Facilitation of a Distributed Shuttle-Box Conditioning with Posttraining Intracranial Self-Stimulation in Old Rats

Old Wistar rats (16–17 months) were trained in a two-way active avoidance task for 5 consecutive days (10 trials/day). Immediately after each training session a lateral hypothalamic intracranial self-stimulation session (ICSS group) or a sham-treatment session (Control group) was given to the animals. Long-term retention was tested 7 days after the last acquisition session. ICSS treatment led to a significant improvement in acquisition. In the long-term retention session the level of avoidance in both groups was similar to that achieved in the last acquisition session, although differences among groups failed to reach statistical significance. These results are compared with those obtained in previous experiments with young adult rats. While ICSS facilitated the process of acquisition in both young and old rats (however, it was much more powerful in young animals), further experiments are needed to elucidate whether this effect is long-lasting in old rats, as occurs in young adult subjects.     

Calcium channel antagonists enhance retention of passive avoidance and maze learning in mice

Although a number of studies have shown that treatment with calcium channel antagonists (CCAs) can ameliorate impairments in learning and memory in aged animals, evidence for a general nootropic effect of CCAs in neurologically normal young adult animals is ambiguous. This study attempts to resolve some of this ambiguity by comparing the effects of several CCAs on retention of passive avoidance learning and acquisition and retention of appetitively motivated spatial discrimination learning in young adult mice. Animals were trained in a step through passive avoidance apparatus and, immediately after training, injected subcutaneously with different doses of nimodipine, nifedipine, amlodipine, flunarazine, diltiazem, or verapamil. Retention was tested 24 h after training. In the maze-learning task mice were treated with the same doses of the aforementioned CCAs immediately after a brief training session in a linear maze and retention was tested 24 h after training. The most effective dose of each agent in the maze-retention experiment was administered to additional groups of animals 1 h prior to training to determine the effects of CCAs on acquisition processes. The effects of central administration of CCAs were examined by intracerebroventricular injection of different doses of amlodipine immediately after passive avoidance training. Results showed (1) all peripherally administered drugs except verapamil facilitated retention of passive avoidance training in a dose-dependent manner, (2) all drugs dose dependently facilitated retention of linear maze learning, (3) all doses of the drugs (except verapamil) which facilitated maze retention also facilitated maze learning, and (4) central administration of the dihydropyridine amlodipine produced a dose-dependent facilitation of the retention of passive avoidance learning. These data indicate that drugs which block calcium channels can enhance retention of two different types of learning in mice.     

The influence of aging on poststroke depression using a rat model via middle cerebral artery occlusion

Poststroke depression (PSD) is the most frequent psychological sequela following stroke. While previous studies describe the impact of age on brain infarct volume, brain edema, and blood–brain barrier (BBB) breakdown following ischemia, the role of age on PSD has yet to be described. Here, we examine the influence of age on PSD progression in a rat model of PSD by middle cerebral artery occlusion (MCAO). One hundred forty-three rats were divided into three groups. 48 rats 20 weeks of age underwent a sham procedure, 51 rats 20 weeks of age had MCAO, and 44 rats 22–26 months of age had MCAO. Groups were further divided into two subgroups. The first subgroup was used to measure infarct lesion volume, brain edema, and BBB breakdown at 24 h. In the second subgroup at 3 weeks after MCAO, rats were subjected to a sucrose preference test, two-way shuttle avoidance task, forced swimming test, and a brain-derived neurotrophic factor (BDNF) protein level measurement. Total and striatal infarct volume, brain edema, and BBB breakdown in the striatum were increased in older rats, as compared with younger rats. While both old and young rats exhibited depressive-like behaviors on each of the behavioral tests and lower BDNF levels post-MCAO, as compared with control rats, there were no differences between old and young rats. Although older rats suffered from larger infarct volumes, increased brain edema and more BBB disruption following MCAO, the lack of behavioral differences between young and old rats suggests that there was no effect of rat age on the incidence of PSD.     

Differential effects of forward or simultaneous conditioned stimulus-unconditioned stimulus intervals on the defensive behavior system of the Norway rat (Rattus norvegicus)

To test several predictions derived from a behavior-systems approach, the authors assessed Pavlovian fear conditioning in rats after 30 trials of forward, simultaneous, or unpaired training. Direct evidence of conditioned fear was collected through observation of flight and freezing reactions during presentations of the conditioned stimulus (CS) alone. The authors also tested the CS's potential to reinforce an instrumental escape response in an escape-from-fear paradigm. On the one hand, rats that received forward training showed conditioned freezing, but no conditioned flight was observed. On the other hand, rats that received simultaneous training showed conditioned flight, but no conditioned freezing was observed. Rats that received either forward or simultaneous pairings showed instrumental learning of the escape-from-fear response. Implications for several theories of Pavlovian conditioning are discussed.     

