Effects of post-training ethanol and group housing upon memory of an appetitive task in mice

It has been shown that post-training ethanol's facilitating effects upon memory disappeared if the mice were kept isolated after training. Since ethanol-treated mice were attacked by their cagemates, it has been hypothesized that the improved retention induced by ethanol resulted from an interaction between ethanol and group housing which added aversive information to training. To investigate the correctness of this interpretation, ethanol effects upon memory of an appetitive task were studied. C57BL/6J mice (isolated the day before training) were individually trained to find a cheese pellet placed in a corner of an open-field. Mice were injected intraperitoneally immediately after training with saline, 0.5, 1.5, or 2.0 g/kg of ethanol. They were then returned to their home cage and left alone, with another mouse, or with five other mice for 2 h after training. All mice were tested 24 h later for retention. Reductions in the number of pellet approaches or in the latency to eat the pellet were taken as measures of learning. Post-training ethanol disrupted retention of the appetitive task in a dose-related manner. Moreover disruption was greater in mice group housed after training. The results support the hypothesis that ethanol's post-training facilitating effects upon aversive memory may be due to added aversive information to the stimulus complex, rather than, or in addition, to enhanced storage of memory traces.     

Effects of MK-801 and ethanol combinations on memory consolidation in CD1 mice: involvement of GABAergic mechanisms

In the present research the effect of the noncompetitive N-methyl-d-aspartate receptor antagonist MK-801 and ethanol combinations on memory consolidation and the involvement of GABAergic mechanisms in this effect were investigated in CD1 mice injected intraperitoneally with the drugs immediately or 120 min after training in a one-trial inhibitory avoidance apparatus and tested for retention 24 h later. The results showed that (a) the retention performances of mice were impaired in a dose-dependent manner by immediate posttraining MK-801 (0.2 and 0.3, but not 0.1 mg/kg) and ethanol (1 and 2, but not 0.5 g/kg) administrations; (b) an otherwise ineffective dose of MK-801 (0.1 mg/kg) enhanced the deleterious effect exerted by ethanol (1 and 2 g/kg); (c) an otherwise ineffective dose of muscimol (0.5 mg/kg) enhanced, while otherwise ineffective doses of picrotoxin (0.25 mg/kg) or bicuculline (0.1 mg/kg) antagonized, this effect; and (d) no effect was observed when the treatments were carried out 120 min after training, suggesting that the effects observed following immediate posttraining administrations were due to the influence on the consolidation of memory. From these experiments it is evident that (a) MK-801 enhances ethanol's effects on memory consolidation and (b) GABAergic mechanisms are involved in this effect.     

The effect of home or novel environment on the facilitation of passive avoidance by post-training ethanol

Passive avoidance behavior of mice is improved when mice are injected with ethanol immediately after footshock training. Further study has shown that avoidance can be affected by ethanol injections given within 1 h, but not at 90 or 180 min, after training. The present study was conducted to investigate the possibility that events which occur in the homecage during this sensitive period may influence the effect of ethanol on subsequent avoidance. Male Swiss-Webster mice were housed either singly in a novel environment for 90 min or returned to their (group) homecage following one-trial, step-through, passive avoidance training (0.1 mA footshock) and intraperitoneal injection of 3.0 g/kg ethanol (15% v/v) or saline. As in previous studies, when ethanol-treated mice were returned to their homecage, avoidance was significantly increased at 24 h compared to the behavior of saline-treated mice. However, when mice were isolated in the novel environment for 90 min immediately following treatment, the memory facilitating effects of ethanol were not observed. The avoidance behavior of mice injected with saline was the same regardless of their post-training environment. Also, the number of mice (6 or 10) housed per homecage did not significantly influence the effects of ethanol or post-training environment on avoidance. These findings indicate that environmental factors may interact with the effects of ethanol to modify avoidance behavior. The possible influence of variables such as aggression, thermoregulation, and behavioral arousal on the effects of ethanol in this paradigm are discussed.     

