Effects of prior aversive experience upon retrograde amnesia induced by hypothermia.

Two experiments examined the extent to which retrograde amnesia (RA) is attenuated by prior learning experiences. In Experiment 1, rats initially received either passive avoidance training in a step-through apparatus, exposure to the apparatus, or noncontingent footshock. When training on a second but different passive avoidance task was followed by hypothermia treatment, RA was obtained only in the latter two groups. In Experiment 2, one-way active avoidance training, yoked noncontingent shocks, or apparatus exposure constituted the initial experience. Subsequent step-down passive avoidance training and amnestic treatment resulted in memory loss for the prior apparatus exposure group, but not for either of the preshocked conditions. These experiments demonstrate that certain types of prior aversive experience can substantially modify the magnitude of RA, and, in conjunction with other familiarization studies, emphasize a paradox for interpretations of RA based solely upon CNS disruption. The possibility that hypothermia treatment serves as an important contextual or encoding cue necessary for memory retrieval was considered. It was suggested that prior experience may block RA by enabling rats to differentiate training and treatment conditions.     

Intraventricular insulin and leptin reverse place preference conditioned with high-fat diet in rats

The authors hypothesized that insulin and leptin, hormones that convey metabolic and energy balance status to the central nervous system (CNS), decrease the reward value of food, as assessed by conditioned place preference (CPP). CPP to high-fat diet was blocked in ad-lib fed rats given intraventricular insulin or leptin throughout training and test or acutely before the test. Insulin or leptin given only during the training period did not block CPP. Thus, elevated insulin and leptin do not prevent learning a food's reward value, but instead block its retrieval. Food-restricted rats receiving cerebrospinal fluid, insulin, or leptin had comparable CPPs. Results indicate that the CNS roles of insulin and leptin may include processes involving memory and reward.     

Extended retrograde amnesia gradients: Peripheral epinephrine and frontal cortex stimulation

This experiment examined the possibility that hormonal responses to training may increase the susceptibility of memory to an amnestic agent. As long as one week after training, rats that received a subcutaneous epinephrine injection shortly before electrical stimulation of frontal cortex exhibited amnesia on later retention tests. These findings suggest that retrograde amnesia gradients may reflect, in part, maximum susceptibility to amnesia shortly after training because the effects on memory of an amnestic agent are potentiated by the neuroendocrine response to training.     

Role of ACTH in recovery from retrograde amnesia induced by hypothermia in rats

The present investigation assessed whether increased congruency between ACTH state present shortly after training and that at testing contributed to memory recovery. If recovery were related to an increased correspondence between internal state present after training and that at testing, then suppressing ACTH release should block memory recovery. This was the hypothesis that was examined in the present investigation. Specifically, animals were trained on a passive avoidance task, administered hypothermia (the amnestic agent) and, shortly prior to testing, given treatments known to be effective in reversing memory loss induced by hypothermia. Before training (Experiment 1) or testing (Experiment 2) animals were injected with either dexamethasone (an agent that suppresses ACTH release) or saline. Results, in general, indicated that when ACTH release was suppressed, a blunted recovery effect was obtained. This reduction in the extent of memory recovery was observed when ACTH was suppressed either at training or at testing. These data are interpreted as providing support for an ACTH-related, state-dependent retention mechanism contributing to recovery from hypothermia-induced retrograde amnesia in rats.     

