Neonatal administrations of a vasopressin analog (DDAVP) and hypertonic saline enhance learning behavior in rats

Groups of newborn Wistar rats received daily 1-desamino-8-D-arginine-vasopressin (DDAVP), oxytocin (OXT), hypertonic saline or normal saline for 14 days from day 1 to day 14 of life. One or three months later they were trained in a maze for brightness discrimination (BD). A group of untreated adult male rats received posttrial DDAVP or normal saline for brightness discrimination. Subsequently all the retentions of BD were tested after one month. We found that the neonatal treatments with both DDAVP and hypertonic saline facilitated acquisition and subsequent maintenance of brightness discrimination in immature and mature rats, and also that posttreatment with DDAVP enhanced retention of BD in adult rats. Oxytocin and normal saline had no effect on these parameters. The results are interpreted as showing that endogenous AVP and its synthetic analog enhance the development and adult function of central neural substrates involved in learning behaviors.     

Prenatal administration of arginine vasopressin impairs memory retrieval in adult rats

Eight pregnant female rats were chronically treated via an osmotic pump with arginine vasopressin or placebo during days 13 to 19 gestation. All offspring were tested as adults in either a discrimination task or a 25 day retention of a passive avoidance response. The results revealed that rats whose mother had been treated with vasopressin did not differ from controls on the acquisition or reversal of a brightness discrimination; however, they did require more trials to reach criterion during the ten day memory test of discrimination reversal. Further, treatment resulted in impaired memory retrieval in male rats on the 25 day memory test, while female rats were not affected. Treatment did not influence body weight. The results indicated that vasopressin administered during the prenatal period of development may have had a teratogenic effect on memory retrieval.     

Influence of MSH and corticosterone on stimulus control over an operant response

Several previous papers have indicated that MSH/ACTH-like neuropeptides facilitate the reversal of brightness discrimination in a runway task. The present experiment was undertaken to explore the development during both acquisition and reversal of stimulus control over an operant response. Male albino adult rats were treated daily with either 10 micrograms of MSH, 500 micrograms of corticosterone or a placebo in a double blind procedure during the establishment of an on-light control over availability of reinforcement. Having completed this regime the conditions were reversed so that reinforcement was present only when the chamber-light was off. The results indicated that treatment with MSH during acquisition produced a significant decrease in % correct responses compared to animals treated with either the placebo or corticosterone with neither of these latter groups differing from the other. During the reversal phase of training there was a trend for both MSH and corticosterone to lower % correct responses. The discussion focuses on other literature which has shown opposite effects of corticosterone on aversive and appetitively motivated tasks.     

An evaluation of transfer suppression phenomenon at different stages of learning-set formation

Three groups of three rhesus monkeys each trained to varying levels of object discrimination learning-set formation were tested for reversal-learning proficiency. Training consisted in presenting discrimination problems by the usual learning-set procedure; whereas reversal-learning proficiency was tested by presenting the reversal problems along with control problems according to the usual learning-set procedure and also according to the serial learning procedure. No substantial change in negative interproblem transfer effects was observed as a result of learning-set proficiency, as reversed-problem performance remained significantly poorer than control-problem performance at all the levels. Learning of a reversed problem was not found to be in any way related to anS's correct or incorrect response on its first acquisition trial.     

Vasopressin and vasotocin facilitate reversal of a brightness discrimination

Male albino rats received vasopressin, vasotocin, pressinoic acid or placebo and were tested on an aversively motivated brightness discrimination task. Treatment with both vasopressin and vasotocin had no effect on acquisition but facilitated the reversal of the discrimination. Pressinoic acid had an inconsistent effect. The results are interpreted to show that the C terminal of the peptides vasopressin and vasotocin influence potency of these peptides. Furthermore, the results are interpreted as showing that both vasotocin and vasopressin influence selective attention during aversively motivated tasks.     