Long-term consequences of early experience on adult avoidance learning in female rats: role of the dopaminergic system

Following our hypothesis that juvenile emotional and/or cognitive experience should affect learning performance at preweaning age as well as adulthood, the present study in female Wistar rats aimed to examine the impact of (i) avoidance training at preweaning age, (ii) exposure to repeated maternal separation, (iii) the combination of both, and (iv) the blockade of dopaminergic neurotransmission on adult two-way active avoidance learning in rats. We found that preweaning, i.e. three week old, rats were less capable of avoidance learning compared to adults. Our main findings revealed that preweaning avoidance training alone improved avoidance learning in adulthood. Furthermore, maternal separation alone also improved avoidance learning in preweaning and in adult rats, but this effect of maternal separation did not add up to the beneficial effect of preweaning avoidance training on adult learning. In addition, the pharmacological blockade of dopamine receptors during preweaning avoidance training via systemic application of haloperidol impaired preweaning avoidance performance in a dose-dependent manner. Testing the haloperidol-treated preweaning presumed "non-learners" as adults revealed that they still showed improved learning as adults. Taken together, our results strongly support the hypothesis that emotional as well as cognitive experience at preweaning age leaves an enduring "memory trace," which can facilitate learning in adulthood. Our pharmaco-behavioral studies suggest that unlike the adult brain, preweaning learning and memory formation is less dependent on dopaminergic mechanisms, which raises the intriguing question of possible alternative pathways.     

Opioid mechanisms are involved in the disruption of arcaine-induced amnesia by context pre-exposure

Previous exposure to the training context disrupts glutamatergic N-methyl-d-aspartate receptor (NMDAr) antagonist-induced amnesia, indicating that novelty is necessary for such an amnestic effect. While there are reports that novelty-related release of opioids cause amnesia, no study has addressed whether the amnestic effect of NMDAr antagonists involve opioid mechanisms. In this study we investigated whether pharmacological manipulation of the opioid system immediately after context pre-exposure alters the amnestic effect of arcaine, a NMDAr antagonist. Adult male Wistar rats were habituated (pre-exposed) to a fear conditioning training apparatus or to a different context (open field). Immediately after pre-exposure, animals were injected with saline or naloxone (0.5 mg/kg, i.p.) or anti-beta-endorphin antibody (1:500, i.c.v.). Forty eight hours after pre-exposure session, all animals were subjected to fear conditioning acquisition protocol and saline or arcaine (30 mg/kg, i.p.) was administered immediately after training. Testing was carried out 24 h later, and freezing responses due to re-exposure to the training apparatus were recorded. Pre-exposure to the training apparatus prevented the impairment of memory induced by post-training arcaine. Administration of naloxone or anti-beta-endorphin antibody, immediately after pre-exposure to the training apparatus, reinstated the amnesic effect of post-training arcaine. The results suggest that endogenous opioid mechanisms are involved in the pre-exposure-induced loss of the amnestic effect of arcaine.     

Age-related memory deficits in rats and mice: enhancement with peripheral injections of epinephrine

Epinephrine peripherally administered to rats and mice immediately following avoidance and/or appetitive training enhances later memory retention in both young and old animals. These findings suggest a possible involvement of peripheral adrenergic systems in memory dysfunctions which accompany aging.     

Rapid forgetting of social transmission of food preferences in aged rats: relationship to hippocampal CREB activation

A major characteristic of age-related changes in memory in rodents is an increase in the rate of forgetting of new information, even when tests given soon after training reveal intact memory. Interference with CREB functions similarly results in rapid decay of memory. Using quantitative immunocytochemistry, the present experiment examined the number of CREB- and pCREB-immunoreactive neurons in three regions of the dorsal and ventral hippocampus (dentate gyrus, CA3, and CA1) as a function of age and training. Rats were trained in a social transmission of food preference task. Using different food pairings, memory was tested in each rat immediately and 1, 2, 3, and 7 d later. Both young and old rats had intact and comparable memory scores at the immediate and 24-h tests, but old rats exhibited more rapid forgetting thereafter relative to that of young rats. The main findings were that training resulted in large increases in the number of pCREB-immunoreactive cells throughout the hippocampus in both young and aged rats. However, particularly in the ventral hippocampus, the training-elicited increase in pCREB-positive neurons was significantly lower in old than in young rats. Based on Western blot analyses in a separate set of rats, CREB levels were not responsive to training but were lower in the ventral hippocampus of old rats than of young rats. The present findings suggest that lower activation of CREB after training may contribute to the rapid forgetting seen in aged rats.     