Intraseptal infusion of oxotremorine impairs memory in a delayed-non-match-to-sample radial maze task

The medial septal nucleus is part of the forebrain circuitry that supports memory. This nucleus is rich in cholinergic receptors and is a putative target for the development of cholinomimetic cognitive-enhancing drugs. Septal neurons, primarily cholinergic and GABAergic, innervate the entire hippocampal formation and regulate hippocampal formation physiology and emergent function. Direct intraseptal drug infusions can produce amnestic or promnestic effects depending upon the type of drug administered. However, intraseptal infusion of the cholinomimetic oxotremorine has been reported to produce both promnestic and amnestic effects when administered prior to task performance. The present study examined whether post-acquisition intraseptal infusion of oxotremorine would be promnestic or amnestic in a delayed-non-match-to-sample radial maze task. In this task rats must remember information about spatial locations visited during a daily sample session and maintain that information over extended retention intervals (hours) in order to perform accurately on the daily test session. Treatments may then be administered during the retention interval. Alterations in maze performance during the test session an hour or more after treatment evidences effects on memory. In the present study, intraseptal infusion of oxotremorine (1.0-10.0 microg) produced a linear dose-related impairment of memory performance. Importantly, we also observed disrupted performance on the day after treatment. This persistent deficit was related only to memory over the retention interval and did not affect indices of short-term memory (ability to avoid repetitive or proactive errors during both the pre- and post-delay sessions). The persistent deficit contrasts with the acute amnestic effects of other intraseptally administered drugs including the cholinomimetics carbachol and tacrine. Thus, intraseptal oxotremorine produced a preferential disruption of memory consolidation as well as a persistent alteration of medial septal circuits. These findings are discussed with regards to multi-stage models of hippocampal-dependent memory formation and the further development of therapeutic strategies in the treatment of mild cognitive impairment as well as age-related decline and Alzheimer's dementia.     

Interaction between drug discriminative stimuli and exteroceptive, sensory signals

Interactions between drug discriminative stimuli (based on 5.6 mg/kg and 10 mg/kg pentobarbital) and exteroceptive stimuli (visual and auditory) were studied in a T-maze. In three groups, visual stimuli (light vs. dark) were differentially paired with drug stimuli; the fourth group discriminated combinations of tonal frequencies (1 kHz or 10 kHz) and the presence or absence of pentobarbital. (10 mg/kg). In general, visual stimuli controlled choice behavior (left or right turn) to a greater extent than did the drug training stimuli, whereas the auditory stimuli exerted no apparent control over the pentobarbital stimulus in Group 4. Tests with doses higher than the training doses indicated augmented stimulus control by the drug dimension in two groups (Group 1, 10 mg/kg pentobarbital vs. saline; Group 2, 5.6 mg/kg vs. 10 mg/kg pentobarbital) but not in the third group (5.6 mg/kg pentobarbital vs. saline) in the "conflict" situation, that is, the exteroceptive conditions signaled one response whereas the drug stimulus signaled the opposite response. Discrimination training with only one of the stimulus dimensions resulted in stimulus control in the following order: 10 mg/kg vs. saline greater than 5.6 mg/kg vs. saline greater than 1 kHz vs. 10 kHz, results indicating that the auditory stimuli were of marginal significance. In conclusion, drugs can complete with exteroceptive, visual stimuli for associative strength.     

Anterograde amnesia induced by hyperthermia in rats

Anterograde amnesia (AA), forgetting of events that occur following a traumatic episode, has recently been demonstrated by using a mild decrease in temperature (hypothermia) as the amnestic agent. However, no data currently exist to indicate if an increase in body temperature (hyperthermia) might affect memory processing in a similar manner. Experiments 1 and 2 demonstrated that increasing the colonic body temperature of the rat to 3-4 degrees C or more above normal during avoidance training produced a significant retention loss when the test occurred 24 hr after training. Slight hyperthermia to 1-2 degrees C above normal did not impair retention. In Experiment 3, AA resulting from an elevation in temperature was reversed by reheating "amnestic" subjects just prior to the 24-hr test. By rapidly reversing hyperthermia immediately after the training trial with a cooling procedure, Experiment 4 demonstrated that hyperthermia-induced AA was not the result of retrograde influences of the heating treatment. Implications of these results are discussed in terms of possible retention deficits which could conceivably follow environmental heat stress or fever hyperthermia resulting from bacterial infection.     