Oral administration of guanosine impairs inhibitory avoidance performance in rats and mice

Extracellular guanine-based purines, mainly the nucleoside guanosine, have recently been shown to exert neuroprotective effects, which seem to be related to antagonism of the glutamatergic system. In this study, we investigated the effects of acute oral administration of guanosine on inhibitory avoidance task in rats and mice. We also studied its effects on locomotor activity, anxiety-related behaviors and mechanisms of action involving the purinergic system. Guanosine (2.0 and 7.5mg/kg, per os), administered 75min pretraining, dose-dependently impaired retention of the inhibitory avoidance task in rats and mice, an effect not prevented by the adenosine receptor antagonist caffeine. Guanosine presented no effects on locomotor activity and anxiety-related behaviors. This amnesic effect of guanosine may be compatible with inhibition of glutamatergic system and seems to be not mediated by adenosine.     

Phlorizin,a Competitive Inhibitor of Glucose Transport,Facilitates Memory Storage in Mice

Posttraining intraperitoneal administration of phlorizin (3.0–300.0 μg/kg), a competitive inhibitor of glucose transport from blood to brain, facilitated 48-h retention, in male Swiss mice, of a one-trial step-through inhibitory avoidance task. The dose–response curve was an inverted-U shape. Phlorizin did not increase the retention latencies of mice that had not received a foot shock during training. The effects of phlorizin (30.0 μg/kg) on retention were time dependent, and the administration of phlorizin (30.0 μg/kg) 5 or 10 min prior to the retention test did not affect the retention performance of mice given posttraining injections of saline or phlorizin (30.0 μg/kg). These findings indicate that phlorizin influenced memory storage, but not memory retrieval. Finally, the simultaneous administration of phlorizin (3.0–300.0 μg/kg, ip) antagonized, in a dose-related manner, the memory impairment induced by insulin (8 IU/kg, ip). Taken together, the results show that phlorizin enhance retention acting as a “glucose-like substance” although the mechanism(s) of this enhancement is unknown.     

Gradual training reduces practice difficulty while preserving motor learning of a novel locomotor task

Motor learning strategies that increase practice difficulty and the size of movement errors are thought to facilitate motor learning. In contrast to this, gradual training minimizes movement errors and reduces practice difficulty by incrementally introducing task requirements, yet remains as effective as sudden training and its large movement errors for learning novel reaching tasks. While attractive as a locomotor rehabilitation strategy, it remains unknown whether the efficacy of gradual training extends to learning locomotor tasks and their unique requirements. The influence of gradual vs. sudden training on learning a locomotor task, asymmetric split belt treadmill walking, was examined by assessing whole body sagittal plane kinematics during 24 hour retention and transfer performance following either gradual or sudden training. Despite less difficult and less specific practice for the gradual cohort on day 1, gradual training resulted in equivalent motor learning of the novel locomotor task as sudden training when assessed by retention and transfer a day later. This suggests that large movement errors and increased practice difficulty may not be necessary for learning novel locomotor tasks. Further, gradual training may present a viable locomotor rehabilitation strategy avoiding large movement errors that could limit or impair improvements in locomotor performance.     

Anandamide and memory in CD1 mice: effects of immobilization stress and of prior experience

Five sets of experiments were carried out with CD1 mice tested in a one-trial inhibitory avoidance task. In a first set, immediately posttraining administrations of the endogenous ligand for the cannabinoid CB1 receptor anandamide (arachidonylethanolamide) (3 or 6 mg/kg) dose-dependently impaired memory consolidation in mice. A lower dose (1.5 mg/kg) was ineffective. In a second set of experiments, which was carried out at the same time of the first set, preexposure of the animals to the testing apparatus decreased the effect of the drug, as compared with non-preexposed mice. In a third set of experiments, administration of anandamide (3 or 6 mg/kg) prior to the retention test did not affect the retention performance of mice given posttraining injections of either saline or anandamide. These findings indicate that the memory-impairing effects of posttraining administration of anandamide are not state-dependent. In the fourth and fifth series of experiments, carried out with non-preexposed mice, an otherwise ineffective immobilization stress (15 min) enhanced the memory-impairing effect of anandamide, and an otherwise ineffective dose of naltrexone (0.1 mg/kg) completely antagonized the effect. The results are discussed in terms of attenuation of emotionality, resulting in impaired retention, following anandamide administration, and of involvement of opioid system in the effect of this drug.     