Effect of pyritinol, a cerebral protector, on learning and memory deficits induced by prenatal undernutrition and environmental impoverishment in young rats

The study was conducted on 64 CF strain albino rats, which were equally distributed into 8 evenly matched groups following a 2 x 2 x 2 factorial design, by varying three independent factors at two levels: nutrition--normal and undernutrition; environment--enrichment and impoverishment, and drug treatment--vehicle and pyritinol (100 mg/kg, ip). Prenatal undernutrition was induced by restricting the mother's food intake. The environmental enrichment/impoverishment and the vehicle/pyritinol treatments were given during the postweaning period of the pups. The rats were subjected to original and subsequent reversal brightness discrimination learning tests in a single unit T-maze at 8-9 weeks of age. Thereafter, the animals were tested for the passive avoidance learning. The results indicate that undernutrition caused significant original discrimination learning deficits whereas environmental deprivation attenuated both the original and reversal learning performance. Environmental impoverishment attenuated the retention of passive avoidance behaviour but undernutrition had no effect on this paradigm. Pyritinol treatment improved the learning and retention performance of normally reared rats and also attenuated the original and reversal learning deficits induced by parental undernutrition and postweaning environmental impoverishment. The results indicate that pyritinol may be useful in learning and memory deficits induced by malnutrition and environmental deprivation.     

Effect of dihydroergotoxine, a cerebral vasodilator, on cognitive deficits induced by prenatal undernutrition and environmental impoverishment in young rats

The study was conducted on 64 Charles Foster strain albino rats, which were equally distributed into 8 evenly matched groups, following a 2 x 2 x 2 factorial design, by varying three independent factors at two levels: nutrition--normal and undernutrition; environment--enrichment and impoverishment, and drug treatment--vehicle and dihydroergotoxine (3 mg/kg, i.p.). Prenatal undernutrition was induced by restricting the mother's food intake. The environmental enrichment/impoverishment and the vehicle/dihydroergotoxine treatments were given during the postweaning period of the pups. The rats were subjected to original and subsequent reversal brightness discrimination learning tests in a single unit T-maze at 8-9 weeks of age. Thereafter, the animals were tested for passive avoidance learning. The results indicate that undernutrition caused significant original and reversal discrimination learning, deficits whereas environmental deprivation attenuated only the original discrimination learning performance. Dihydroergotoxine treatment facilitated the learning performance of rats in both the original and reversal learning tests. Nutritional, environmental and dihydroergotoxine treatments had no effect on the retention of the passive avoidance learning, both at 24 hr and 1 week intervals. Dihydroergotoxine treatment attenuated the learning deficits induced by prenatal undernutrition. The results indicate that dihydroergotoxine is not likely to be useful in cognitive deficits, induced by malnutrition, though it facilitated learning acquisition, since it had no effect on retention.     

Effects of lateral hypothalamic stimulation on acquisition,reversal and extinction of a visual discriminative learning task

The present experiment was carried out to investigate the effects of lateral hypothalamic (LH) stimulation on a negatively reinforced complex learning task including acquisition, reversal and extinction of a visual discrimination in an Y-maze. Male swiss mice were stimulated 45 sec after each training session during 60 sec (group ST). The stimulation intensity administrated in post-session was that which produced a rate of 50 responses by min during intracranial self-stimulation (ICSS) testing carried out prior to the learning experiment. Three control groups were constituted by animals either submitted to ICSS testing but not stimulated after training session (group NST). The post-session stimulated (group I) or non-implanted (group NI). The post-session stimulation improved the learning performance of the animals, but this effect was significant only during reversal learning of the task. ICSS testing carried out before learning, as well as electrode implantation, had no effect by themselves on the acquisition of the visual discrimination task. Moreover, no sign of extinction was observed in any group tested. These results suggest that facilitating effects induced by LH stimulation may depend on the complexity of the task and that cues of the learning situation have to reach a minimum of salience in order for LH stimulation to be effective.     

Characterisation of learning and memory deficits following NMDA receptor antagonism

Summary The effects of the non-competitive NMDA antagonist dizocilpine in tests of cognitive function have been compared with its effects on motor function in rats. Severe motor impairments were observed at doses above 0.1 mg/kg. Dizocilpine (0.075 mg/kg) had no effect on the acquisition of a spatial discrimination task in a Y-maze, but disrupted reversal learning. Both the acquisition and reversal of a visual discrimination task were impaired following dizocilpine (0.075 mg/kg). Dizocilpine (0.04 mg/kg) also disrupted performance of a fivechoice visual reaction time task. It is clear that dizocilpine can impair cognitive function at doses which do not induce pronounced motor dysfunction. The impairment induced by dizocilpine includes a disruption of spatial discrimination learning and a deficit in tasks with sustained attentional demands.     

