Systemic and local administration of estradiol into the prefrontal cortex or hippocampus differentially alters working memory

The influence of estradiol on learning and memory is dependent on a number of factors. The effects of physiological levels of estradiol on the acquisition of a spatial working memory task mediated by the prefrontal cortex (PFC) and the hippocampus were examined in Experiment 1. Ovariectomized Long-Evans rats received daily injections of estradiol or vehicle were tested on the win-shift version of the radial arm maze. A high dose of estradiol benzoate (5 microg) enhanced acquisition of the task, whereas a low dose of estradiol (0.3 microg) increased the number of errors committed over 17 days of testing. Experiment 2 was conducted to examine site-specific influences of estradiol on spatial working memory in well-trained rats. Saline and estradiol cyclodextrin (0.1 and 0.9 microg) were infused into the prelimbic region of the PFC or dorsal hippocampus 40 min prior to testing on the win-shift task. Infusions of estradiol into both brain areas attenuated saline-infusion disruptions in working memory. Specifically, the higher dose of estradiol facilitated working memory when infused into the PFC, whereas the lower dose of estradiol facilitated performance when infused into the dorsal hippocampus. Moreover, working memory was significantly impaired 24 h after infusions of estradiol into the dorsal hippocampus but not the PFC. These data provide further evidence for the notion that estradiol can dose-dependently alter memory processes and suggest that facilitation or disruptions of working memory by estradiol are site- and time-specific.     

Place learning in scopolamine-treated rats: the roles of distal cues and catecholaminergic mediation

Experiments 1 and 2 tested the hypothesis that cholinergic receptor antagonists impair place learning in a water maze by interfering with the processing of distal, visual cues. Extramaze cues were offered to rats in the form of geometrical patterns arranged on the inner circumference of a curtain surrounding the water maze. In Experiment 1 the animals were offered both the distal cues and proximal cues in the form of pingpong balls in fixed positions on the surface of the water while only distal cues were present in Experiment 2. Animals were injected with either scopolamine (0.5 mg/kg body wt) or saline 20 min prior to the daily place learning sessions. Upon reaching criterion level performance the animals were tested on "rotation" sessions on which the distal cues were displaced. The outcome of such "rotations" demonstrated that-regardless of the presence or absence of proximal cues-scopolamine-treated rats relied at least as much as normal animals on the distal cues. The acquisition phase of both Experiments 1 and 2 demonstrated an almost complete lack of scopolamine-associated impairment in acquisition and performance of the place learning task. In Experiment 3 (when scopolamine was no longer administered) the subjects of Experiment 2 were exposed to a series of pharmacological "challenges" of their place learning performance and eventually to surgical ablation of the anteromedial prefrontal cortex. The outcome of the pharmacological challenges and the postoperative test of task performance demonstrated that the place learning performance of animals which had acquired the task under scopolamine was mediated by a neural substrate dissimilar to the substrate of task performance in normal animals. Rats acquiring the task while deprived of the cholinergic system demonstrated above-normal contributions to task mediation from catecholaminergic-probably dopaminergic-mechanisms and tentative results pointed to a "shift" toward prefrontal task mediation.     

The effect of vibrato on the recognition of masked vowels

Five experiments on the identifiability of synthetic vowels masked by wideband sounds are reported. In each experiment, identification thresholds (signal/masker ratios, in decibels) were measured for two versions of four vowels: a vibrated version, in which FO varied sinusoidally around 100 Hz; and a steady version, in which F0 was fixed at 100 Hz. The first three experiments were performed on naive subjects. Experiment 1 showed that for maskers consisting of bursts of pink noise, vibrato had no effect on thresholds. In Experiment 2, where the maskers were periodic pulse trains with an F0 randomly varied between 120 and 140 Hz from trial to trial, vibrato slightly improved thresholds when the sound pressure level of the maskers was 40 dB, but had no effect for 65-dB maskers. In Experiment 3, vibrated rather than steady pulse trains were used as maskers; when these maskers were at 40 dB, the vibrated versions of the vowels were slightly less identifiable than their steady versions; but, as in Experiment 2, vibrato had no effect when the maskers were at 65 dB. Experiment 4 showed that the unmasking effect of vibrato found in Experiment 2 disappeared in subjects trained in the identification task. Finally, Experiment 5 indicated that in trained listeners, vibrato had no influence on identification performance even when the maskers and the vowels had synchronous onsets and offsets. We conclude that vibrating a vowel masked by a wideband sound can affect its identification threshold, but only for tonal maskers and in untrained listeners. This effect of vibrato should probably be considered as a Gestalt phenomenon originating from central auditory mechanisms.     

