mice. This impairment in neural activity was evidenced in areas involved in wake-sleep cycle regulation (anterior hypothalamus and supraoptic nucleus), but also in memory (frontal cortex and hippocampus) and emotions (amygdala). Finally, to demonstrate that modafinil 64 mg/kg is able to restore on the one hand memory performance after a 10-h sleep deprivation period, and on the other hand, the neural activity level in the very same brain areas where it was previously impaired by sleep deprivation and cognitive task.