Involvement of Glutamate Receptors, Protein Kinases, and Protein Synthesis in Memory for Visual Discrimination in the Young Chick

Two-day-old chicks were trained to discriminate between edible chick crumbs and arrays of colored beads glued to the floor of their cage. Normal chicks learned this task within a few minutes and retained it for at least 24 h. The role of several biochemical systems known to be required for other forms of early learning in the chick was explored in this task. Antagonists and inhibitors of these systems were used in the doses known to produce amnesia in a related passive avoidance learning model. Drugs were injected intracerebrally just before training, and retention was tested at various times subsequently. The protein synthesis inhibitor anisomycin (240 nmol/chick) was without effect on retention at 30 min posttraining, but chicks were amnestic at 3 and 24 h. The protein kinases inhibitors melittin (1.2 nmol/chick) and 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine hydrochloride (100 nmol/chick) were without effect on retention at 30 min posttraining but were amnestic by 3 h. While these effects are similar to those found for one-trial passive avoidance training, neither theN-methyl-D-aspartate receptor antagonists (+)-5-methyl-10,11-dihydro-5H-dibenzo[a, d]cyclohepten-5,10-imine maleate (up to 15 nmol/chick) orDL-2-amino-5-phosphonovalerate (1.3 nmol/chick), both of which are amnestic for passive avoidance, nor the non-NMDA-glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3,-dione (4 nmol/chick) were amnestic for the visual discrimination task. By contrast, the metabotropic glutamate receptor blocker (RS)-α-methyl-4-carboxyphenylglycine (300 nmol/chick) injected 5 min pretraining resulted in amnesia at 3 h posttraining. The implications of these findings for the putative “memory consolidation cascade” are discussed.     

Norepinephrine infused into the basolateral amygdala posttraining enhances retention in a spatial water maze task

Recent evidence indicates that the amygdala plays a role in modulating memory processes in other brain regions. For example, posttraining intra-amygdala infusions of amphetamine enhanced memory in both spatial and cued training water maze tasks; these tasks are known to depend on the integrity of the hippocampus and caudate nucleus, respectively. To determine whether this modulation is dependent on noradrenergic activation within a subregion of the amygdala (the basolateral nucleus), the present study examined the effects of posttraining microinfusions (0.2 microl) of norepinephrine or propranolol into the basolateral amygdala immediately following training in a spatial version of the water maze task. Rats received a four-trial training session on each of 2 consecutive days. On the third day, rats were given a 60-s probe test in the absence of a platform. Retention latencies obtained on the second training day revealed that norepinephrine dose-dependently enhanced retention for the location of the hidden platform. In contrast, propranolol significantly impaired retention. Probe trial analysis revealed that rats treated with 0.25 microg norepinephrine demonstrated a selective spatial bias for the training platform location relative to all other groups. These findings are consistent with others and support the view that the basolateral amygdala has a role in modulating memory storage by interacting with other brain regions.     

Undernutrition by rearing in large litters delays the development of reflexive, locomotor, and memory processes in mice

In three experiments, the effects of early postnatal undernutrition on the ontogeny of several behavioral capacities of varying complexity were investigated in the mouse. Following birth, mouse pups in all experiments were reared in either "normally nourished" or "undernourished" conditions by maintaining litter sizes at 6 or 16, respectively. Experiments 1 and 2 examined the development of adultlike patterns of swimming behaviors and spontaneous locomotor activity, respectively, as a function of litter size. The maturation of both behavior patterns was delayed by about 2 days in the 16-litter mice. In Experiment 3, normally nourished and undernourished mice received 25 trials in a shock-escape T-maze at 9, 11, and 13 days of age, followed by similar retention tests 24 hr later. Although litter size had little effect upon correct turns at each age during training, mice reared in litters of six exhibited significant retention of prior training by 12 days of age, whereas comparable retention was not noted for the large litter mice until 14 days of age. Overall, these results suggest that nutritional deficits, imposed by rearing in large litters during the postnatal period of rapid central nervous system maturation, retard the development of behavioral capacities involving both unlearned and learned responses.     

