Enhanced Learning Protects Brain against Effects of Amnesic Treatments

Roberto A. Prado-Alcalá; Rigoberto Salado-Castillo; César Quiroz; María Eugenia Garín-Aguilar; Arnulfo Díaz-Trujillo; Selva Rivas-Arancibia; Gina L. Quírarte

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Bermúdez-Rattoni F, editor. Neural Plasticity and Memory: From Genes to Brain Imaging. Boca Raton (FL): CRC Press/Taylor & Francis; 2007.

Neural Plasticity and Memory: From Genes to Brain Imaging.

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Chapter 9Enhanced Learning Protects Brain against Effects of Amnesic Treatments

Roberto A. Prado-Alcalá, Rigoberto Salado-Castillo, César Quiroz, María Eugenia Garín-Aguilar, Arnulfo Díaz-Trujillo, Selva Rivas-Arancibia, and Gina L. Quírarte.

9.1. INTRODUCTION

9.1.1. Brief History

The beginning of the 20th century coincided with a conceptual advancement that has guided most of the experimental research on the neurobiology of memory: the hypothesis of memory consolidation. Georg Elias Müller and his pupil Alfons Pilzecker published an ample monograph in which they reported 40 experiments carried out between 1892 and 1900, with the aim of identifying laws that govern the establishment and retrieval of memory. They devised the concept of memory consolidation and introduced it into scientific literature. The major conclusions of their work were that memory fixation requires time (consolidation) and that memory is vulnerable during the period of consolidation.¹

The 100 years that followed Müller and Pilzecker’s seminal work witnessed rapid development in the field of the neurobiology of memory.² The first descriptions of cerebral structures necessary for storing learned information were made with the use of physiological and pharmacological tools, coupled to behavioral and neuroanatomic techniques. Thus, it was found that lesions, electric stimulation, and reversible inactivation of a number of brain regions produce significant deficiencies of memory. The use of systemic or direct administration into the cerebral parenchyma of drugs that activate or block the action of neurotransmitter molecules indicated that specific neurotransmitter systems were involved in memory consolidation.^3–6

Evidence that began accumulating decades ago strongly indicates that de novo gene expression is required to establish long-term memory.⁷^,⁸ Recently, molecular and genetic techniques have permitted the identification and characterization of genes and molecules that seem to play key roles in memory consolidation.⁹ For example, numerous experiments strongly suggest that the cyclic AMP-dependent activation pathway, the cAMP response element binding proteins, and a cyclic AMP-dependent cascade of gene expression are necessary for consolidation of simple and complex forms of memory.^10–13

In general, data obtained using the methodologies described above are consistent with one another. In other words, if a lesion of a particular cerebral structure produces a memory deficit, then the same consequence is observed after functional interference with the same structure produced by electric stimulation, pharmacologic blockade of some of its neurotransmission systems, or by other means including inhibition of protein synthesis. On the other hand, local administration of agonists or precursors of the corresponding neurotransmitters brings about improvement of memory processes. In this manner, it was possible to identify specific cerebral structures whose activities are essential for storage of particular types of memory or for storage of several types of memory.

White and McDonald¹⁴^,¹⁵ put forth an interesting proposition about multiple memory systems. In an elegant experimental series in which three versions of the eight-arm radial maze were studied, they demonstrated¹⁴ that damage to the striatum impedes the establishment of procedural memory (habit learning), while lesions of the amygdala or hippocampus did not. On the other hand, amygdalar lesions, but not lesions of the striatum or hippocampus, caused deficiencies of emotional memory. Furthermore, hippocampal lesions interfered with spatial memory, but no interference was produced by lesions of the striatum or amygdala. In other words, they found that particular types of memory are dependent upon normal activity of particular cerebral structures.

A learning task that has been widely used to study the acquisition, consolidation, and retrieval of memory is one-trial inhibitory avoidance. The procedure used in many laboratories involves a box with two compartments (bright and dark) divided by a sliding door. The floor of the dark compartment can be electrified. The subject, usually a small rodent, is placed first in the bright compartment while the sliding door is closed. The door is then opened and if the rodent passes through the door to the dark compartment, the door is closed and the floor is electrified. After a few seconds the door is opened again and the rodent usually escapes to the bright compartment. The retention (memory) test session can be performed shortly after the training session to evaluate short-term memory and 24 hours or more after training to check the integrity of long term-memory. The test session consists of placing the rodent again in the bright compartment and measuring the time it takes the animal to cross to the dark compartment; if an animal does not cross after a predetermined maximum time, the session is ended. High latencies reflect a well established memory, while disruptions in memory are revealed as short latencies to cross to the dark side.

