Posttraining intrahippocampal estradiol injections enhance spatial memory in male rats: interaction with cholinergic systems

Male Long-Evans rats received an 8-trial training session in a spatial water maze task, followed by a unilateral posttraining intrahippocampal injection of either estradiol (1.0 microgram/0.5 microliter) or saline. Retention was tested 24 hr later, and latency to escape was used as a measure of memory. Retention test escape latencies of rats given intrahippocampal injections of estradiol were lower than those of saline-treated rats, indicating an enhancement of memory. Intrahippocampal injections of estradiol delayed 2 hr posttraining did not affect retention. In Experiment 2, the memory enhancing effect of intrahippocampal injection of estradiol was blocked by peripheral administration of a subeffective dose (0.1 mg/kg) of the cholinergic antagonist scopolamine. Intrahippocampal injections of estradiol enhance memory in male rats, and estradiol may influence memory through an interaction with muscarinic cholinergic systems.     

Molecular mechanisms of transforming growth factor-beta signaling

The present experiments examined the effects of posttraining intrahippocampal injections of the degradative enzyme-resistant methylcarbamyl analog of the bioactive phospholipid platelet-activating factor (mc-PAF) and the platelet-activating factor (PAF) receptor antagonists BN52021 and BN 50730 on memory in male Long-Evans rats trained in a hidden platform version of the Morris water maze. Following an eight-trial training session, rats received a unilateral intrahippocampal injection of mc-PAF (0.5, 1.0, or 2.0 microgram/0.5 microliter), lyso-PAF (1.0 microgram/0.5 microliter), the cell surface PAF receptor antagonist BN 52021 (0.25, 0.5, or 1.0 micrigram/0.5 microliter/, the intracellular PAF receptor antagonist BN 50730 (2.0, 5.0, or 10.0 microgram/0.5 microliter), or vehicle (50% DMSO in 0.9% saline; 0.5 microliter). On a retention test conducted 24 h after training, the escape latencies of rats administered mc-PAF (1.0 or 2.0 microgram) were significantly lower than those of the vehicle-injected controls, demonstrating a memory-enhancing effect of mc-PAF. Injections of lyso-PAF, a structurally similar metabolite of PAF, had no influence on memory, indicating that the memory-enhancing effect of mc-PAF is not caused by membrane perturbation by the phospholipid. The retention test escape latencies of rats administered BN 52021 (0.5 microgram) and BN 50730 (5.0 or 10 microgram) were significantly higher than those of the controls, indicating a memory impairing effect of both PAF antagonists. When mc-PAF, BN 52021, or BN 50730 was administered 2 h posttraining, no effect on retention was observed, indicating a time-dependent effect of the neuroactive substances on memory storage. The findings suggest a role for endogenous PAF in hippocampal-dependent memory processes.     

Intra-hippocampal estradiol infusion enhances memory in ovariectomized rats

Ovariectomized adult Long-Evans rats received an eight-trial training session in a hippocampal-dependent hidden platform water maze task. Following trial 8, rats received an intra-hippocampal injection of estradiol in a water soluble cyclodextrin inclusion complex (1.0, 2.0 or 5.0 micrograms/0.5 microliter), or saline. Twenty-four hours later, the retention test escape latencies of rats administered post-training intra-hippocampal injections of estradiol (5.0 micrograms) were significantly lower than those of saline treated rats, indicating a memory-enhancing effect of estradiol. Injections of estradiol (5.0 micrograms) given 2 h post-training had no effect on retention, indicating a time-dependent effect of estradiol on memory storage processes.     

Double dissociation of hippocampal and dorsal-striatal memory systems by posttraining intracerebral injections of 2-amino-5-phosphonopentanoic acid.