Arginine vasopressin facilitates reversal learning in albino, but not hooded rats

Male Holtzman albino and Long-Evans hooded rats were administered one microgram of arginine vasopressin (AVP) or a placebo each day after the acquisition trials of a visual white-black discrimination. Animals were then trained in the reversal of the discrimination. Performance was assessed by the number of trials to criterion during acquisition and reversal. Treatment with AVP resulted in significantly fewer trials to criterion during reversal learning in Holtzman albino rats, but did not influence reversal learning in Long-Evans hooded rats. These results provide evidence that AVP may have differential actions on memory processes in different strains of rats.     

Vasopressin analog (DDAVP) facilitates concept learning in human males

The effects of desmopressin acetate (DDAVP) were studied in normal males. Subjects were given 60μg of DDAVP, a placebo, or no treatment and were given several behavioral tests. DDAVP enhanced learning of all problems on a concept shift task but had no effect on visual memory, anxiety, blood pressure or heart rate. It was suggested that DDAVP may influence memory via its actions on attention.     

Sex chromosome complement affects multiple aspects of reversal-learning task performance in mice

Determining the mechanisms by which the sex-chromosome complement (SCC) affects learning, attention, and impulsivity has implications for observed sex differences in prevalence, severity, and prognosis of psychiatric/neurodevelopmental disorders and syndromes associated with sex-chromosome aneuploidy. Here, Four Core Genotypes (FCG) mice were evaluated in order to assess the separable and/or interacting effects of gonads (testes vs. ovaries) and their secretions and/or SCC (XX vs. XY) acting via non-gonadal mechanisms on behavior. We tested FCG mice on a reversal-learning task that enables the quantification of aspects of learning, attention and impulsivity. Across testing phases (involving the initial acquisition of a spatial discrimination and subsequent reversal learning), overall error rate was larger in XY compared with XX mice. Although XX and XY groups did not differ in the total number of trials required in order to reach a preset performance criterion, analyses of reversal error types showed more perseverative errors in XY than XX mice, with no difference in regressive errors. Additionally, prepotent-response latencies during the reversal phase were shorter in XY males, as compared with both XX gonadal males and females of either SCC, and failures to sustain the observing response were more frequent in XY mice than XX mice during the acquisition phase. These results indicate that SCC affects the characteristic pattern of response selection during acquisition and reversal performance without affecting the overall learning rate. More broadly, these results show direct effects of the SCC on cognitive processes that are relevant to psychiatric/neurodevelopmental disorders and syndromes associated with sex-chromosome aneuploidies.     

Galanthamine plus estradiol treatment enhances cognitive performance in aged ovariectomized rats

We hypothesize that beneficial effects of estradiol on cognitive performance diminish with age and time following menopause due to a progressive decline in basal forebrain cholinergic function. This study tested whether galanthamine, a cholinesterase inhibitor used to treat memory impairment associated with Alzheimer's disease, could enhance or restore estradiol effects on cognitive performance in aged rats that had been ovariectomized in middle-age. Rats were ovariectomized at 16–17 months of age. At 21–22 months of age rats began receiving daily injections of galanthamine (5 mg/day) or vehicle. After one week, half of each group also received 17ß-estradiol administered subcutaneously. Rats were then trained on a delayed matching to position (DMP) T-maze task, followed by an operant stimulus discrimination/reversal learning task. Treatment with galanthamine + estradiol significantly enhanced the rate of DMP acquisition and improved short-term delay-dependent spatial memory performance. Treatment with galanthamine or estradiol alone was without significant effect. Effects were task-specific in that galanthamine + estradiol treatment did not significantly improve performance on the stimulus discrimination/reversal learning task. In fact, estradiol was associated with a significant increase in incorrect responses on this task after reversal of the stimulus contingency. In addition, treatments did not significantly affect hippocampal choline acetyltransferase activity or acetylcholine release. This may be an effect of age, or possibly is related to compensatory changes associated with long-term cholinesterase inhibitor treatment. The data suggest that treating with a cholinesterase inhibitor can enhance the effects of estradiol on acquisition of a DMP task by old rats following a long period of hormone deprivation. This could be of particular benefit to older women who have not used hormone therapy for many years and are beginning to show signs of mild cognitive impairment. Potential mechanisms for these effects are discussed.     

