Pilar Segura-Torres

The tuberomammillary nucleus region as a reinforcement inhibiting substrate: facilitation of ipsihypothalamic self-stimulation by unilateral ibotenic acid lesions

The tuberomammillary nucleus (TM), located in the posterior hypothalamic region, consists of five subgroups and is the only known source of brain histamine. Knowledge about the function of this nucleus is still scarce. In a previous study we found an increase in the rate of ipsihemispheric hypothalamic self-stimulation following a dc lesion in the rostroventral part of this nucleus, suggesting that this region has an inhibitory action on a neuronal reward system or on the brains reinforcement mechanism. In the present study we examined whether this facilitating effect on reinforcement was due to the destruction of fibers passing through the lesion area or of intrinsic cells, by lesioning subgroups of the TM with ibotenic acid, an excitatory amino acid, that selectively destroys neural cell bodies, leaving fibers largely intact. Following such lesions in the rostroventral part of the TM the operant response rates increased over the six days of testing when the animals stimulated themselves in the lateral hypothalamus in the hemisphere located ipsilateral but not contralateral to the lesion. No significant changes in response rate occurred following the lesion in the caudal part of the ventral TM. The results indicate that the region influenced by the lesion exerts inhibitory control over lateral hypothalamic self-stimulation, and that it is possible that histamine-containing neurons are involved in this effect.

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.

Improvement of shuttle-box avoidance with post-training intracranial self-stimulation, in rats : a parametric study

Rats were trained in a two-way active avoidance task followed immediately by a lateral hypothalamic intracranial self-stimulation (ICSS) treatment, during 5 consecutive days. The effects of the number of ICSS trains allowed (0, 500, 2500 or 4500) were studied upon acquisition and long-term retention (LTR, 10 and 30 days). The number of ICSS trains administered and the number of avoidances at the last acquisition session (5th) showed a positive lineal relation, that is, the more number of ICSS trains, the more number of avoidances. The level of learning achieved during the 5th session was maintained after the LTR periods in all experimental groups. It is concluded that the number of ICSS trains could be a critical parameter in the facilitatory effect of lateral hypothalamic ICSS upon learning, and it is suggested that the facilitatory effect of post-training lateral hypothalamic ICSS might be due to the activation of general activatory neural systems.

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.

Correlations between paradoxical sleep and shuttle-box conditioning in rats.

Eighteen male Wistar rats were given one daily two-way active avoidance conditioning session followed immediately by 5 hr of sleep recording, for 5 consecutive days. The group of rats that achieved 80% or greater avoidance in some of the 5 training sessions showed significant linear increases of paradoxical sleep (PS), compared with baseline levels, throughout the successive conditioning sessions. Furthermore, (a) the group of rats showing PS increases (more than 1 SD above baseline) after some of the training sessions achieved a significantly higher final number of avoidances than the remaining animals: (b) a high and positive correlation was observed between avoidance increases in the 3rd conditioning session and previous PS; and (c) maximum increases in correct performance often occurred following high PS increases. It is concluded that PS increases facilitate the consolidation of learning.

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.