The types of memory studied by McDonald and White¹⁴ are implicated in this task: (1) it has a high emotional component, (2) it is established through spatial cues, and (3) it implies the association between a particular context and a motor response. According to the proposal of McDonald and White, the striatum, amygdala, and hippocampus should be necessary for memory consolidation of this task. Indeed, this is the case.^16–21

Despite the antecedents described above, a series of experimental studies initiated systematically in our laboratory indicate that the prevailing theory of memory consolidation does not apply to memory of relatively strong learning situations, such as those mediated by multiple learning sessions (overtraining) or by relatively high aversive stimulation (over-reinforcement). It should be kept in mind that consolidation theory postulates that memory fixation requires the passage of time (consolidation) and that memory is fragile during the period of consolidation.¹^,²

What follows is an account of data that have led us to an alternative proposal germane to the way memory consolidation occurs in situations of enhanced training. The experiments to be described do not necessarily follow a chronological order. They deal with studies of inhibitory avoidance unless stated otherwise.

9.2. PROTECTIVE EFFECT OF ENHANCED TRAINING

9.2.1. Systemic Treatments

9.2.1.1. Cholinergic System

One neurotransmission system that has received ample attention because of its probable involvement in memory processes is the cholinergic system. Although exceptions²²^,²³ exist, numerous studies demonstrate that systemic or intracerebral administration of acetylcholine antagonists produces significant deficiencies in a great variety of learned behaviors including inhibitory avoidance; likewise, administration of agonists or precursors of memory formation.³^,^24–28

In 1990, Durán-Arévalo, Cruz-Morales, and Prado-Alcalá²⁹ reported that intraperitoneal (i.p.) administration of scopolamine (a muscarinic receptor blocker) immediately after training produced the known amnesic effect when retention was tested 24 hours later. However, when other groups of rats were submitted to stronger learning experiences by increasing the intensity of foot-shock during training, scopolamine did not produce any detrimental effect on memory, as depicted in Figure 9.1.

FIGURE 9.1

Median retention scores obtained 24 hours after training with low or high foot-shock intensities. INT = intact animals. The rest of the groups were injected i.p. with SAL (isotonic saline), M8 (8 mg methylscopolamine — a cholinergic blocker that (more...)

Along these lines, Cruz-Morales et al.³⁰ conducted a study to determine whether the protective effect of enhanced learning against the amnesic effect of scopolamine was a gradual phenomenon or whether a certain intensity threshold had to be reached in order to observe this effect. Independent groups of rats were trained with increasing intensities of foot-shock at 0.1-mA intervals. They found that all intensities produced optimal retention scores in the control groups and a strong amnesic effect, within a range of relatively low intensities, in those treated with scopolamine. A further increment of less than 4% of the intensity that previously produced amnesia completely counteracted the effect of scopolamine. In other words, it seems that within an ample range of intensities, the cholinergic blocker produces amnesia, but when the aversive stimulation is slightly increased beyond a certain value, the cholinergic system is disengaged from the process of memory consolidation.

Later we assessed the effects of posttraining systemic scopolamine on memory with groups of rats trained with very low, medium, or high levels of foot-shock intensities. As expected, scopolamine produced the typical amnesic state in the animals with an intermediate level of training and no effect in animals with high levels of training. Surprisingly, animals with low degrees of training (very low foot-shock intensity) did not show memory deficits.³¹

Taken together, these data indicate that cerebral cholinergic activity is necessary for memory consolidation under conditions of intermediate levels of training, but is not required when very low magnitudes of aversive stimulation (sufficient only to produce some amount of retention) or relatively high levels of the negative reinforcer are administered. Thus, it can be concluded that enhanced learning and weak learning as well protect memory from the amnesia typically produced by anticholinergic agents. One important question was whether this phenomenon can be generalized to other neurochemical systems. As described below, the answer is positive.