Rats received an 8-trial training session on a spatial or cued task in a water maze, followed by a posttraining intracerebral injection of AP5 or saline. On a retention test 24 hr later, latency to mount the escape platform was used as a measure of memory. Intrahippocampal (10 μg), but not intra-dorsal striatal (2, 5, or 10 μg), injection of AP5 impaired memory in the spatial task. In contrast, intra dorsal striatal (2 μg), but not intrahippocampal (2, 5, or 10 μg) injection of AP5 impaired memory in the cued task. Intracerebral injections of AP5 delayed 2 hr posttraining were ineffective. The findings indicate a double dissociation of the roles of the hippocampus and dorsal striatum in memory, a role for N -methyl-{d}-aspartate receptor function in posttraining memory processes, and a glutamatergic modulation of both hippocampal and dorsal striatal memory processes, suggesting that different forms of memory may share a similar neurochemical basis. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Long-term memory modulation by posttraining epinephrine in rats: Differential effects depending on the basic learning capacity.

Effects of posttraining epinephrine on retention of a massed (1 session, 30 trials) 2-way active avoidance task were studied in rats. Immediately after the training session rats received an injection of 0.05 or 0.01 mg/kg intraperitoneal/ly (ip) epinephrine, or distilled water. Retention was tested 11, 20 or 45 days after training, in independent groups of rats. The 20- and 45-day retention was improved in poor-learning rats and disrupted in good-learning rats. It was concluded that the effect (facilitatory or disruptive) of posttraining epinephrine on memory consolidation depends on the basic learning capacity of rats for this task and needs a long time to be expressed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pre- and posttraining infusion of N-methyl-D-aspartate receptor antagonists into the amygdala impair memory in an inhibitory avoidance task

Involvement of amygdaloid N-methyl-D-aspartate (NMDA) receptors in memory processes was investigated. Rats with cannulas implanted in the basolateral amygdala were trained on a 1 trial step-through inhibitory avoidance task and tested for 24-hr retention. Pretraining infusion of 2-amino-5-phosphonovaleric acid (APV) into the amygdala, but not striatum or hippocampus, produced a dose-dependent retention deficit, which was attenuated by immediate posttraining intra-amygdala infusion of NMDA. Posttraining APV infusion also caused a dose- and time-dependent retention deficit. Pretest APV infusion had no effect on performance in the retention test. Further, pre- or posttraining infusion of 5.0 micrograms APV failed to affect acquisition and retention in the Morris water maze task. These findings suggest that amygdala NMDA receptors are normally activated by aversive training and play a critical role in memory formation for affective experience.     

Long-term memory facilitation in rats by posttraining epinephrine.

Effects of posttraining epinephrine (EPI) on retention of a massed (1 session, 30 trials) 2-way active avoidance task in rats were studied. The rats received an injection of 0.05 mg/kg EPI, 0.01 mg/kg EPI, or distilled water immediately after the training session. EPI did not improve retention 24 hrs after the training session (Exp 1) but enhanced retention 20 days after the training session (Exp 2). The group receiving the smaller dose of EPI had better retention than the group receiving the larger dose, indicating dose dependency. The authors suggest that the process of consolidation of massed 2-way active avoidance conditioning is long and elaborative. Posttraining EPI would facilitate this active process of consolidation, improving performance as consolidation goes on. This facilitation needs, at least under certain conditions, more than 24 hrs to be expressed as a higher level of performance on the retention test. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Memory retention is modulated by acute estradiol and progesterone replacement.

Ovarian hormones alter spine density of hippocampal granule and pyramidal cells in young adult and aging female rats. (P. Miranda, C. L. Williams, and G. Einstein, 1999; C. S. Woolley, see record 1998-11866-006). The present study used a delay matching-to-place version of the water maze to investigate a behavioral correlate of these hormone-induced changes in hippocampal connectivity in 3- and 8-mo-old female rats. When primed with 10-mg injections of estradiol 72 and 48 hrs before testing, the memory retention of ovariectomized rats was improved compared with retention after priming with oil. A single injection of progesterone maintained the enhancement if testing occurred within 8 hrs of the progesterone injection but not if testing occurred more than 34 hrs after the progesterone injection. These findings indicate that estradiol and progesterone alter memory retention and suggest that these changes may be the result of hormone-induced increased in hippocampal connectivity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Investigations on the role of hippocampal protein kinase C on memory processes: pharmacological approach

