Laura Aldavert-Vera

Post-training intracranial self-stimulation facilitates a hippocampus-dependent task

Previous research has shown that post-training intracranial self-stimulation facilitates implicit or procedural memory. To know whether it can also facilitate explicit memory, post-training intracranial self-stimulation was given to Wistar rats immediately after every daily session of a delayed spatial alternation task that seems to depend on the integrity of the hippocampal memory system. We tested the effects of intracranial self-stimulation in three consecutive learning phases which tried to make the task progressively more difficult: 10 s delay (D10 phase), 30 s delay (D30 phase), and inverting the starting position of the animals to make their response more dependent on allocentric cues (INV phase). Every phase finished when each rat achieved a fixed learning criterion. Intracranial self-stimulation facilitated the flexible expression of the learned response (INV phase). That is, when the starting position was randomly inverted, only the rats that received intracranial self-stimulation maintained the performance level acquired in the previous training phases. Changing the starting position reduced the correct performance of the non-treated subjects, which need more training sessions to achieve the learning criterion and made less correct responses than treated rats. These findings show that post-training intracranial self-stimulation can facilitate hippocampus-dependent memories.

Shuttle-box memory facilitation by posttraining intracranial self-stimulation : Differential effects in rats with high and low basic conditioning levels

The effects of intracranial self-stimulation (ICSS) on retention (after 24 hr, 7, 15, or 60 days) of a massed 2-way active avoidance task were studied in independent groups of rats. All groups showed a higher performance on the retention session than on the acquisition one. In the control subjects, the higher retention performances were observed in the 7- and 15-day groups. However, the ICSS treatment facilitated the 24-hr retention compared with its control group, allowing the treated subjects to achieve the same level of performance on the 24-hr retention session than that achieved by the control rats at the 7-day retention test. In the 24-hr groups, the facilitatory ICSS effect was stronger in the subjects with a low level of conditioning and weaker in those with a high level. Results suggest that posttraining ICSS accelerates memory consolidation and equalizes the performance of poor and good learners.

Posttraining intracranial self-stimulation ameliorates the detrimental effects of parafascicular thalamic lesions on active avoidance in young and aged rats

To evaluate whether intracranial self-stimulation (SS) ameliorates conditioning deficits induced by parafascicular nucleus (PF) damage in young and aged rats, the authors gave rats a daily session of 2-way active avoidance until a fixed criterion was achieved. Four experimental groups were established in both young and aged rats: SS treatment after every conditioning session (SS groups), pretraining PF lesions (lesion groups), PF lesions and SS treatment (L + SS groups), and controls. SS treatment not only canceled the detrimental effects of PF lesions, but also improved conditioning in lesioned rats (L + SS groups). This effect was more powerful in aged rats. SS treatment compensated for memory deficits generated by hypofunctionality of arousal systems such as that involving the PF.

Intracranial self-stimulation to the lateral hypothalamus, a memory improving treatment, results in hippocampal changes in gene expression

Intracranial self-stimulation (ICSS) within the medial forebrain bundle of the lateral hypothalamus (LH) facilitates consolidation of implicit and explicit memories for a variety of learning paradigms in rats. However, the neural and molecular mechanisms involved in memory facilitation by ICSS are not known. Here, we investigated the influence of ICSS treatment on hippocampal gene expression in order to identify potential signaling pathways and cellular processes involved in ICSS-mediated cognitive improvements. Immunohistochemistry studies demonstrated that ICSS caused a rapid induction of c-Fos expression in hippocampal cornu ammonis (CA) 3 and dentatus gyrus areas. Moreover, using microarray or quantitative real-time polymerase chain reaction (PCR) analysis, we showed that ICSS modulates the expression of 62 hippocampal genes shortly after training. Most of the proteins encoded by these genes, such as calmodulin-dependent-phosphodiesterase 1 A (Pde1a), are part of signal transduction machineries or are related to anti-apoptosis, as heat shock 70 kDa protein 1A (Hspa1a). Importantly, 10 of the regulated genes have been previously related with learning and memory or neural plasticity, including the cocaine and amphetamine-regulated transcript (Cart), adenylate cyclase activating polypeptide 1 (Adcyap1), serum/glucocorticoid regulated kinase (Sgk), Ret proto-oncogene (Ret), and Fos. The fact that the Fos gene was differentially expressed in our microarray experiments validated our findings from our immunohistochemical studies mentioned above. In addition, using quantitative real-time PCR, we confirmed the observed expression changes for several of the genes identified by our microarray analyses. Our results suggest that ICSS may facilitate learning and memory by regulation of multiple signaling pathways in the hippocampus that may promote neuroplasticity.

Involvement of the parafascicular nucleus in the facilitative effect of intracranial self-stimulation on active avoidance in rats

To evaluate whether parafascicular nucleus (PF) is involved in the facilitative effect of lateral hypothalamic intracranial self-stimulation (LH-ICSS) on two-way active avoidance acquisition (5 sessions, 10 trials each, one daily) and long-term retention (10 days), rats were lesioned bilaterally at the PF and implanted with an electrode aimed at the LH to obtain ICSS behavior. After each acquisition session rats were allowed to self-administer 2500 trains of LH-ICSS. The main results were: (1) LH-ICSS facilitated the acquisition and retention of conditioning; (2) PF lesions impaired both acquisition and retention of two-way active avoidance; (3) there was a positive relationship between PF lesions size and learning disruption, and (4) LH-ICSS failed to facilitate learning when PF was lesioned. We concluded that the lesion size is a critical variable to evaluate the effects of PF lesions on learning and memory, and that LH-ICSS treatment may exert their effects through the PF nucleus or, at least, the integrity of PF is required for LH-ICSS to improve clearly the task.