Effects of the selective M1 muscarinic receptor antagonist dicyclomine on emotional memory

The nonselective muscarinic antagonist scopolamine is known to impair the acquisition of some learning tasks such as inhibitory avoidance. There has been recent research into the effects of this drug in contextual fear conditioning and tone fear conditioning paradigms. The purpose of the present study was to assess the role of the selective M1 muscarinic antagonist dicyclomine in these paradigms and in the inhibitory avoidance test. Rats were administered different doses of dicyclomine or saline 30 min before acquisition training. The animals were tested 24 hr later, and it was observed that 16 mg/kg of dicyclomine impaired both contextual fear conditioning and inhibitory avoidance. However, dicyclomine (up to 64 mg/kg) did not affect tone fear conditioning. These results suggest that the selective M1 muscarinic antagonist dicyclomine differentially affects aversively motivated tasks known to be dependent on hippocampal integrity (such as contextual fear conditioning and inhibitory avoidance) but does not affect similar hippocampus-independent tasks.     

Effects of pre- or post-training paradoxical sleep deprivation on two animal models of learning and memory in mice

The aim of the present study was to verify the effects of pre- or post-training paradoxical sleep (PS) deprivation in mice tested in the passive and the plus-maze discriminative avoidance tasks. Three-month-old Swiss male mice were placed in narrow platforms in a water tank for 72 h to prevent the occurrence of PS. Control animals were kept in the same room, but in their home cages. Before or after this period, the animals were submitted to the training session of one of the behavioral tasks. The test sessions were performed 3 and 10 days after the training. The animals that were PS-deprived before the training session showed retention deficits in the test sessions performed 3 days later in both tasks (decreased latency to enter the dark chamber of the passive avoidance apparatus or increased percent time spent in the aversive arm of the plus-maze discriminative avoidance apparatus). Animals that were PS deprived after the training session showed no differences from control animals in the test sessions performed 3 days after the training in any of the tasks, but showed passive and discriminative avoidance retention deficits in the test performed 10 days after the training. The results suggest that both pre- and post-training paradoxical sleep deprivation produce memory deficits in mice. However, these effects have different temporal characteristics.     

Effects of green tea extract on learning, memory, behavior and acetylcholinesterase activity in young and old male rats

Objective

To study the effects of green tea extract administration on age-related cognition in young and old male Wistar rats.

Methods

Young and old rats were orally administered 0.5% green tea extract for a period of eight weeks and were evaluated by passive avoidance, elevated maze plus paradigm and changes in acetylcholinesterase activity.

Results

Treatment of young and old rats with the extract resulted in no significant difference in performance on the rota rod treadmill test/righting reflex time. Green tea extract significantly improved learning and memory in older rats, with increased retention latency to enter difference in passive avoidance test. In the elevated maze test, green tea treatment resulted in significantly more number of entries in the enclosed arm by the young and old rats. Decline in acetylcholinesterase activity was observed in the cerebrum of green tea treated old rats in comparison to the green tea treated young rats.

Conclusion

Green tea extract administration is effective in enhancing learning and memory in aged rats, and hence, may serve useful in reversing age-related deficits.     

Fear of the warning signal during overtraining of avoidance

The present experiment assessed the Pavlovian properties of a tone used as a warning signal in discrete-trial avoidance training of rats by measuring its ability to block conditioning to a light when the tone-light compound signalled shock in a conditioned suppression procedure. The results, although based on a different measure of Pavlovian conditioning, confirmed those reported by Starr and Mineka (1977). After moderate levels of avoidance training, the tone blocked conditioning to the light; but after extended avoidance training it no longer did so, even though a yoked group exposed to the same Pavlovian relation between tone and shock showed no such decline.     