Effect of substance P on the retention of a brightness discrimination task in rats

The effect of substance P (SP) on acquisition and retention of a footshock-motivated brightness discrimination was investigated in rats, 250 micrograms SP/kg were injected intraperitoneally either 30 min before or immediately after the training session. Acquisition of the brightness discrimination was not affected by SP administered 30 min before training. However, both the pre-training and post-training injections of SP resulted in a significant improvement of retention tested 24 h after training. The effect of SP on memory consolidation is discussed.     

Galanthamine plus estradiol treatment enhances cognitive performance in aged ovariectomized rats

We hypothesize that beneficial effects of estradiol on cognitive performance diminish with age and time following menopause due to a progressive decline in basal forebrain cholinergic function. This study tested whether galanthamine, a cholinesterase inhibitor used to treat memory impairment associated with Alzheimer's disease, could enhance or restore estradiol effects on cognitive performance in aged rats that had been ovariectomized in middle-age. Rats were ovariectomized at 16–17 months of age. At 21–22 months of age rats began receiving daily injections of galanthamine (5 mg/day) or vehicle. After one week, half of each group also received 17ß-estradiol administered subcutaneously. Rats were then trained on a delayed matching to position (DMP) T-maze task, followed by an operant stimulus discrimination/reversal learning task. Treatment with galanthamine + estradiol significantly enhanced the rate of DMP acquisition and improved short-term delay-dependent spatial memory performance. Treatment with galanthamine or estradiol alone was without significant effect. Effects were task-specific in that galanthamine + estradiol treatment did not significantly improve performance on the stimulus discrimination/reversal learning task. In fact, estradiol was associated with a significant increase in incorrect responses on this task after reversal of the stimulus contingency. In addition, treatments did not significantly affect hippocampal choline acetyltransferase activity or acetylcholine release. This may be an effect of age, or possibly is related to compensatory changes associated with long-term cholinesterase inhibitor treatment. The data suggest that treating with a cholinesterase inhibitor can enhance the effects of estradiol on acquisition of a DMP task by old rats following a long period of hormone deprivation. This could be of particular benefit to older women who have not used hormone therapy for many years and are beginning to show signs of mild cognitive impairment. Potential mechanisms for these effects are discussed.     

Acquisition of an olfactory learning-set in rats with lesions of the mediodorsal thalamic nucleus

Rats with lesions of the mediodorsal thalamic nucleus had goodretention of a preoperatively leamed odor detection task butmade more errors than controls in the acquisition of a seriesof two-odor discrimination problems. While controls showed rapidacquisition of a learning-set, the performance of experimentalrats was highly variable. Deficits in acquisition occurred ondifferent problem for different rats and appeared unrelatedto problem difficulty or serial position of the discrimination.Experimental rats also had a significant deficit in the acquisitionof an odor reversal task. Error scores in both the learing-setand reversal task were related to lesion size. Small lesionsconfined to the rostral third of the nucleus or asymmetricallesions which spared the central (olfactory) division of mediodorsalnucleus on one side were without effect. The results suggestthat the deficit in olfactory learning produced by destructionof the mediodorsal thalamic nucleus is complex and is not adequatelyaccounted for by stimulus novelty, problem difficulty or bypoor interproblem transfer of learning.     