9.2.1.2. Serotonergic System

Depletion and blockade of cerebral serotonin and lesions of central serotonergic pathways impede normal learning and memory, while activation of some of the 14 serotonin-receptor subtypes improves these cognitive processes.^32–39

In a first attempt to find out whether enhanced learning counteracts the typical amnesic effects of interference with serotonergic activity, we used p-chloroamphet-amine (PCA). When injected i.p., PCA produces a large depletion of cerebral serotonin associated with lesions of neurons that synthesize and of axons that contain this neurotransmitter. Rats treated with PCA were trained with relatively low or high foot-shock levels. PCA produced amnesia, regardless of the intensity of the aversive stimulation.⁴⁰

Subsequently, Solana-Figueroa et al.⁴¹ administered PCA to independent groups of rats trained with the same intensities of electric shocks as those in the previous study,⁴⁰ but they also included training at still higher intensities. As expected, PCA produced amnesia in the groups that had been trained with the lower intensities. No significant amnesia was found in those trained with the highest intensities, thus confirming the protective effect of enhanced training (Figure 9.2).

FIGURE 9.2

Median retention scores of intact (INT) rats and rats injected i.p. with isotonic saline (SAL) or p-chloramphetamine (PCA) 30 min before training with low, medium or high foot-shock intensity. * = p <0.02. ** = p <0.0005 versus SAL.

In line with the results described above, extended training ameliorated behavioral deficits in active avoidance that were consistently produced by peripheral depletion of noradrenaline.⁴² Moreover, animals that were pretrained with as few as two sessions of active avoidance were significantly less impaired by pimozide than animals that were not pretrained.⁴³

The results described above clearly indicate that enhanced training impedes the amnesic states typically observed as consequences of systemic administration of anticholinergic and antiserotonergic drugs. Nevertheless, these findings do not reveal where in the brain this protective effect occurs. To answer this question, we designed experiments in which drugs were injected into discrete zones of the brains of animals that had previously been subjected to low and high degrees of training.

9.2.2. Intracerebral Treatments

9.2.2.1. Striatum

Haycock et al.⁴⁴ showed that scopolamine infusion into the striatum produced amnesia. This result was confirmed,⁴⁵ but it was also shown that the same treatment produced no changes in memory in animals that received aversive stimulation of relatively high intensities during training (Figure 9.3). A few years later, Díaz del Guante et al.⁴⁶ reported the same protective effect of enhanced training.

FIGURE 9.3

Retention scores of groups of rats microinjected after training into the caudate–putamen with atropine (ATR). UI = unimplanted intact group. Atropine produced amnesia only in the group trained with the lowest foot-shock intensity.

These results strongly suggested that the striatal cholinergic system is not required for the process of memory consolidation or retention of enhanced inhibitory avoidance training, and led to two alternative hypotheses to explain the protective effect: (1) that the participation of the striatum in memory under these conditions depends upon intrinsic neurotransmitter systems other than the cholinergic system, and (2) that the striatum is no longer necessary for consolidation. If the second hypothesis turned out to be correct, the first one would be discarded. Hence, the second hypothesis was tested experimentally.

Groups of rats were trained with relatively low or high foot-shock intensities; immediately after training, they received bilateral infusions of lidocaine, and retention of the task was tested 24 hours later. We expected to find amnesia in the low foot-shock group, and indeed this was the case. On the other hand, the high foot-shock group showed optimal retention (Figure 9.4). These results indicated that under conditions of enhanced training the striatum is not necessary for memory consolidation,⁴⁷ thus supporting the second hypothesis.

FIGURE 9.4

Median retention scores of groups of rats trained with low or high foot-shock intensities. INT = intact rats. The rest of the groups were microinjected with lidocaine into the parietal cortex (L-CX), with isotonic saline into the striatum (SAL) or with (more...)

9.2.2.2. Substantia Nigra

Based on the theoretical importance of the protective effect, we decided to explore the possibility that it might also be found in other cerebral nuclei known to participate in memory. We first selected the substantia nigra because it is directly connected, functionally and anatomically, to the striatum and because it is, without doubt, involved in memory processes.^48–52

One of the main projections of the striatum to the substantia nigra is GABAergic; for this reason Cobos-Zapiaín et al.⁵³ explored the effects of posttraining infusions of bicuculine or picrotoxin (GABA blockers with different modes of action) into the substantia nigra of rats given low or high levels of foot-shock. The results were not surprising: both drugs produced amnesia in the low foot-shock groups, while no significant retention deficits were observed in the high foot-shock groups (Figure 9.5).