Intracerebroventricular insulin enhances memory in a passive-avoidance task

Previous studies have indicated a possible enhancing effect of hyperinsulinemia on certain cognitive tasks in human subjects. Further, brain areas important in these tasks have high concentrations of insulin receptors, suggesting that insulin might modulate memory by activity at specific central sites. Extending this observation to the laboratory rat would provide a convenient model system for determining factors important for this possible cognitive effect. The present experiment determined whether intracerebroventricular administration of insulin improves memory formation in rats. Long-Evans rats were trained on a step-through passive-avoidance task, in which they were either shocked or not after entering a darkened compartment. After training, the animals received an intracerebroventricular injection of 4 mU insulin, heat-deactivated insulin or saline vehicle. After 24 h, the animals were tested for retention of the task. Rats receiving insulin after being shocked had an increased latency to enter the dark compartment, compared to those rats that had received saline or heat-deactivated insulin after shock. This difference is consistent with an enhanced memory for the negative consequences of entering.     

A comparison of state dependent learning induced by electroconvulsive shock and pentobarbital

Two experiments compared the efficacy of electroconvulsive shock (ECS) and ECS preceded by footshock (FS-ECS) to produce state dependent learning relative to pentobarbital (12 and 25 mg/kg). In Experiment 1, rats were trained in a water T-maze and retrained 72 hr later. Comparison with controls indicated: (a) FS-ECS administered 24 hr prior to training but not retraining (Agent-O order) produced state dependency but did not when animals were trained in the normal state and received FS-ECS 24 hr prior to retraining (O-Agent order) as in most retrograde amnesia experiments; (b) pentobarbital, 12 or 25 mg/kg, injected just prior to either training or retraining produced state dependency in the O-Agent order but not the Agent-O order; and, (c) ECS alone was not effective in either treatment order. Experiment 2 used reversal training to determine the state dependency effect of the agents. Conclusions were the same as in Experiment 1 except that FS-ECS produced state dependency in both treatment orders. These data indicate that FS and ECS interact to produce a dissociation effect 24 hr later that is as complete as that produced shortly after pentobarbital injections. The results of Experiment 2 but not of Experiment 1 support the notion that amnesia observed 24 hr after a training trial FS followed 0.5 sec later by ECS may be due to a state dependency effect rather than the failure of memory fixation.     

Selective Impairments to Memory Consolidation in Chicks Produced by 5′-Iodo-2′-Deoxyuridine

The aim of the present work was to study the role of DNA synthesis in the formation of different types of memory in neonatal chicks. The nucleotide analogs 5′-iodo-2′-deoxyuridine (IdU) and 5′-bromo-2′-deoxyuridine (BrdU) were used; these are incorporated into DNA, impairing its function, and have amnestic actions in defined models of learning in mice. We studied the effects of 5′-iodo-2′-deoxyuridine of the formation of long-term memory in chicks during training in different models: passive avoidance, imprinting, taste aversion, and spatial learning in a maze. In the taste aversion model, i.p. administration of IdU (10 mg/kg 5 min before or 50 min after training) had an amnestic effect on testing 1–2 days after training. IdU-induced amnesia developed more than 6 h after training, while administration of IdU 2 h after training had no amnestic effect. 5′-Bromo-2′-deoxyuridine also had a similar amnestic action in the taste aversion model. In the passive avoidance, imprinting, and spatial maze learning models, administration of IdU at the same dose before and after training did not induce amnesia. These data lead to the suggestion that DNA synthesis in the brain may play a critical role in the mechanisms of memory consolidation in chicks in types of learning such as taste aversion.     