Loss of GluN2A‐containing NMDA receptors impairs extra‐dimensional set‐shifting

Glutamate neurotransmission via the N‐methyl‐d ‐aspartate receptor (NMDAR) is thought to mediate the synaptic plasticity underlying learning and memory formation. There is increasing evidence that deficits in NMDAR function are involved in the pathophysiology of cognitive dysfunction seen in neuropsychiatric disorders and addiction. NMDAR subunits confer different physiological properties to the receptor, interact with distinct intracellular postsynaptic scaffolding and signaling molecules, and are differentially expressed during development. Despite these known differences, the relative contribution of individual subunit composition to synaptic plasticity and learning is not fully elucidated. We have previously shown that constitutive deletion of GluN2A subunit in the mouse impairs discrimination and re‐learning phase of reversal when exemplars are complex picture stimuli, but spares acquisition and extinction of non‐discriminative visually cued instrumental response. To investigate the role of GluN2A containing NMDARs in executive control, we tested GluN2A knockout (GluN2A^KO), heterozygous (GluN2A^HET) and wild‐type (WT) littermates on an attentional set‐shifting task using species‐specific stimulus dimensions. To further explore the nature of deficits in this model, mice were tested on a visual discrimination reversal paradigm using simplified rotational stimuli. GluN2A^KO were not impaired on discrimination or reversal problems when tactile or olfactory stimuli were used, or when visual stimuli were sufficiently easy to discriminate. GluN2A^KO showed a specific and significant impairment in ventromedial prefrontal cortex‐mediated set‐shifting. Together these results support a role for GluN2A containing NMDAR in modulating executive control that can be masked by overlapping deficits in attentional processes during high task demands.     

Performance correlates of social behavior and organization: Social rank and reversal learning in crab-eating macaques (M. fascicularis)

Seventeen male crab-eating macaques drawn from two captive troops, were tested on a brightness discrimination, reversal learning task. Fourteen of these animals completed ten reversals. It was found that the performance of the three highest ranking animals from each troop, taken together, was poorer than that of the lower ranking animals that were tested. The high ranking animals made more errors before reaching criterion on both initial learning and the reversal problems. Analysis of error patterns revealed that, while the high ranking animals had no more difficulty than the others in withholding their responses to the previously correct stimulus following reversals, they did not adopt the correct strategy as soon as the low ranking animals. The results have been interpreted in terms of a carry-over of a hypothetical factor or factors resulting from pressures created by the ongoing social dynamics involved in establishing and maintaining a given social rank at the time laboratory testing occurred. Supported by USAMRDC Contract No. DADA 17-73-C-3007.     

Effects of DDAVP on movement planning and execution processes in the healthy elderly.

Effects of DDAVP on speed and consistency of planning and executing simple and complex movements in healthy older adults were studied. A simple reaction time (SRT) task, a single-plane movement task, and two tasks involving multiplane movements of distal upper extremities were performed with and/or without a 0.6 ml intranasal dose (60 micrograms) of DDAVP or placebo. Results indicated that DDAVP had no significant effect on speed or consistency of SRT processes, or the speed with which simple or complex movements were planned or executed. There was also no effect on retention of motor responses.     

Sleep Deprivation in the Dark Period Does Not Impair Memory in OF1 Mice

There is increasing evidence that sleep facilitates memory acquisition and consolidation. Moreover, the sleep-wake history preceding memory acquisition and retention as well as circadian timing may be important. We showed previously that sleep deprivation (SD) following learning in OF1 mice impaired their performance on an object recognition task. The learning task was scheduled at the end of the 12 h dark period and the test 24 h later. To investigate the influence of the prominent circadian sleep-wake distribution typical for rodents, we now scheduled the learning task at the beginning of the dark period. Wakefulness following immediately after the learning task was attained either by gentle interference (SD; n?=?20) or by spontaneous wheel running (RW; n?=?20). Two control groups were used: one had no RW throughout the experiment (n?=?23), while the other group's wheel was blocked immediately after acquisition (n?=?16), thereby preventing its use until testing. Recognition memory, defined as the difference in exploration of a novel and of familiar objects, was assessed 24 h later during the test phase. Motor activity and RW use were continuously recorded. Remarkably, performance on the object recognition task was not influenced by the protocols; the waking period following acquisition did not impair memory, independent of the method inducing wakefulness (i.e., sleep deprivation or spontaneous running). Thus, all groups explored the novel object significantly longer than the familiar ones during the test phase. Interestingly, neither the amount of rest lost during the SD interventions nor the amount of rest preceding acquisition influenced performance. However, the total amount of rest obtained by the control and SD mice subjected to acquisition at “dark offset” correlated positively (r?=?0.66) with memory at test, while no such relationship occurred in the corresponding groups tested at dark onset. Neither the amount of running nor intermediate rest correlated with performance at test in the RW group. We conclude that interfering with sleep during the dark period does not affect object recognition memory consolidation.