Gina L. Quirarte

Selective M1 muscarinic receptor antagonists disrupt memory consolidation of inhibitory avoidance in rats

The effect of three different M1 muscarinic antagonists, pirenzepine, biperiden, and trihexyphenidyl on memory consolidation was investigated. Rats were trained in a one-trial step-through inhibitory avoidance task and injected intraperitoneally immediately afterwards, either with pirenzepine, biperiden, or trihexyphenidyl (dose range from 0 to 16 mg/kg). The non-selective antimuscarinic compound scopolamine, was also administered for comparison. One day later, rats were tested for retention. Results show that biperiden, trihexyphenidyl and scopolamine produced a dose-dependent impairment of inhibitory avoidance consolidation, while pirenzepine had no effect. The amnestic state produced by biperiden and trihexyphenidyl was comparable to that observed after the administration of scopolamine. These results indicate that the selective blockade of the central M1 muscarinic receptors interfere with memory consolidation of inhibitory avoidance and suggest that this receptor subtype is critically involved in mnemonic functions.

Corticosterone infused into the dorsal striatum selectively enhances memory consolidation of cued water-maze training

Glucocorticoid hormones enhance memory consolidation of hippocampus-dependent spatial/contextual learning, but little is known about their possible influence on the consolidation of procedural/implicit memory. Therefore, in this study we examined the effect of corticosterone (2, 5, or 10 ng) infused into the dorsal striatum of male Wistar rats immediately after training on either a cued or spatial version of the water maze. We found that corticosterone dose-dependently enhanced 48-h retention of the cued training without affecting the retention of the spatial training. These findings indicate that corticosterone acts within the dorsal striatum to enhance memory consolidation of procedural/implicit training.

Glucocorticoids enhance taste aversion memory via actions in the insular cortex and basolateral amygdala

It is well established that glucocorticoid hormones strengthen the consolidation of hippocampus-dependent spatial and contextual memory. The present experiments investigated glucocorticoid effects on the long-term formation of conditioned taste aversion (CTA), an associative learning task that does not depend critically on hippocampal function. Corticosterone (1.0 or 3.0 mg/kg) administered subcutaneously to male Sprague-Dawley rats immediately after the pairing of saccharin consumption with the visceral malaise-inducing agent lithium chloride (LiCl) dose-dependently increased aversion to the saccharin taste on a 96-h retention test trial. In a second experiment, rats received corticosterone either immediately after saccharin consumption or after the LiCl injection, when both stimuli were separated by a 3-h time interval, to investigate whether corticosterone enhances memory of the gustatory or visceral stimulus presentation. Consistent with the finding that the LiCl injection, but not saccharin consumption, increases endogenous corticosterone levels, corticosterone selectively enhanced CTA memory when administered after the LiCl injection. Suppression of this training-induced release of corticosterone with the synthesis-inhibitor metyrapone (35 mg/kg) impaired CTA memory, and was dose-dependently reversed by post-training supplementation of corticosterone. Moreover, direct post-training infusions of corticosterone into the insular cortex or basolateral complex of the amygdala, two brain regions that are critically involved in the acquisition and consolidation of CTA, also enhanced CTA retention, whereas post-training infusions into the dorsal hippocampus were ineffective. These findings provide evidence that glucocorticoid effects on memory consolidation are not limited to hippocampus-dependent spatial/contextual information, but that these hormones also modulate memory consolidation of discrete-cue associative learning via actions in other brain regions.

Spared retention of inhibitory avoidance learning after posttraining amygdala lesions.

Previous findings indicate that the memory-impairing effects of posttraining amygdala lesions are attenuated by increasing the number of training trials given prior to the induction of the lesion. The aim of this experiment was to determine whether the degree of impairment is also influenced by the footshock intensity used during training. Rats were given 1 trial of inhibitory avoidance (IA) training with either no footshock or a footshock at 1 of 3 intensities. Sham or neurotoxic amygdala lesions were induced 1 week later. On a retention test performed 4 days after surgery, the performance of all amygdala-lesioned rats given footshock training, including those given the lowest training footshock, was better than that of amygdala-lesioned rats given no training footshock. These findings of preserved retention of IA learning in rats given posttraining amygdala lesions do not support a general hypothesis that the amygdala is a locus of permanent changes underlying aversively motivated learning.

Increase of mushroom spine density in CA1 apical dendrites produced by water maze training is prevented by ovariectomy.

Dendritic spine density increases after spatial learning in hippocampal CA1 pyramidal neurons. Gonadal activity also regulates spine density, and abnormally low levels of circulating estrogens are associated with deficits in hippocampus-dependent tasks. To determine if gonadal activity influences behaviorally induced structural changes in CA1, we performed a morphometric analysis on rapid Golgi-stained tissue from ovariectomized (Ovx) and sham-operated (Sham) female rats 7 days after they were given a single water maze (WM) training session (hidden platform procedure) or a swimming session in the tank containing no platform (SC). We evaluated the density of different dendritic spine types (stubby, thin, and mushroom) in three segments (distal, medial, and proximal) of the principal apical dendrite from hippocampal CA1 pyramidal neurons. Performance in the WM task was impaired in Ovx animals compared to Sham controls. Total spine density increased after WM in Sham animals in the proximal and distal CA1 apical dendrite segments but not in the medial. Interestingly, mushroom spine density consistently increased in all CA1 segments after WM. As compared to the Sham group, SC-Ovx rats showed spine pruning in all the segments, but mushroom spine density did not change significantly. In Ovx rats, WM training increased the density of stubby and thin, but not mushroom spines. Thus, ovariectomy alone produces spine pruning, while spatial learning increases spine density in spite of ovariectomy. Finally, the results suggest that mushroom spine production in CA1 after spatial learning requires gonadal activity, whereas this activity is not required for mushroom spine maintenance.