Glucocorticoids are not responsible for paradoxical sleep deprivation-induced memory impairments

STUDY OBJECTIVES: To evaluate whether paradoxical sleep deprivation-induced memory impairments are due to release of glucocorticoids, by means of corticosterone inhibition with metyrapone. DESIGN: The design was a 2 (Groups [control, paradoxical sleep-deprived]) x 2 (Treatments [vehicle, metyrapone]) study, performed in 2 experiments: Acute treatment (single injection given immediately after 96 hours of sleep deprivation) and chronic treatment (8 injections, twice per day, throughout the sleep-deprivation period). Animals were either paradoxical sleep-deprived or remained in their home cages for 96 hours before training in contextual fear conditioning and received intraperitoneal injections of a corticosterone synthesis inhibitor, metyrapone. Memory performance was tested 24 hours after training. SUBJECTS: Three-month old Wistar male rats. Measurements: Freezing behavior was considered as the conditioning index, and adrenocorticotropic hormone and corticosterone plasma levels were determined from trunk blood of animals sacrificed in different time points. Animals were weighed before and after the paradoxical sleep-deprivation period. RESULTS: Acute metyrapone treatment impaired memory in control animals and did not prevent paradoxical sleep deprivation-induced memory impairment. Likewise, in the chronic treatment, paradoxical sleep-deprived animals did not differ from control rats in their corticosterone or adrenocorticotropic hormone response to training, but still did not learn as well, and did not show any stress responses to the testing. Chronic metyrapone was, however, effective in preventing the weight loss typically observed in paradoxical sleep-deprived animals. CONCLUSIONS: Our results suggest that glucocorticoids do not mediate memory impairments but might be responsible for the weight loss induced by paradoxical sleep deprivation.     

Alleviation of infantile amnesia in rats by means of a pharmacological contextual state

Although a number of studies have demonstrated that the relatively rapid rate of forgetting in young rats (i.e., infantile amnesia) can be alleviated by various reminder treatments, the possibility of enhancing retention by other procedures seems largely unexplored. Given the putative importance of contextual cues as sources of memory retrieval, this experiment examined whether the presence of a distinctive pharmacological state at training and testing could override infantile amnesia. Weanling rats were given pentobarbital or saline prior to Pavlovian fear-conditioning. When tested 1 week later, subjects in the same-state drug condition showed better retention than the same-state saline group. This finding extends previous work on memory recovery in young animals by demonstrating alleviation of infantile amnesia without a re-exposure to the CS or UCS during the retention interval.     

Influence of the neuropeptide galanin on active avoidance in rats

It was demonstrated in experiments on rats that the injection of the neuropeptide, galanin (200, 500, and 1000 ng), into the lateral cerebral ventricles induced a dose-dependant decrease in the number of successful attempts at avoidance in rats trained preliminarily to active avoidance by jumping. The preliminary administration of the cholinolytic, atropine (1 mg/kg, intraperitoneally), to the rats also caused an acceleration of the damping of the conditioned reflex and potentiated the indicated effect of galanin during the experiment. The use of the opioid antagonist, naloxone (1 mg/kg, intraperitoneally), did not exert an influence on the animals' behavior, but blocked the galanin-provoked acceleration of the extinction of the active avoidance habit. The intraperitoneal administration of a noncompetitive antagonist of excitatory amino acids, ketamine (10 mg/kg), did not influence the character of the animals' behavior nor the indicated effects of galanin. It was concluded that galanin possesses an amnestic action in the active avoidance test, and that this effect of the peptide is determined by the suppression of cholinergic and activation of opiatergic transmission in the central nervous system.     

Postconditioning recovery from the latent inhibition effect in conditioned taste aversion

Two experiments were conducted examining the effects of flavor (CS) preexposure on the retention of conditioned taste aversion. In Experiment 1, rats received preexposure to sucrose solution followed by a sucrose-illness pairing. The expected “latent inhibition” effect was obtained when testing occurred after a two-day but not an eleven-day training-to-test interval. Experiment 2 extended these results by employing five- and twenty-one-day training-to-test interval parameters and provided evidence that the stronger taste aversion displayed by preexposed subjects following long retention intervals is not attributable to differences in training consumption of sucrose solution. This posttraining increase in conditioned taste aversion (CTA) suggests that preexposure blocks expression of memory.     