Effects of gonadectomy and androgen supplementation on attention in male rats

Androgens are hypothesized to enhance aspects of mnemonic processing. However, it is unclear whether the memory improvement is associated with changes in earlier aspects of information processing, such as attention. The present experiments examined the effects of gonadectomy or supplementation with testosterone or dihydrotestosterone on performance of male rats in a two-lever attention task that required discrimination of visual signals and non-signals. In Experiment 1, Long-Evans rats were trained in the attention task and then underwent gonadectomy or sham-surgery. Postsurgically, animals were tested for 20 sessions in the attention task and then received manipulations designed to increase attentional demands. Gonadectomized and sham-treated animals performed similarly during immediate postsurgical testing and across all manipulations. Finally, the effects of administering the muscarinic receptor antagonist scopolamine (0, 0.1, and 0.2 mg/kg) on attentional performance were assessed for all animals. Scopolamine decreased accuracy of signal detection but did not differentially affect gonadectomized and sham-treated animals. In Experiment 2, a new group of rats (not gonadectomized) was trained to perform the attention task and subsequently administered testosterone (0, 0.1, and 0.5 mg/kg) or dihydrotestosterone (0, 0.1, and 0.5mg/kg) prior to performing the standard version of the attention task and in the presence of a visual distractor. Testosterone (0.5 mg/kg) decreased accuracy on non-signal trials and, at 0.1 mg/kg, decreased latencies to retrieve a reward. Dihydrotestosterone (0.5 mg/kg) decreased accuracy on non-signal trials during visual distractor sessions. The present data do not support the hypothesis that alterations in attention critically mediate androgen-induced changes in mnemonic processing. Supra-physiological androgen levels appear to be capable of impairing attentional processing.     

The involvement of the orbitofrontal cortex in learning under changing task contingencies

Previous investigations examining the rat prefrontal cortex subregions in attentional-set shifting have commonly employed two-choice discriminations. To better understand how varying levels of difficulty influence the contribution of the prefrontal cortex to learning, the present studies examined the effects of orbitofrontal cortex inactivation in a two- or four-choice odor reversal learning test. Long-Evans rats were trained to dig in cups that contained distinct odors. In the two-choice odor discrimination, one odor cup was always associated with a cereal reinforcement in acquisition while the opposite odor cup was associated with a cereal reinforcement in reversal learning. In the four-choice odor discrimination, an additional two cups containing distinct odors were used that were never associated with reinforcement in acquisition or reversal learning. Bilateral infusions of the GABA-A agonist, muscimol (0.5 microg) into the orbitofrontal cortex did not impair acquisition of either the two- or four-choice discrimination task. However, muscimol infusions into the orbitofrontal cortex impaired two- and four-choice reversal learning. In the two-choice odor reversal, muscimol treatment selectively increased perseverative errors. In the four-choice odor reversal, muscimol treatment increased perseverative, regressive, as well as irrelevant errors. These findings suggest that the orbital prefrontal cortex not only enables task switching by supporting the initial inhibition of a previously relevant choice pattern, but under increasing task demands also enables the reliable execution of a new choice pattern and reduction of interference to irrelevant stimuli.     

Effects of preexposure flavor concentration on conditioned aversion and neophobia

In Experiment 1, 128 experimentally naive, water-deprived rats (Rattus norvegicus) received pretraining access to either 0.25 or 1.5% saccharin, distilled water, or 2.0% saline, followed either by a pairing of 0.25 or 1.5% saccharin with an intraperitoneal injection of 0.15 M lithium chloride (LiCl) or by a pairing of distilled water with LiCl. Preexposure to either saccharin concentration reliably reduced conditioned aversion effects to 0.25% saccharin, relative to that for preexposure to distilled water or saline. But only preexposure to 1.5% saccharin reduced aversion effects to that concentration. In Experiment 2, 48 naive, water-deprived rats received preexposure procedures as in Experiment 1. Afterwards, the rats were tested for neophobia to 0.25 or 1.5% saccharin. Neophobia was reliably greater to the 1.5% concentration. However, preexposure to either saccharin concentration obliterated evidence for neophobia to saccharin, relative to that following preexposure to distilled water or saline.     