FIGURE 9.5

Median retention scores of groups of rats trained with low or high levels of foot-shock and injected with isotonic saline (SAL), 0.25 or 0.5 μg of picrotoxin (P), 0.5 or 1.0 μg of bicuculine (B) into the substantia nigra, or 0.5 μg (more...)

Up to this point, the protective effect of enhanced training against memory deficits had been demonstrated in the nigrostriatal system (striatum and substantia nigra). We then decided to study the possibility that this effect might be generalized to another system. Two neuronal conglomerates of the limbic system play important roles in processing emotional information and in the integration of spatial cues: the amygdala and the hippocampus, respectively.

9.2.2.3. Amygdala

A wealth of experimental data supports the idea that the amygdala contributes to memory formation.¹⁸^,²⁸^,⁵⁴ In an early study, Thatcher and Kimble⁵⁵ found that lesions of the amygdala produced a significant memory deficit of an avoidance task; such deficit was not found when the intensity of training was increased. About three decades later, in an important series of experiments conducted in the laboratory of J.L. McGaugh, Parent et al. demonstrated that lesions or temporary inactivation of the amygdala of rats trained on multiple-trial inhibitory avoidance or with relatively high foot-shock intensities did not show the typical amnesia obtained with lower levels of training.^56–59

Consistent with these results are those of Salado-Castillo et al.⁶⁰ who reported that infusions of lidocaine into the amygdala, striatum, or substantia nigra immediately after training produced marked amnesic states in rats trained with a low intensity foot-shock, but they detected no effect on memory in rats trained with relatively high levels of foot-shock.

9.2.2.4. Hippocampus

The hippocampus is essential for memory consolidation of inhibitory avoidance and other types of tasks.^61–64 In a recent experiment, Martínez et al.⁶³ found that lesions of hippocampal fields CA1 and CA3 produced by microinjections of kainic acid caused the well-known impairment of long-term memory; however, when short-term memory was evaluated in these same animals, it remained intact. To test whether long-term memory could be saved after an enhanced training experience, Quiroz et al.⁶⁵ induced temporary inactivation of the hippocampus, infusing tetrodotoxin immediately after training. The toxin produced amnesia when a foot-shock of low intensity was administered; in contrast, tetrodotoxin was totally ineffective in animals trained with higher foot-shocks (Figure 9.6). Data obtained from the animals submitted to high levels of training before normal activity of the amygdala or hippocampus was disrupted (via lesions or reversible inactivation) indicated that the protective effect of enhanced training also occurs in structures of the limbic system.

FIGURE 9.6

Retention scores of rats trained with low or high intensity of foot-shock and injected with tetrodotoxin (TTX) or vehicle solution (VEH) into the parietal cortex (CX) or dorsal hippocampus (HIPP). * = p <0.05 as compared with the rest of the groups. (more...)

9.3. OVERTRAINING OF POSITIVELY REINFORCED LEARNING

The experiments described to this point are germane to the protection of memory against typical amnesic treatments and have dealt with learning and memory of an inhibitory avoidance task mediated by aversive stimulation. Can this protective effect be seen when learning is mediated by positive reinforcers?

The effects of microinjections of atropine into the caudate nuclei of cats on the retention of a positively reinforced fixed ratio-1 (FR-1) task (lever pressing reinforced with milk) was reported by Prado-Alcalá et al.⁶⁶ A few years later, it was reported for the first time that when this instrumental task was overtrained, cholinergic blockade of the caudate did not interfere with retention of the task.⁶⁷ The same protective effect was found when cholinergic activity of the striatum was blocked in rats overtrained in a spatial alternation task, reinforced with water.⁶⁸

The next logical step was to determine whether, as in the case of inhibitory avoidance, the caudate and striatum as a whole were no longer needed for retention of overtrained tasks. To this end, both cats⁶⁹ and rats⁷⁰ were trained on an FR-1 schedule for a low, medium, or high number of sessions. After training, the memories of the animals were tested under the influence of a high concentration of potassium chloride (KCl, 3 M), infused into the caudate or striatum. The results of both experiments were equivalent: groups trained for fewer sessions showed marked amnesia; those with intermediate degrees of training showed moderate amnesia; overtrained animals showed the same performance as the control animals treated with vehicle solution (Figure 9.7).