Chemosensory and hormonal mediation of social memory in male rats

The persistence with which adult male rats investigated a juvenile conspecific was significantly reduced following preexposure to either the juvenile or chemosensory stimuli (soiled bedding or urine) from that juvenile. The reduced persistence did not occur when the chemosensory stimulus came from a juvenile different from the one with which the subject was subsequently tested, which suggests the presence of a chemosensorily mediated social memory. It is suggested that any such memory may have adaptive value in that it permits a male rat to more readily identify a novel conspecific. Also, the lack of reduced persistence of social investigatory behavior in castrated subjects demonstrates the importance of male gonadal hormones in the formation, storage, and/or retrieval of the proposed chemosensorily mediated social memory.     

Effects of combined acetylcholinesterase inhibition and serotonergic receptor blockade on age-associated memory impairments in rats

We recently reported that post-training administration of serotonergic receptor antagonists attenuated the inhibitory-avoidance memory deficits normally exhibited by aged rats. In the present study, we determined whether a subeffective dose of the serotonergic type-2 receptor antagonist, ketanserin, would augment the facilitative effects produced by the acetylcholinesterase inhibitor, physostigmine, on memory in aged rats using the same task. The drugs were injected intraperitoneally alone, or in combination, immediately following training. Retention testing occurred 24 hours following training. A dose-dependent enhancement of memory was demonstrated as a result of the two treatment conditions (physostigmine 0.01–10.0 μ/kg, ketanserin 1.0 mg/kg + physostigmine 0.001–0.01 μ/kg). The facilitation of memory produced by the combined treatment was observed at doses well below those required to produce a similar effect when each drug was administered alone. The results provide additional evidence for an interaction between the cholinergic and serotonergic neurotransmitter systems in learning and memory, and may have important implications in the treatment of age-related memory impairments.     

Modulation of the satiating effect of amylin by central ghrelin, leptin and insulin

Amylin is a pancreatic hormone that is considered to be a satiating signal acting on neurons of the area postrema (AP) in the hindbrain. The adiposity signals leptin and insulin act in the hypothalamus to influence feeding. They also enhance the hindbrain's responsivity to satiating signals, e.g. cholecystokinin (CCK). The orexigenic hormone ghrelin is thought to use the same hypothalamic pathways as leptin and insulin, with opposite actions on feeding behaviour. In fact, CCK and ghrelin also seem to interact in the control of feeding. Because CCK's anorectic effect depends on endogenous amylin, the aim of this study was therefore to evaluate a possible functional interaction between amylin and these hormones on short-term food intake in rats. The experiments were performed with male Wistar rats. Intracerebroventricular injection (i3vt) of an orexigenic dose of ghrelin (5 ng/5 microl) reduced but did not completely reverse the intraperitoneal amylin (5 microg/kg)-induced inhibition of food intake. In comparison, administration of a sub-threshold dose of ghrelin (3 ng/5 microl) did not affect the anorexigenic action of peripheral amylin. Leptin administered into the third ventricle (i3vt; 3.5 microg/5 microl) and intraperitoneal amylin (5 microg/kg) synergistically reduced food intake in chow-fed rats. I3vt insulin, administered at a sub-threshold dose (0.5 mU/5 microl), significantly enhanced the response to peripheral amylin. These results indicate that the lipostatic signals leptin and insulin may synergize with amylin to reduce food intake. In contrast, under the conditions tested, the orexigenic hormone ghrelin does not seem to influence the feeding response to peripheral amylin.     