Facilitation of a distributed shuttle-box conditioning with posttraining intracranial self-stimulation in old rats.

Old Wistar rats (16-17 months) were trained in a two-way active avoidance task for 5 consecutive days (10 trials/day). Immediately after each training session a lateral hypothalamic intracranial self-stimulation session (ICSS group) or a sham-treatment session (Control group) was given to the animals. Long-term retention was tested 7 days after the last acquisition session. ICSS treatment led to a significant improvement in acquisition. In the long-term retention session the level of avoidance in both groups was similar to that achieved in the last acquisition session, although differences among groups failed to reach statistical significance. These results are compared with those obtained in previous experiments with young adult rats. While ICSS facilitated the process of acquisition in both young and old rats (however, it was much more powerful in young animals), further experiments are needed to elucidate whether this effect is long-lasting in old rats, as occurs in young adult subjects.

Intracranial self-stimulation facilitates memory consolidation, but not retrieval: its effects are more effective than increased training

To evaluate possible differential effects of lateral hypothalamic intracranial self-stimulation (ICSS) on memory consolidation and retrieval, independent groups of Wistar rats were trained in a single session of two-way active avoidance task (acquisition session) and tested 24 h later (retention session). The post-ICSS groups received an ICSS treatment immediately after the acquisition session, and the pre-ICSS groups received the same treatment immediately before the retention session. Because the ICSS effects on memory seem to be dependent on the initial performance level shown by the subjects, the possible influence of initial training (number of trials) on ICSS effects was also studied. Therefore, we used different control and experimental groups, which received either 30 or 50 trials in the acquisition session. Post-training ICSS facilitated the 24-h retention in both training conditions (30 and 50 trials). In contrast, pre-retention ICSS treatment did not facilitate performance in the retention test. We also observed that post-training ICSS was more effective for improving the 24-h retention than increasing the initial training from 30 to 50 trials. This findings confirm that ICSS treatment improves memory consolidation and suggest that it might not affect memory retrieval mechanisms.

Intracranial self-stimulation improves memory consolidation in rats with little training

Post-training intracranial electrical self-stimulation can improve learning and memory consolidation in rats. However, the molecular mechanisms involved are not known yet. Since previous paradigms of this kind of facilitation are relatively unsuitable to try a molecular approach, here we develop a single and short model of learning and memory facilitation by post-training self-stimulation that could make easier the research of its neural and molecular basis. Thus, three consecutive experiments were carried out to ascertain whether post-training self-stimulation is able to facilitate memory when learning consists of only a brief (5 trials) two-way active avoidance conditioning session. The results of Experiment 1 showed that it is actually possible, and that 48 h after the acquisition session is a very good time to observe the memory improvement. As a way to probe the retroactive effect of self-stimulation, in Experiment 2 we observed that the same self-stimulation treatment given to the subjects not post-training but 48 h before a single two-way active avoidance session does not improve the acquisition of conditioning. In Experiment 3, we showed that the SS facilitative effect observed 48 h after the acquisition session in Experiment 1 was still maintained one week later. We concluded that post-training intracranial self-stimulation can consistently improve memory consolidation even when little acquisition training is given to the animals in a single training session.

Tuberomammillary nucleus lesion facilitates two-way active avoidance retention in rats.

To evaluate whether the tuberomammillary nucleus might be involved in the acquisition and/or retention of a two-way active avoidance conditioning, rats were given a unilateral lesion of the tuberomammillary nucleus (E2 region) 24 h prior to the first conditioning session. Four learning sessions were performed: one acquisition and 3 retention sessions (short-term, 24 h; and long-term, 8 and 18 days). Results showed that the lesion facilitated the long-term retention of conditioning, but no effects were observed on acquisition and short-term retention. Since rewarding intracranial electrical stimulation seems to be a consistent way to facilitate learning and memory processes, and tuberomammillary lesion has been shown to improve intracranial self-stimulation behavior (ICSS), we suggest that lesions in the present experiment could have facilitated two-way active avoidance retention by enhancing the function of brain reward mechanisms.

Intracranial self-stimulation induces expression of learning and memory-related genes in rat amygdala

Intracranial self‐stimulation (ICSS) in the lateral hypothalamus improves memory when administered immediately after a training session. In our laboratory, ICSS has been shown as a very reliable way to increase two‐way active avoidance (TWAA) conditioning, an amygdala‐dependent task. The aim of this work was to study, in the rat amygdala, anatomical and molecular aspects of ICSS, using the same parameters facilitating TWAA. First, we examined the activation of ipsilateral and contralateral lateral (LA) and basolateral (BLA) amygdala, the main amygdalar regions involved in the TWAA, by the immunohistochemical determination of c‐Fos protein expression. Second, we tested the effects of the ICSS treatment on the expression of 14 genes related to learning and memory processes using real‐time polymerase chain reaction. Results showed a bilateral increase in c‐Fos protein expression in LA and BLA nuclei after ICSS treatment. We also found that Fos, brain‐derived nerve growth factor (BDNF), Arc, inducible cAMP early repressor (ICER), COX‐2, Dnajb1, FKpb5 and Ret genes were upregulated in the amygdala 90 min and 4.5 h post ICSS. From this set of genes, BDNF, Arc and ICER are functionally associated with the cAMP‐responsive element‐mediated gene transcription molecular pathway that plays a pivotal role in memory, whereas Dnajb1 and Ret are associated with protein folding required for plasticity or neuroprotection. Our results suggest that ICSS induces expression of genes related with synaptic plasticity and protein folding functions in the rat amygdaloid area, which may be involved in the molecular mechanisms by which ICSS may improve or restore memory functions related to this brain structure.