We report here investigations on the functional involvement of hippocampal protein kinase C (PKC) in learning and long-term retention of spatial discrimination in a radial maze. A pharmacological approach was employed to test the behavioural effects of intrahippocampal injections of drugs that either activate or inhibit PKC activity. Mice with intrahippocampal guide cannula were trained in a mixed spatial reference-working memory task during 7 daily sessions. Sixteen days later, the animals were submitted to a retention session. In the first experiment, the animals were treated before each learning session with polymyxin B (PMB, a PKC inhibitor) and their scores were compared to those of an appropriate control group. In the second experiment, a group received the injection of 1-oleoyl-2-acetyl glycerol (OAG, a PKC activator) before and after the 7th learning session in order to test the effect of activation of PKC on long-term retention. The results showed that: (1) PMB administration delayed the acquisition of the reference memory component of the task, whereas long-term retention appeared to be improved; and (2) administration of OAG at the end of the acquisition phase improved long-term retention. Neither PMB nor OAG appeared to affect working memory. Taken together, the results point to an involvement of hippocampal PKC in the acquisition of information destined for long-term storage.     

Lack of task specificity and absence of posttraining effects of atropine on learning.

Three experiments, with 91 male Lister rats, examined the effect of the cholinergic antagonist atropine on the acquisition of learning tasks known to be sensitive or insensitive to impairment by hippocampal lesions, on the retention of performance acquired in the absence of the drug, and on memory consolidation immediately after daily training trials. In Exp I, intraperitoneal atropine sulfate (10 or 50 mg/kg) injected 30 min prior to training severely impaired learning of both spatial and nonspatial discrimination tasks when compared with saline or atropine methylnitrate (50 mg/kg). In Exp II, atropine sulfate (50 mg/kg) also impaired spatial discrimination accuracy in Ss previously trained to asymptote under drug-free conditions. These deficits were not due to either peripheral drug effects of gross sensorimotor impairments. In Exp III, daily posttraining injections of atropine sulfate (50 mg/kg) failed to influence either learning or subsequent retention of place navigation in Ss trained to find a single hidden escape platform. The data confirm that profound learning deficits occur when training is conducted under atropine but offer no support to the hypotheses that cholinergic neurons play an important role in memory consolidation or other posttraining processes. Results demonstrate dissimilarities between the behavioral impairments induced by cholinergic blockade and hippocampal lesions under appropriate test regimes. (50 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Posttraining intra-basolateral amygdala scopolamine impairs food- and amphetamine-induced conditioned place preferences.

The present study investigated the role of cholinergic muscarinic receptor function within the basolateral amygdala memory in the consolidation of conditioned place preference (CPP) memory. Adult male Long-Evans rats were confined to treatment- or nontreatment-paired compartments for 30 min on 4 alternating days. After training, rats received intrabasolateral amygdala infusions of scopolamine (2.5 μg or 5.0 μg/0.5 μl) or saline. The rats were then given a 20-min test session, and the time spent in each of the compartments was recorded. Immediate posttraining (but not delayed 2 hr) scopolamine (5.0 μg) blocked acquisition of food- and amphetamine-induced CPPs. The findings indicate a time-dependent role for basolateral amygdala muscarinic receptors in memory consolidation underlying CPPs for natural and drug rewards. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Stria terminalis lesions attenuate the effects of posttraining naloxone and beta-endorphin on retention.

These experiments examined the effect of posttraining administration of naloxone and β-endorphin in rats with lesions of the stria terminalis (ST). Rats with sham or bilateral ST lesions were trained either in an inhibitory avoidance task or in a Y-maze discrimination task and, immediately after training, received an ip injection of saline, naloxone (0.5, 2.0, or 5.0 mg/kg in the avoidance task; 3.0 mg/kg in the Y-maze task), or β-endorphin (10.0 μg/kg). Retention of each task was tested 24 hrs following training. In the Y-maze task, retention was assessed by training on a reversed discrimination. The ST lesions did not affect retention of either task in otherwise untreated animals. However, in both tasks, ST lesions attenuated the memory-enhancing effects of naloxone as well as the memory-impairing effects of β-endorphin. These findings are consistent with other recent evidence suggesting that the amygdala may be involved in posttraining memory modulation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Posttraining paradoxical sleep in rats is increased after spatial learning in the Morris water maze.