ERbeta-selective SERMs produce mnemonic-enhancing effects in the inhibitory avoidance and water maze tasks

Estradiol (17beta-E2) can have mnemonic-enhancing effects; however, its mechanisms for these effects are not well-understood. The present studies examined effects of 17beta-E2 and selective estrogen receptor modulators (SERMs) on emotional and spatial memory of female, Long-Evans rats. First, whether or not 17beta-E2 has dose-dependent effects on inhibitory avoidance memory was investigated. Only the highest concentration of 17beta-E2 examined (10 microg), which produces physiological concentrations of E2, was effective at enhancing inhibitory avoidance memory (Experiment 1). Further studies were designed to elucidate whether SERMs may produce mnemonic effects similar to those of 17beta-E2. Compounds utilized were, the ERalpha-selective SERMs, propyl pyrazole triol (PPT) or 17alpha-E2, the ERbeta-specific SERMs, diarylpropionitrile (DPN) or 7,12-dihydrocoumestan (coumestrol), or vehicle (oil). Post-training administration of 10 microg 17beta-E2 or coumestrol enhanced memory in the inhibitory avoidance task compared to vehicle (Experiment 2). Memory in the water maze was enhanced by post-training administration of 17beta-E2, coumestrol, or DPN, compared to vehicle (Experiment 3). Co-administration of 17alpha-E2&DPN enhanced inhibitory avoidance memory similar to that seen following 17beta-E2 or coumestrol (Experiment 4). Administration of E2 2 h post-training was not effective at enhancing memory in the inhibitory avoidance or water maze tasks (Experiment 5). Lordosis of rats was enhanced by 17beta-E2, 17alpha-E2, or PPT, compared to vehicle (Experiment 6). These data suggest that: E2's actions at ERbeta, rather than ERalpha, may enhance spatial memory, E2's actions at ERalpha can facilitate sexual behavior, and that E2's actions involving both ERalpha and ERbeta may be important for emotional memory.     

Working memory theory of hippocampal function needs qualification

To compare the predictive value of "cognitive map" and "working memory" theories of hippocampal function, the performance of rats with dorsal hippocampal lesions was compared to that of control rats in a series of experiments. In Experiment I, experimental rats learned a spatial alternation task with normal ease, but in Experiment II, they were significantly impaired on an elevated 8-arm radial maze. In Experiment III, the performance of the same experimental and control rats was compared on two versions of a 16-arm enclosed radial maze. In the first version, carpet inserts served as cues to mark eight unbaited arms and each of the remaining arms contained one food pellet. While both experimental and control rats successfully avoided the set of cued arms, experimental rats reentered uncued baited arms more frequently than did control rats. In the second version no intramaze cues were provided, but the spatial distribution of baited and unbaited arms remained the same as that used in the first version. In this uncued version, experimental rats both entered unbaited arms and reentered baited arms more frequently than did control rats, i.e., they were impaired in both "reference" and "working" memory. These findings are compatible with the hypothesis that hippocampal lesions result in an impaired capacity to form cognitive maps but they are not compatible with the working memory hypothesis. Furthermore, twelve separate evaluators classed experimental rats as using fewer mapping and more orientation strategies than control rats in the 8-arm maze.     

Noradrenergic receptor blockade of the NTS attenuates the mnemonic effects of epinephrine in an appetitive light-dark discrimination learning task

These experiments examined the contribution of noradrenergic neurons in the nucleus of the solitary tract (NTS) in mediating the memory-facilitating effects of epinephrine. In Experiment 1, saline or 0.05 or 0.1 mg/kg of epinephrine was given intraperitoneally (ip) to rats after the second day of training in a light-dark Y-maze discrimination task. On a 20-trial retention test given 2 and 7 days later, the 0.1 mg/kg epinephrine group made significantly more correct responses than controls and required fewer trials to reach criterion. In Experiment 2, phosphate-buffered saline or the noradrenergic antagonist dl-propranolol (0.3 or 1.0 microg/0.5 microl) was infused into the NTS prior to an ip injection of saline or 0.1 mg/kg of epinephrine. The memory-enhancing effects of epinephrine were attenuated by the infusion of 0.3 microg/0.5 microl of dl-propranolol into the NTS. These findings indicate an involvement of NTS noradrenergic neurons in mediating the effects of peripheral epinephrine on memory storage processes.     

Amygdala and "emotional" modulation of the relative use of multiple memory systems