Involvement of central cholinergic mechanisms in the effects of oxytocin and an oxytocin receptor antagonist on retention performance in mice

Oxytocin (OT, 0.10 microg/kg, sc) impaired retention of a one-trial step-through inhibitory avoidance task when injected into male Swiss mice 10 min after training, as indicated by retention performance 48 h later. In contrast, the immediate post-training administration of the putative oxytocin receptor antagonist d(CH(2))(5)[Tyr(Me)(2), Thr(4), Thy-NH(9)(2)] OVT (AOT, 0.30 microg/kg, sc) significantly enhanced retention performance. Neither OT nor AOT affected response latencies in mice not given footshock on the training trial, and neither the impairing effects of OT nor the enhancing effects of AOT were seen when the training-treatment interval was 180 min, suggesting that both treatments influenced memory storage. The effects of OT (0.10 microg/kg, sc) on retention were prevented by AOT (0.03 microg/kg, sc) given immediately after training, but 10 min prior to OT treatment. The central acting anticholinesterase physostigmine (35, 70, or 150 microg/kg, i.p.), but not its quaternary analogue neostigmine (150 microg/kg, i.p.), reversed the impairment of retention performance induced by OT, whereas low subeffective doses of the centrally active muscarinic cholinergic antagonist atropine (0.5 mg/kg, i.p.) or the central acting nicotinic cholinergic antagonist mecamylamine (5 mg/kg, i.p.), but not methylatropine (0.5 mg/kg, i.p.) or hexamethonium (5 mg/kg, i.p.) prevented the enhancement of retention performance caused by AOT. We suggest that oxytocin negatively modulates the activity of central cholinergic mechanisms during the posttraining period that follows an aversively motivated learning experience, leading to an impairment of retention performance of the inhibitory avoidance response.     

Inhibition of monoADP-ribosylation prevents long-term memory consolidation of a single-trial passive avoidance task in the day-old chick

The cytosolic posttranslational protein-modifying mechanism of monoADP-ribosylation has been implicated in long-term potentiation, a synaptic model of memory formation. The current study investigated the effect of inhibiting mono(ADP-ribosyl) transferase on memory for the passive avoidance task in day-old chicks (white Leghorn-black Australorp). Various doses of novobiocin or menadione sodium bisulfite were administered intracranially at different times before or after training. Control chicks were administered saline at matched times. Novobiocin (650 microM) or menadione sodium bisulfite (250 microM) administered between 5.0 min pretraining and 2.5 min posttraining was found to cause a persistent loss of retention from 120 min posttraining. These data provide the first demonstration that monoADP-ribosylation is required for the maintenance of long-term memory. Furthermore, the temporal characteristics of the memory loss caused by monoADP-ribosylation inhibition appears to exclude this mechanism as a downstream effect of the well-established nitric oxide activity previously shown to occur within 40 min of passive avoidance training.     

Phthalic acid amygdalopetal lesion of the nucleus basalis magnocellularis induces reversible memory deficits in rats

The basolateral amygdala (BLA) is extensively implicated in emotional learning and memory. The current study investigated the contribution of cholinergic afferents to the BLA from the nucleus basalis magnocellularis in influencing aversive learning and memory. Sprague-Dawley rats were given permanent unilateral phthalic acid (300 ng) lesions of the nucleus basalis magnocellularis and were chronically implanted with cannulas aimed at the ipsilateral BLA. Lesioned rats showed a pronounced inhibitory avoidance task retention deficit that was attenuated by acute posttraining infusions of the muscarinic cholinergic agonist oxotremorine (4 ng) or the indirect agonist physostigmine (1 microg) into the BLA. Continuous multiple-trial inhibitory avoidance training and testing revealed that lesioned rats have a mild acquisition deficit, requiring approximately 1 additional shock to reach the criterion, and a pronounced consolidation deficit as indicated by a shorter latency to enter the shock compartment on the retention test. Because lesioned rats did not differ from sham-operated controls in performance on a spatial water maze task or in shock sensitivity, it is not likely that the memory impairments produced by the phthalic acid lesions are due to any general sensory or motor deficits. These findings suggest that the dense cholinergic projection from the nucleus basalis magnocellularis to the BLA is involved in both the acquisition and the consolidation of the aversive inhibitory avoidance task.     