The role of posttraining paradoxical sleep (PS) in spatial or nonspatial learning in the Morris water maze was evaluated. Sprague-Dawley rats were given a 12-trial training session in either the hidden or the visible platform versions of the task. Subgroups then underwent paradoxical sleep deprivation (PSD) beginning at different times after training. Rats with PSD imposed from 14 hr after spatial training had poorer retest scores than any other group. Other rats, implanted with electrodes to permit continuous recording of sleep electroencephalography, were found to undergo a prolonged period of elevated PS after spatial training. By contrast, rats trained in the nonspatial version of the water maze task did not show retention deficits after PSD or elevated PS after training. These results support a role for PS in spatial, but not nonspatial, learning in the Morris water maze. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Involvement of hippocampal NMDA receptors in retention of shuttle avoidance conditioning in rats

The purpose of this research was to evaluate the role of hippocampal N-methyl-D-aspartate (NMDA) receptors in acquisition and consolidation of memory during shuttle avoidance conditioning in rats. Adult male Wistar rats were surgically implanted with cannulae aimed at the CA1 area of the dorsal hippocampus. After recovery from surgery, animals were trained and tested in a shuttle avoidance apparatus (30 trials, 0.5-mA footshock, 24-h training-test interval). Immediately before or immediately after training, animals received a bilateral intrahippocampal 0.5-microliter infusion containing 5.0 microgram of the NMDA competitive receptor antagonist aminophosphonopentanoic acid (AP5) or vehicle (phosphate-buffered saline, pH 7.4). Infusion duration was 2 min per side. Pre-training infusion of AP5 impaired retention test performance (mean +/- SEM number of conditioned responses (CRs) during retention test session was 16.47 +/- 1.78 in the vehicle group and 9.93 +/- 1.59 in the AP5 group; P < 0.05). Post-training infusion of AP5 did not affect retention (mean +/- SEM number of conditioned responses during retention test session was 18.46 +/- 1.94 in the vehicle group and 20.42 +/- 2.38 in the AP5 group; P > 0.10). This impairment could not be attributed to an effect on acquisition, motor activity or footshock sensitivity since AP5 affected neither training session performance measured by the number of CRs nor the number of intertrial crossings during the training session. These data suggest that NMDA receptors in the hippocampus are critical for retention of shuttle avoidance conditioning, in agreement with previous evidence showing a role of NMDA receptors in fear memory.     

Differential effects of selective immunotoxic lesions of medial septal cholinergic cells on spatial working and reference memory.

The effect of injection into the medial septum of a toxin selective for cholinergic neurons, 192 IgG-saporin, was examined in rats trained to perform 2 versions of the radial 8-arm maze task. Rats were first trained to perform a task with varying delays (0, 1, 2 min) imposed between the 4th correct arm choice and access to all 8 arms. Lesioned rats made significantly more errors in the first 4 choices compared with controls and significantly more errors after delays; however, this effect was not delay dependent. Rats were then trained on a different version of this 8-arm maze task in which they learned to avoid 2 arms that were never baited. There was no treatment effect on acquisition of this task. These data are consistent with the hypothesis that the cholinergic projection to the hippocampus facilitates the acquisition of information into the system responsible for short-term memory for locations visited (spatial working memory) but is not involved in retention of this information. It also appears to play no role in either the acquisition or retention of place-nonreward associations (spatial reference memory). (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Basolateral amygdala lesions block glucocorticoid-induced modulation of memory for spatial learning.

This study examined the role of the amygdala in mediating the effects of glucocorticoids on spatial memory in rats. Adrenalectomy (ADX) induced 4–5 days prior to training impaired memory in a water-maze spatial task. This effect was reversed by a posttraining injection of dexamethasone (0.3 mg/kg sc) but not by corticosterone (0.3 mg/kg). Lesions of the basolateral (BLA), but not the central (CEA) or the medial (MEA), amygdala blocked the effects of ADX and dexamethasone. ADX also impaired acquisition. CEA, MEA, and BLA lesions blocked the ADX effect on acquisition. In adrenally intact rats, intracerebroventricular posttraining injections of a specific glucocorticoid receptor (GR or Type-ll) antagonist impaired retention, and BLA lesions blocked the effect of the GR antagonist. These findings provide evidence that the BLA is involved in mediating glucocorticoid influences on learning and memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of adrenal demedullation on the conditioned emotional response and on the memory improving action of glucose.