The basolateral amygdala modulates the cognitive and habit memory processes mediated by the hippocampus and caudate nucleus, respectively. The present experiments used a plus-maze task that can be acquired using either hippocampus-dependent "place" learning or caudate-dependent "response" learning to examine whether peripheral or intra-basolateral amygdala injection of anxiogenic drugs would bias rats towards the use of a particular memory system. In Experiment 1, adult male Long-Evans rats were trained to swim from the same start point to an escape platform located in a consistent goal arm, and received pre-training peripheral injections of the alpha(2)-adrenoceptor antagonists yohimbine (2.5 or 5.0 mg/kg), RS 79948-197 (0.05, 0.1, or 0.2 mg/kg), or vehicle. On a drug-free probe trial from a novel start point administered 24h following acquisition, vehicle treated rats predominantly displayed hippocampus-dependent place learning, whereas rats previously treated with yohimbine (2.5, 5.0 mg/kg) or RS 79948-197 (0.1 mg/kg) predominantly displayed caudate-dependent response learning. In Experiment 2, rats receiving pre-training intra-basolateral amygdala infusions of RS 79948-197 (0.1 microg/0.5 microl) also predominantly displayed response learning on a drug-free probe trial. The findings indicate (1) peripheral injections of anxiogenic drugs can influence the relative use of multiple memory systems in a manner that favors caudate-dependent habit learning over hippocampus-dependent cognitive learning, and (2) intra-basolateral amygdala infusion of anxiogenic drugs is sufficient to produce this modulatory influence of emotional state on the use of multiple memory systems.     

Extinction of appetitive learning is disrupted by cycloheximide and propranolol in the sand maze in rats

The present study investigated whether memory for extinction in an appetitive task (the sand maze) could be attenuated by administration of cycloheximide (protein synthesis inhibitor) or propranolol (β-adrenergic receptor antagonist). Ninety-day-old male Long-Evans rats were trained to retrieve a sweet cereal reinforcer from an open container in the sand maze. One day following this non-spatial training, rats received three extinction trials in which they were placed in the maze with the reinforcer present, but unattainable. Thirty minutes prior to the first extinction trial, rats received an intraperitoneal injection of cycloheximide (1mg/kg), propranolol (25mg/kg), or vehicle (1mg/kg distilled water). Twenty-four hours later, rats were tested in the sand maze with the reinforcer again available. Results from the test trial showed that both cycloheximide and propranolol groups found the reinforcer more quickly than controls. Two weeks later, rats were trained on a spatial version of the sand maze in which they had to search for a buried reinforcer using extramaze cues. Cycloheximide and propranolol groups learned this task significantly faster than the control group, demonstrating the long-lasting effect of cycloheximide and propranolol on the blocking of memory for extinction.     

Inferior olive lesions impair concurrent taste aversion learning in rats.

Taste aversion learning can be established according to two different procedures, concurrent and sequential. For the concurrent task, two different taste stimuli are offered at the same time, one associated with simultaneous intragastric administration of an aversive stimulus and the other associated with physiological saline. This discrimination is learned by sham-lesioned control animals and by animals with lesions in the cerebellar cortex but not by rats lesioned in the inferior olive. At the same time, animals with lesions in the inferior olive and sham-lesioned animals achieve sequential learning when the gustatory stimuli are offered individually during each daily session. The results obtained show that electrolytic lesions in the inferior olive impair acquisition of concurrent learning and are analyzed in terms of an anatomical system consisting of the vagus nerve, inferior olive, and cerebellum, which differentiates between the two modalities of taste aversion learning, concurrent and sequential.     

Complete recovery of olfactory associative learning by activation of 5-HT4 receptors after dentate granule cell damage in rats

Bilateral intradentate injections of 3.0 μg of colchicine induced a substantial loss of granule cells and damage to the overlying pyramidal cell layer in region CA1 in adult male Long-Evans rats. All rats with such lesions showed a significant associative learning deficit in an olfactory discrimination task, while being unimpaired in the procedural component of this task. Injection of a partial selective 5-HT₄ agonist (SL65.0155; 0.01 mg/kg, i.p., vs. saline) before the third of six training sessions enabled complete recovery of associative learning performance in the lesioned rats. Activation of 5-HT₄ receptors by a selective agonist such as SL65.0155 might therefore provide an opportunity to reduce learning and memory deficits associated with temporal lobe damage, and could be useful for the symptomatic treatment of memory dysfunctions related to pathological aging such as Alzheimer’s disease.     

The facilitative effect of positive stimuli on 3-year-olds’ flexible rule use

This study examined the effect of emotional stimuli on 3- to 4-year old children's flexible rule use, as measured by the Dimensional Change Card Sort (DCCS). In Experiment 1, children in two countries (Canada and China) were given 2 versions of the DCCS. The Standard version required children to sort red and blue boats and rabbits first by shape and then by color (or vice versa); the Emotional Faces version required children to sort happy and sad male and female faces first by emotion and then by gender (or vice versa). Children performed significantly better on the Emotional Faces version, and performance on the 2 versions was related. Order in which dimensions were presented had no effect. Experiment 2 examined which aspects of the emotional faces were responsible for the facilitation of children's performance. Performance on the Standard version was compared to performance on three contextual faces versions, in which children were shown happy, sad, or neutral faces and required to sort them by age (child versus adult) and then by gender (or vice versa). Facilitation was only seen in the context of happy faces. Results are consistent with the suggestion that positive stimuli promote cognitive flexibility, perhaps by increasing dopamine levels in prefrontal cortex.     