Spatial memory and visual evoked potentials in young and old rats after housing in an enriched environment

The effects of aging and of housing in an enriched environment on performance in an 8-arm radial maze were evaluated in young adult (7-8 months) and old (30-33 months) male Brown-Norway rats, using a procedure in which the rats were confined for 8 s to the central platform of the maze between consecutive choices. Although the old rats attained a level of performance which was clearly above change, they were shown to perform worse than the young rats. No performance differences were found between differentially housed rats of the same age group. In a second experiment recovery cycles of visual evoked potentials were determined in the same rats by using paired flashes with an interstimulus time of 400, 300, 200, or 100 ms. Recovery was consistently smaller in the old rats as compared to the young ones. No correlation could be demonstrated, however, between radial maze performance or housing condition and recovery functions of the visual evoked potentials. This finding indicates that a decline in visual sensitivity cannot readily explain the impaired radial maze performance of old rats. Evidence which suggests that age-related hippocampal changes play a major role in the radial maze performance deficit is discussed.     

Lever attacking and pressing as a function of conditioning and extinguishing a lever-press avoidance response in rats

Six experimental rats were conditioned to press one of two available levers to avoid shock. The levers registered bites as well as presses. For four of these rats, shock was contingent on lever bites when a specified time period had elapsed after the previous shock. An extinction period, in which only periodic noncontingent shocks were presented, followed avoidance training. Six yoked-control rats received the same sequence of shocks as did the corresponding experimental rats in both the conditioning and extinction phases. All six experimental rats repeatedly bit the avoidance lever. Four bit it more than the nonavoidance lever during conditioning, and five bit it more during extinction. Five of the six experimental rats consistently bit the levers many more times during each session than did their respective control rats, suggesting that avoidance conditioning facilitated lever biting. Rates of lever biting and pressing by all of the experimental rats and by some of the control rats were highest immediately following shock throughout both phases. During later portions of the intervals following shock, characteristic effects of conditioning and extinction were observed. This finding suggests that extinction of avoidance behavior by unavoidable shock presentations can be demonstrated more readily when shock-elicited responding is extricated from the data.     

Retention of massed vs distributed response-prevention treatments in rats and a revised training procedure.

Two experiments were conducted to estimate the retention of response-prevention effects using massed vs distributed treatments in a model of animal avoidance-learning. In Exp. I, 120 rats were trained to avoid shock in a one-way platform avoidance apparatus. Groups received response-prevention treatment or nontreatment in a 36-min. massed session or in several sessions distributed over a four-day period. In Exp. II, 160 rats were given two trials of escape training in a one-way shuttle box. Groups received response-prevention treatment or nontreatment in a 24-min. session of massed or distributed treatments delivered in one day. Subjects in both studies were tested using a passive-avoidance paradigm immediately following treatment, 24 hours later, and 30 days later. Analysis showed that response-prevention treatments were effective in reducing avoidance behavior and there were no significant differences in retention of avoidance associated with massed vs distributed response-prevention treatments. Implications for animals and humans are discussed, and researchers are encouraged to change from a criterion training procedure to an escape procedure since the latter is a closer analogue to the human condition.     

Glucocorticoid-induced impairment of long-term memory retrieval in rats: an interaction with dopamine D2 receptors

This study investigated glucocorticoid-dopaminergic interactions in modulating retrieval of long-term memory in an inhibitory avoidance task. Young adult male rats were trained in one trial inhibitory avoidance task (0.5 mA, 3 s footshock). On the retention test given 48 h after training, the latency to re-enter the dark compartment of the apparatus was recorded. Systemically administered corticosterone (1 or 3 mg/kg) given to rats 30 min before retention testing impaired their memory retrieval, but the lower dose was more effective than the higher one. Administration of the dopamine (DA) D2 receptor antagonist sulpiride (6 or 20 mg/kg) 30 min before corticosterone attenuated the impairing effects of corticosterone (1 mg/kg) on memory retrieval. Administration of the DA D1 receptor antagonist SCH23390 (25 or 50 microg/kg) had no effect on corticosterone-induced impairment of memory retrieval. Further, applied doses of sulpiride or SCH23390 alone were ineffective in modulating memory retrieval. These findings provide evidence for the existence of an interaction between glucocorticoids and DA D2 receptor on memory retrieval process.     