Results of previous experiments have demonstrated that posttraining, noncontingent ingestion of sucrose solutions, or injection of glucose solutions improve retention of various learning tasks. In the present experiment, we tested the hypothesis that this effect is due to a glucose-stimulated release of epinephrine from the adrenal medulla by testing the effect of posttraining glucose injections on retention of a conditioned response (CER) in demedullated rats. In a preliminary experiment, demedullated rats were found to be deficient at acquiring the CER, but a similar deficit in sham-operated animals suggested that this was due to the surgical procedure rather than to the absence of the adrenal medulla. When appropriate shock parameters were used, posttraining glucose improved retention of the CER in a manner parallel to the effect of this treatment in normal rats. It was concluded that the memory improving effect of posttraining glucose does not involve an effect of this substance on the adrenal medulla. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of posttraining injection of cholinergic agonists and antagonists into the amygdala on retention of passive avoidance training in rats.

144 adult male Long-Evans rats were given a single footshock while licking a water tube and tested 24 hrs later for retention of the footshock experience. A single bilateral injection of a subseizure dose of physostigmine into the amygdala applied immediately but not 18 hrs after the footshock impaired retention. This effect appeared to be somewhat localized, as physostigmine injected into the hippocampus or lateral ventricles did not disrupt retention. Conversely, a subseizure dose of atropine sulfate into the amygdala, given immediately or 18 hrs after the footshock did not impair retention. Atropine injected concurrently with physostigmine into the same amygdaloid loci counteracted a potential physostigmine-induced retention deficit. Injection of carbachol into the amygdala also impaired retention; however, carbachol precipitated seizures and possibly exerted proactive consequences on performance. The time-dependent nature of the deficit following physostigmine is consistent with the view that injection of cholinergic agonists into the amygdala disrupts memory for the footshock experience. (36 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Involvement of mechanisms dependent on NMDA receptors, nitric oxide and protein kinase A in the hippocampus but not in the caudate nucleus in memory

The effects of the NMDA receptor antagonist AP5, the nitric oxide synthase (NO) inhibitor NO-arg or the protein kinase A (PKA) inhibitor KT5720 on memory were evaluated. Rats bilaterally implanted in the CA1 region of the dorsal hippocampus were trained and tested in a step-down inhibitory avoidance task, and rats unilaterally implanted in the left posteroventral region of the caudate nucleus were trained and tested in a cued water maze task. Previous findings from this and other laboratories had found that lesions or pharmacological treatments of these sites significantly altered memory of these two tasks. Immediately after training, animals received intrahippocampal or intracaudate 0.5 microliter microinfusions of saline, AP5, NO-arg or KT5720. All three drugs impaired retention of inhibitory avoidance, but did not affect retention of the cued water maze. The findings suggest that NMDA receptor-, NO- and PKA-mediated processes in the dorsal hippocampus, but not in the caudate nucleus, are involved in memory.     

Preserving the presence of the past: Hormonal influences on memory storage.

Reviews current research on memory storage, particularly that pertaining to the modulating influences of peripheral epinephrine and of amygdala stimulation on memory. It is known that memory in animals and humans is influenced by treatments such as drugs and electrical stimulation of the brain administered shortly after training. The fact that newly acquired memories are so readily influenced suggests that memory storage processes may be modulated by endogenous physiological systems activated by experience. This suggestion is supported by findings that retention is influenced by posttraining administration of hormones of the adrenal medulla as well as other hormones released by training experiences. It is suggested that the effects of amygdala stimulation on memory are due to influences mediated by the stria terminalis. Further, findings indicating that the effect of electrical stimulation on memory is altered by treatments affecting peripheral epinephrine suggest that endogenous modulation of memory may involve cooperative influences of peripheral hormones and brain systems. Endogenous modulating systems seem to provide a basis for selecting experiences for storage. (87 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)