Common coding in symbolic matching tasks with humans: Training with a common consequence or antecedent

The present experiments explored the importance of training with a common antecedent or consequence for common coding in symbolic matching-to-sample tasks with human subjects using reversal and transfer tests. Experiment 1 assessed common coding following training in many-to-one (MTO) and one-to-many (OTM) symbolic matching-to-sample tasks by comparing learning of partial and total reversals of these contingencies. Experiment 2 assessed common coding in MTO and OTM tasks by comparing performances in transfer tests when the common coding relations in the transfer phase were either consistent or inconsistent with those present during initial training. Evidence for common coding in the MTO and OTM discriminations was obtained in both experiments, although the amount of common coding was greater in the MTO discrimination in Experiment 1. These data are discussed in terms of associative mediational approaches to common coding phenomena. It is suggested that a basic requirement of an associative theory is that common coding should be more likely to occur when the stimuli are trained with a common consequence than when they are trained with a common antecedent, and that this requirement has been at least partly satisfied in the present studies.     

Discrimination of structure: I. Implications for connectionist theories of discrimination learning

In each of 4 experiments animals were given a structural discrimination task that involved visual patterns composed of identical features, but the spatial relations among the features were different for reinforced and nonreinforced trials. In Experiment 1 the stimuli were pairs of colored circles, and pigeons were required to discriminate between patterns that were the mirror image of each other. A related task was given to rats in Experiment 2. Subjects solved these discriminations. For Experiment 3, some pigeons were given a discrimination similar to that used in Experiment 1, which they solved, whereas others received a comparable task but with 3 colored circles present on every trial, which they failed to solve. The findings from Experiment 3 were replicated in Experiment 4 using different patterns. The results are difficult to explain by certain connectionist theories of discrimination learning, unless they are modified to take account of the way in which compound stimuli are structured.     

Challenging the role of implicit processes in probabilistic category learning

Considerable interest in the hypothesis that different cognitive tasks recruit qualitatively distinct processing systems has led to the proposal of separate explicit (declarative) and implicit (procedural) systems. A popular probabilistic category learning task known as the weather prediction task is said to be ideally suited to examine this distinction because its two versions, “observation” and “feedback,” are claimed to recruit the declarative and procedural systems, respectively. In two experiments, we found results that were inconsistent with this interpretation. In Experiment 1, a concurrent memory task had a detrimental effect on the implicit (feedback) version of the task. In Experiment 2, participants displayed comparable and accurate insight into the task and their judgment processes in the feedback and observation versions. These findings have important implications for the study of probabilistic category learning in both normal and patient populations.     

Cycloheximide produces amnesia for extinction and reconsolidation in an appetitive odor discrimination task in rats

A considerable literature has shown deficits in memory resulting from the administration of protein synthesis inhibitors; however, most of the past literature in this field has focused on acquisition of new memory using aversively-motivated tasks. The effect of protein synthesis inhibition on appetitive learning and memory as well as extinction is less clear. The present study employed an appetitive odor discrimination paradigm to examine the effects of acute cycloheximide administration (1 mg/kg) on reconsolidation and extinction.Male, Long-Evans adult rats were trained to discriminate between two odors (i.e., cocoa and cinnamon) and then received extinction trials following an intraperitoneal injection of cycloheximide or vehicle. Twenty-four hours later, rats were tested via one non-reinforced test trial. Results showed amnesia for extinction as well as original training (i.e., correct odor choice) in cycloheximide-injected rats in this appetitive task, while vehicle-injected controls showed good memory for extinction. These data add to a growing literature showing the importance of protein synthesis inhibition for extinction and reconsolidation in appetitive learning and memory.     

Age and Skill Differences in the Processing Demands of Visual Inspection

Two experiments investigated the effects of age and domain-specific experience on the speed and accuracy of visual inspection performance. In Experiment 1, young (M age = 26.5 years) and middle-aged (M age = 45.7 years) medical laboratory technologists (MTs) and matched novices were tested on a domain-specific version and on a domain-general version of a probe recognition task. Middle-aged subjects were slower than younger subjects on both versions, and MTs were more accurate but slower than controls on the domain-specific task. In Experiment 2, MTs and controls were tested on the same tasks under single-task and dual-task conditions. Middle-aged adults were slower and less accurate than young adults under dual-task conditions in the general version. For the domain-specific version, the response times and error data suggested that skilled performance is less demanding of age-limited general-purpose processing resources.