Pretest administration of glucose attenuates infantile amnesia for passive avoidance conditioning in rats

Infantile amnesia in rats may be attenuated by a wide variety of retrieval cues which reactivate memory for the training episode. The present study investigated the effects of glucose on memory retrieval in infant rats. In Experiment 1, 17-day-old preweanling rats were trained to criterion on passive avoidance conditioning. Twenty-four hours later, each subject received a subcutaneous injection of either saline, 100 mg/kg, or 250 mg/kg of glucose just prior to testing. Saline animals displayed poor retention scores, suggesting infantile amnesia; however, glucose significantly attenuated the 24-hr retention loss. Experiment 2 attempted to replicate the previous experiment, control for age and general drug effects, and extend the dose of glucose to 400 mg/kg. The results of Experiment 2 were consistent with Experiment 1 and also indicated that infant subjects performed significantly worse than adults. Both 100 and 250 mg/kg of glucose significantly attenuated infantile amnesia; however, 400 mg/kg had no effect. These results support a retrieval failure view of infantile amnesia and extend the memory-influencing properties of glucose to infants. Context and neuroendocrine views of memory retrieval are discussed. © 1997 John Wiley & Sons, Inc. Dev Psychobiol 31: 207–216, 1997     

Post-training N-methyl-D-aspartate receptor blockade offers protection from retrograde interference but does not affect consolidation of weak or strong memory traces in the water maze

Memory consolidation is the process where labile memory traces become long-lasting, stable memories. Previous work has demonstrated that spatial memory consolidation, several days after training in a water maze had ceased, can be disrupted by a temporary intra hippocampal infusion of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate antagonist LY326325 (Riedel et al., 1999). Such reversible pharmacological techniques offer advantages over the permanent lesion studies that had first suggested a role for the hippocampus in memory consolidation. However, to date the role of N-methyl-D-aspartate receptors in such systems level processes remains controversial with evidence for impairments and augmentation of performance. Here we investigate the role of post-training hippocampal N-methyl-D-aspartate receptor blockade in rats and mice on the consolidation of weak and strong memory traces using an Atlantis water maze protocol. A hidden Atlantis platform was employed and rats (experiments 1 and 2) and mice (experiment 3) were required to dwell within 20 cm of the trained location to activate and subsequently reveal the escape platform. In experiments 1 and 3 a strong memory trace was established by training rats or mice for several days in the water maze. In experiment 2 a significantly weaker trace was instituted by reducing the training period. N-methyl-D-aspartate receptor blockade was induced after the last training trial and continued for seven days. Reliable memory for the trained platform location in a retention test 15 days after the last training day demonstrated that N-methyl-D-aspartate receptor blockade did not affect memory consolidation in rats or mice. Our results also show that post-training N-methyl-D-aspartate receptor blockade can lead to better performance in further retention tests conducted after the consolidation and drug administration period. Those data suggest that specific post-training N-methyl-D-aspartate receptor blockade does not impair memory consolidation and it may also offer a memory trace mild protection from retrograde interference.     

Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype

Raising insulin acutely in the periphery and in brain improves verbal memory. Intranasal insulin administration, which raises insulin acutely in the CNS without raising plasma insulin levels, provides an opportunity to determine whether these effects are mediated by central insulin or peripheral processes. Based on prior research with intravenous insulin, we predicted that the treatment response would differ between subjects with (epsilon4+) and without (epsilon4-) the APOE-epsilon4 allele. On separate mornings, 26 memory-impaired subjects (13 with early Alzheimer's disease and 13 with amnestic mild cognitive impairment) and 35 normal controls each underwent three intranasal treatment conditions consisting of saline (placebo) or insulin (20 or 40 IU). Cognition was tested 15 min post-treatment, and blood was acquired at baseline and 45 min after treatment. Intranasal insulin treatment did not change plasma insulin or glucose levels. Insulin treatment facilitated recall on two measures of verbal memory in memory-impaired epsilon4- adults. These effects were stronger for memory-impaired epsilon4- subjects than for memory-impaired epsilon4+ subjects and normal adults. Unexpectedly, memory-impaired epsilon4+ subjects showed poorer recall following insulin administration on one test of memory. These findings suggest that intranasal insulin administration may have therapeutic benefit without the risk of peripheral hypoglycemia and provide further evidence for apolipoprotein E (APOE) related differences in insulin metabolism.