FIGURE 9.7

Effects of isotonic saline and 3 M potassium chloride (KCl) injections into the caudate nuclei of cats trained for 15, 30, 45, or 60 sessions on a FR-1 schedule, reinforced with milk. KCl produced amnesia in all groups except the overtrained group trained (more...)

Taken together, the experiments summarized above clearly show that the protective effect of enhanced training occurs regardless of the type of task (inhibitory avoidance, spatial alternation, FR schedule), reinforcer (negative or positive), or animal species (feline or rodent). Importantly, enhanced training protects against the amnesic effects of a number of treatments (lidocaine, tetrodotoxin, potassium chloride, permanent lesions, and drugs that interfere with the synaptic activities of acetylcholine, GABA, and serotonin). This result has been observed with systemic and intracerebral interventions. In the latter case, the effect was found after disrupting normal activities of the caudate, striatum, substantia nigra, amygdala, and hippocampus.

9.4. TWO MODELS

In 1995, two theoretical models were proposed. They involved series and parallel models of memory that aimed for parsimonious interpretations of the data related to the protective effects of enhanced training.⁷¹ These will be briefly explained below.

Numerous examples indicate that interference with normal activity of any of a number of cerebral structures brings about deficiencies in memory consolidation or retention. The point is that a set of cerebral nuclei is essential for the establishment of memory for particular types of tasks, and that if any one of these nuclei does not function normally, the information derived from a learning situation cannot be stored in long-term memory.

We postulated that the members of this set of nuclei were functionally connected in series, that is, the neural activity derived from the learning experience must flow through all of them before reaching a hypothetical integrative “center” whose activation is necessary for consolidating memory. This flow is halted when any component of this ensemble of structures is not functional and thus consolidation is not achieved. The nature of the integrative center is far from known (it may be one particular cerebral structure, a fixed system of structures, or a number of structures involved in a probabilistic fashion).

The second model hypothesizes that in conditions of learning mediated by enhanced training (high levels of positive or negative reinforcers, a high number of trials or training sessions, or some combination of these factors), those structures that were originally connected in series undergo a functional change whereby they become functionally reconnected in parallel (additional structures may become involved in this process). Consequently, even when one or several components of this circuit are damaged or do not function normally, the neural activity produced by the learning experience will be able to continue its trajectory toward the putative integrative center, thus allowing for memory consolidation to occur. Figure 9.8 and Figure 9.9 depict these models.

FIGURE 9.8

Model that represents the way in which, under conditions usually considered to be normal learning, interference with activity of cerebral structures produces amnesia. Information about the learning experience activates afferent sensory systems that convey (more...)

FIGURE 9.9

Model that represents the manner in which enhanced training protects memory against the amnesic effects commonly produced by treatments that interfere with activities of cerebral structures involved in memory processes. Information derived from the learning (more...)

9.5. CONCLUSIONS

The vast majority of experiments dealing with the effects on memory of interference with normal activity of the brain support the century-old theory of memory consolidation because of the consistent finding that administration of a variety of treatments shortly after a learning experience produces amnesia. This detrimental effect diminishes as the interval between learning and treatment increases, until the treatments become ineffective. Evidence has accumulated, however, that does not fit the consolidation theory. Treatments that produce amnesia of learning mediated by positive and negative reinforcers become innocuous when the same learning is overtrained. This effect has been found independently of the amnesic agents used and the mode of their administration.

Based on the kind of data reviewed in this chapter, two models have been proposed to help explain the protective effect of enhanced training against amnesic treatments. More experiments are under way to test the validity of these models. If the new data are consistent with the predictions that can be derived from these models, then it will be possible to think about the brain as having at least two different ways to store learned information, depending on whether it is dealing with normal or enhanced learning.

ACKNOWLEDGMENTS

We thank Dr. Dorothy D. Pless for reviewing the manuscript and M.V.Z. Norma Serafín for technical assistance. Some experiments described in this chapter were financed by PAPIIT-DGAPA-UNAM and by CONACYT.

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Bookshelf ID: NBK3909PMID: 21204428

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