Intracerebroventricular effects of angiotensin II on a step-through passive avoidance task in rats

A wealth of evidence indicates that angiotensin II (Ang II) is involved in learning and memory. However, the precise role of this peptide in these cognitive processes is still controversial, with data indicating either an inhibitory or an enhancing action. The present study was designed to further investigate the effects of intracerebroventricular injections of Ang II (0.5, 1 or 3nmol/5microl) on a step-through passive avoidance task in male adult Wistar rats. When administered pretraining, Ang II did not affect the acquisition of passive avoidance, but markedly improved avoidance performance when given before the retrieval test. The latter effect was observed in retest sessions performed up to 72h after training. Administration of the peptide five minutes after training impaired retention of inhibitory avoidance. Therefore, Ang II may exert opposite effects on passive avoidance memory according to its interference with brain mechanisms leading to the storage or retrieval of this aversively motivated task.     

Effects of opiate antagonists on spatial memory in young and aged rats

The effects of post-training opiate antagonist administration on spatial memory were assessed in young and aged male Long Evans rats. In Experiment I rats were trained to visit each arm of an eight-arm radial maze once in a session to obtain a food reward placed at the end of each arm. During training aged rats required significantly more trials to achieve criterion performance when compared to young mature rats. However, administration of the opiate antagonist naloxone (2.0 mg/kg) immediately after each training trial did not significantly alter the rate of achieving accurate performance in either age group. In Experiment II young and aged rats that were previously trained to a comparable criterion on the radial maze were tested on the same maze apparatus in novel spatial environments. When animals were exposed to novel spatial information, the effects of post-trial opiate antagonists were examined using a within-subjects counter-balanced design. In Experiment IIa naloxone (2 mg/kg) enhanced the performance of both young and aged rats. In Experiment IIB naltrexone (1.0 mg/kg) was found to have a comparable effect of enhancing the performance of both age groups. In addition, in Experiment IIb a significant age-related deficit was found in rats tested in novel spatial environments. These results indicate that opiate antagonists are capable of improving memory for new spatial information in both young and aged rats on a task that is sensitive to behavioral deficits during normal aging.     

Retrieval effects of beta-endorphin and naloxone, and the novelty-induced antinociception in the developing rat

Three experiments were conducted to assess the retrieval effects of a single dose of beta-endorphin and of naloxone, and of the novelty-induced antinociception response in the developing rat. Wistar rats 30, 45, 60, and 90 days old from our breeding stock were used. Animals were trained and tested, with a 24-h interval between sessions, in a two-way active avoidance task (using 20 presentations of a 5-s, 1-kHz tone and a 0.4-mA footshock) or in a step-down inhibitory avoidance task (using a 60-Hz, 0.2-mA footshock). Saline (1.0 ml/kg), beta-endorphin (2.0 microgram/Kg), or naloxone (0.8 mg/kg), was administered ip immediately after training, and saline or beta-endorphin was administered 6 min before testing. The retrieval enhancing effects of post-training naloxone and pretest beta-endorphin, and the retrieval impairing effect of post-training beta-endorphin, were consistently observed only in 60- and 90-day-old rats, on both tasks. In a third experiment, another group of naive rats was placed for 2 min in a novel environment (the shuttlebox) and nociception was assessed by the tail-flick method. Novelty-induced antinociception was observed only for 60- and 90-day-old rats, and this response was cancelled by naloxone given 6 min before exposure to novelty. These results suggest that both the retrieval effects of naloxone and beta-endorphin, in the doses used, and the novelty-induced antinociception response, which are possibly dependent on the activity of hypothalamic beta-endorphin system, become established between 45 and 60 days postnatal in the rat.     

Testosterone fails to reverse spatial memory decline in aged rats and impairs retention in young and middle-aged animals

Recently, the vasopressin (AVP) innervation in the rat brain was shown to be restored in senescent rats following long-term testosterone administration. In order to investigate whether this restoration is accompanied by an improvement in learning and memory, both sham- and testosterone-treated young (4.5 months), middle-aged (20 months), and aged (31 months) male Brown-Norway rats were tested in a Morris water maze. All animals learned to localize a cued platform equally well, indicating that the ability to learn this task was not affected by sensory, motoric, or motivational changes with aging or testosterone treatment. There were no significant differences in retention following cue training. Subsequent training with a hidden platform in the opposite quadrant of the pool (place training) revealed impaired spatial learning in middle-aged and aged animals. Retention following place training was significantly impaired in the sham-treated aged rats as compared with sham-treated young rats. Testosterone treatment did not improve spatial learning nor retention of spatial information, but, on the contrary, impaired retention in young and middle-aged animals. The present results confirm earlier reports on an impairment of spatial learning and memory in senescent rats but fail to support a role of decreased plasma testosterone levels and central AVP innervation in this respect.