Amygdala or hippocampus inactivation after retrieval induces temporary memory deficit

The hypothesis that memory is stored through a single stage of consolidation that results in a stable and lasting long-term memory has been challenged by the proposition that reactivation of a memory induces reconsolidation of the memory. The reconsolidation hypothesis is supported by evidence that, under some conditions, post-retrieval treatments affecting amygdala and hippocampus functioning impair subsequent retention performance. We now report that repeated retention testing attenuates the performance impairment induced by post-retrieval reversible inactivation of the amygdala and hippocampus of rats induced by tetrodotoxin. These findings challenge the reconsolidation hypothesis and suggest that the post-retrieval retention performance impairment is best explained as due to temporary retrieval failure.

A threshold for the protective effect of over-reinforced passive avoidance against scopolamine-induced amnesia.

Acetylcholine-receptor blockers produce amnesia of aversively motivated behaviors. However, when animals are submitted to relatively high intensities of footshock (over-reinforcement), anticholinergic treatment does not induce memory impairments. The aim of this work was to determine whether the antiamnesic effect produced by increasing the magnitude of the negative reinforcer is gradually established or if a threshold should be reached to obtain such an effect. Wistar rats were trained in passive avoidance using 2.5, 2.6, 2.7, 2.8, 2.9 or 3.0 mA; 5 min after training they were given one systemic injection of scopolamine (8 mg/kg). An amnesic state was produced in the groups that were trained with the lower intensities (2.5-2.7 mA); with the three higher intensities near-perfect retention was evident. These results suggest that acetylcholine is critically involved in memory consolidation, and that by increasing the magnitude of the negative reinforcer, a threshold is reached where cholinergic activity of the nervous system is not necessary for the development of the consolidation process.

Effects of Lesions of Hippocampal Fields CA1 and CA3 on Acquisition of Inhibitory Avoidance

Performance decrements of inhibitory avoidance (IA) induced by lesions in either the dorsal or ventral hippocampus have been interpreted as a deficiency in acquisition. Alternative interpretations are that short-term learning occurs despite the lesions and the long-term performance decrements reflect a failure of consolidation or retrieval. To assess the alternative explanations of the performance decrements, rats received lesions in either CA1 or CA3 fields of dorsal and ventral hippocampus, respectively, 8 days before IA training. Retention was tested at 30 min or 24 h after training. Kainic acid lesions were also produced in either hippocampal field 1 day after training and retention measured 8 days later. The group assessed 30 min after IA training showed little or no performance decrements, whereas the remaining groups did show marked performance decrements. These results do not support the conclusion that the hippocampus is essential for acquisition and support the idea that the hippocampus is highly involved in the consolidation or retrieval of information germane to these procedures.

Enhanced inhibitory avoidance training protects against the amnesic effect of p–chloroamphetamine

The contribution of acetylcholine (ACh) to memory processing is well documented, but it has been proposed that it is not necessary for memory consolidation after an enhanced learning experience. It has been suggested that serotonin (5-HT) interacts with ACh during memory consolidation, although the nature of this interaction is unknown in the case of strong learning. As an initial approach to the study of these interactions, we determined whether training of inhibitory avoidance using relatively high aversive stimulation protects against the typical retention deficits produced by pre-training administration of the 5-HT releaser p-chloroamphetamine (PCA). Rats were trained after intraperitoneal administration of PCA or isotonic saline, using 2.0, 2.5, 3.0 or 3.5 mA and retention of the task was measured 24 h later. A significant amnesic state was observed only in the PCA groups that had been trained with the two lower intensities. These results indicate that 5-HT systems behave similarly to ACh systems, in the sense that the amnesic effect produced by interference with their physiological activity may be cancelled when animals are submitted to an intense learning situation.

Dose- and time-dependent scopolamine-induced recovery of an inhibitory avoidance response after its extinction in rats.

The present investigation was aimed at elucidating the dose and time dependency of scopolamine-induced recovery of inhibitory avoidance after its extinction. Two experiments were conducted: in the first, we analyzed the effects of four doses (1, 2, 4, and 8 mg/kg) of the musacrinic receptor antagonist scopolamine, on the expression of this conditioned response once it had been extinguished. Independent groups of rats were trained in a one-trial, step-through inhibitory avoidance task and submitted to daily retention (extinction) tests. After extinction had occurred, animals were injected intraperitoneally 10 min before retention testing, either with saline or scopolamine. Results show that scopolamine produced a dose-dependent recovery of the avoidance response. The second experiment was carried out in the same animals, which were now tested for retention of inhibitory avoidance at 1, 2, 3, 6, and 9 months after completion of the first experiment. All rats received counterbalanced injections of saline or scopolamine 10 min before testing at each time interval. Reliable recovery of the avoidance response was observed at the 1-month interval with a clear dose dependency while, after the second month, only the groups treated with the two higher doses continued responding. The results indicate that recovery of the extinguished response produced by muscarinic blockade follows dose- and time-dependent curves, and can be achieved long after a single training session. These data suggest that the inhibitory avoidance memory trace is retained in the brain after behavioural extinction of this response, thus supporting the view of extinction as new learning that affects the retrieval of the original memory, but does not modify its storage.