David Costa-Miserachs

Effects of long-term voluntary exercise on learning and memory processes: dependency of the task and level of exercise

The effect of long-term voluntary exercise (running wheel) on anxiety-like behaviour (plus maze and open field) and learning and memory processes (object recognition and two-way active avoidance) was examined on Wistar rats. Because major individual differences in running wheel behaviour were observed, the data were analysed considering the exercising animals both as a whole and grouped according to the time spent in the running wheel (low, high, and very-high running). Although some variables related to anxiety-like behaviour seem to reflect an anxiogenic compatible effect, the view of the complete set of variables could be interpreted as an enhancement of defensive and risk assessment behaviours in exercised animals, without major differences depending on the exercise level. Effects on learning and memory processes were dependent on task and level of exercise. Two-way avoidance was not affected either in the acquisition or in the retention session, while the retention of object recognition task was affected. In this latter task, an enhancement in low running subjects and impairment in high and very-high running animals were observed.

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.

Automated sleep staging in rat with a standard spreadsheet

A new method of automated sleep-wake staging in the rat is described. Hippocampal electroencephalographic (HPC) and nuchal electromyographic signals were recorded by a digital polygraph. The HPC channel was filtered off-line to obtain the original plus theta and delta waves. Statistics of each of these four channels were obtained every 5 s and exported to a standard spreadsheet. The automated staging consisted of five steps: (1) automatic detection of waking, nonrapid eye movement sleep and rapid eye movement sleep patterns (5-s periods); (2) calculation of statistics for each vigilance state; (3) final classification of 5-s periods; (4) construction of a primary 20-s epoch hypnogram; and (5) automatic refinement of the previous hypnogram. The system includes indices about the accuracy of the staging and was validated with five recordings of 23 h each. The global agreement between human and automatic scoring in the validation recordings was 94.32%.

Long-term memory modulation by posttraining epinephrine in rats : Differential effects depending on the basic learning capacity

Effects of posttraining epinephrine on retention of a massed (1 session, 30 trials) 2-way active avoidance task were studied in rats. Immediately after the training session rats received an injection of 0.05 or 0.01 mg/kg ip epinephrine, or distilled water. Retention was tested 11, 20, or 45 days after training, in independent groups of rats. The 20- and 45-day retention was improved in poor-learning rats and disrupted in good-learning rats. It was concluded that the effect (facilitatory or disruptive) of posttraining epinephrine on memory consolidation depends on the basic learning capacity of rats for this task and needs a long time to be expressed.

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.

Improvement of shuttle-box performance by anterodorsal medial septal lesions in rats

Septal lesions impair a variety of tasks, including inhibitory avoidance and one way active avoidance. In contrast, these lesions improve two-way active avoidance, probably by reducing anxiety. The present work aimed to study whether anterodorsal medial septal lesion (a) improves performance of two-way active avoidance task (Experiment I), as it has been observed with wider septal lesion, and (b) affect anxiety and/or locomotor activity (Experiment II). This precise region was chosen because some evidences suggest that its lesion do not lead to a reduction of anxiety. Lesioned rats tended to make a higher, but statistically non-significant (P=0.074), number of avoidances regardless of the session, being this difference statistically significant on the retention session (RT). The same lesion did not appear to have an anxiolytic effect, and did not affected basal locomotor activity. Different possible explanations of our results are discussed.

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.

Intracranial self-stimulation facilitates active-avoidance retention and induces expression of c-Fos and Nurr1 in rat brain memory systems

Intracranial self-stimulation (ICSS), a special form of deep brain stimulation in which subjects self-administered electrical stimulation in brain reward areas as the lateral hypothalamus, facilitates learning and memory in a wide variety of tasks. Assuming that ICSS improves learning and memory increasing the activation of memory-related brain areas, the present work examined whether rats receiving an ICSS treatment immediately after the acquisition session of a two-way active avoidance conditioning (TWAA) show both an improved retention and a pattern of increased c-Fos and Nurr1 protein expression in the amygdala, hippocampus, dorsal striatum and/or lateral hypothalamus. The response of both activity-induced IEGs to ICSS was examined not only as markers of neural activation, but because of their reported role in the neural plasticity occurring during learning and memory formation. Results showed that the TWAA conditioning alone increased the expression of the two analysed IEGs in several hippocampal areas, and TWAA retention increased Nurr1 expression in amygdala. ICSS treatment increased the number of c-Fos and Nurr1 positive cells in almost all the brain regions studied when it was measured 70min, but not 48h, after the stimulation. Post-training ICSS treatment, as expected, facilitated the 48h retention of the conditioning. It is noteworthy that in CA3 conditioning and ICSS separately increased c-Fos expression, but this increasing was greater when both, conditioning and ICSS, were combined. Present results suggest that rapid and transient increased expression of these two synaptic plasticity and memory related IEGs in some hippocampal areas, such as CA3, could mediate the facilitative effects of ICSS on learning and memory consolidation.

Presumed 'prefrontal cortex' lesions in pigeons: effects on visual discrimination performance

The posterodorsolateral neostriatum (PDLNS) in pigeons may be an equivalent of the prefrontal cortex (PFC) in mammals. Here we report that lesions of this brain region in pigeons have a detrimental effect on various learned visual discriminations. Pigeons with lesions of the overlying area corticoidea dorsolateralis (CDL) served as controls. Both the postoperative re-learning to criterion of a preoperatively learned simultaneous double visual mirror pattern discrimination and the learning of a simple successive go, no-go discrimination were impaired by the PDLNS lesions. The PDLNS and CDL groups did not differ significantly in the postoperative learning of a reversal of the simultaneous discrimination. The results are discussed in relation to the presumed equivalence between the avian PDNLS and the mammalian PFC.

Facilitation of a distributed shuttlebox conditioning with post-training epinephrine in rats

Forty-two male Wistar rats were trained in a two-way active avoidance task during 5 consecutive days (10 trails/session). Immediately after each training session animals were given an injection, ip, of 0.1 mg/kg (EPI 0.1 group) or 0.05 mg/kg (EPI 0.05 group) of epinephrine, or vehicle (Vehicle group). Long-term retention was tested 20 days after the last acquisition session. Our results showed that the lower dose of epinephrine (0.05 mg/kg) led to a significant improvement of acquisition, compared with both the Vehicle and the EPI 0.1 group. On the long-term retention session the level of avoidances in both EPI 0.05 and Vehicle groups was similar to that achieved on the last acquisition session, although differences between groups failed to reach statistical significance. Concerning the EPI 0.1 group, a significant increase in the number of avoidances was observed between the last acquisition session and the long-term retention session. This later result might suggest that the higher dose of epinephrine would need a longer period to manifest its effectiveness. We conclude that the facilitatory effects of epinephrine are dose-dependent, and that under a distributed paradigm epinephrine modulates memory consolidation processes leading to an improvement of the magnitude of learning rather than merely speeding up learning.