The Impairment of Retention Induced by Insulin in Mice May Be Mediated by a Reduction in Central Cholinergic Activity

Immediate posttraining intraperitoneal injection of nonconvulsive doses of insulin (2-20 IU/kg) significantly impaired retention of male Swiss mice tested 24 h after training in a one-trial step-through inhibitory avoidance task. The dose-response curve showed a U-shaped form. However, of the doses tested, only 8 IU/kg was effective. Insulin did not affect response latencies in mice not given the footshock on the training trial, indicating that the actions of insulin on retention performance were not due to nonspecific proactive effects on response latencies. The impairing effects of insulin (8 IU/kg) on retention were time-dependent, which suggests that insulin impaired memory storage. The simultaneous administration of glucose (10-1000 mg/kg) antagonized, in a dose-related manner, the actions of insulin (8 IU/kg) on retention, suggesting that the hormone may have produced a hypoglycemic response leading to a decrease in CNS glucose availability with a subsequent memory impairment. Low subeffective doses of atropine (0.5 mg/kg) or mecamylamine (5 mg/kg), but not methylatropine (0.5 mg/kg) or hexamethonium (5 mg/kg), given immediately after training but 10 min before an ineffective dose of insulin (4 IU/kg), interacted with and impaired retention. The central anticholinesterase physostigmine (35 or 70 μg/kg), but not its quaternary analog neostigmine (35 or 70 μg/kg), prevented the memory impairment induced by insulin (8 IU/kg). Considered together, these findings are consistent with the view that a decrease in the CNS glucose availability impairs the synthesis and/or release of acetylcholine in brain regions critically involved in memory storage.     

Involvement of the rostral anterior cingulate cortex in consolidation of inhibitory avoidance memory: interaction with the basolateral amygdala

Previous findings suggest that the rostral anterior cingulate cortex (rACC) is involved in memory for emotionally arousing training. There is also extensive evidence that the basolateral amygdala (BLA) modulates the consolidation of emotional arousing training experiences via interactions with other brain regions. The present experiments examined the effects of posttraining intra-rACC infusions of the cholinergic agonist oxotremorine (OXO) on inhibitory avoidance (IA) retention and investigated whether the BLA and rACC interact in enabling OXO effects on memory. In the first experiment, male Sprague-Dawley rats were implanted with bilateral cannulae above the rACC and given immediate posttraining OXO infusions. OXO (0.5 or 3 ng) induced significant enhancement of retention performance on a 48-h test. In the second experiment, unilateral posttraining OXO infusions (0.5, 3.0 or 10 ng) enhanced retention when infused into rACC, but not caudal ACC, consistent with previous evidence that ACC is composed of functionally distinct regions. A third experiment investigated the effects of posttraining intra-rACC OXO infusions (0.5 or 10 ng) in rats with bilateral sham or NMDA-induced lesions of the BLA. The BLA lesions did not impair IA retention, but blocked the enhancement induced by posttraining intra-rACC OXO infusions. Lastly, unilateral NMDA lesions of rACC blocked the enhancement of IA retention induced by posttraining ipsilateral OXO infusions into the BLA. These findings support the hypothesis that the rACC is involved in modulating the storage of emotional events and provide additional evidence that the BLA modulates memory consolidation through interactions with efferent brain regions, including the cortex.     

The Effect of Distributed Practice on Immediate Posttraining,and Long-Term Performance on a Complex Command-and-Control Simulation Task

Using 192 paid participants who trained on a command-and-control microworld simulation, we examined the comparative effectiveness of two distributed practice schedules in enhancing performance at the end of training as well as after an 8-week nonuse period. Longer interstudy intervals (10 hr of practice over 2 weeks) led to higher levels of skill at the end of training and after nonuse than shorter interstudy intervals (10 hr of practice over 1 week). The study begins to address gaps in the skill retention literature by using a cognitively complex task and an extended nonuse interval. The primary implication of our findings is that scheduling longer interstudy practice intervals is a viable means of enhancing immediate posttraining performance and promoting long-term skill retention for cognitively complex tasks.     

Strain-dependent interactions between MK-801 and cocaine on retention of C57BL/6 and DBA/2 mice tested in a one-trial inhibitory avoidance task: involvement of dopaminergic mechanisms

Two sets of experiments were carried out with C57BL/6 (C57) and DBA/2 (DBA) mice tested in a one-trial inhibitory avoidance task. In the first set C57 and DBA mice were injected posttraining with saline or with the D1 DA receptor antagonist SCH 23390 and then with saline, cocaine (5 mg/kg), MK-801 (0.1 mg/kg), or with a combination of these two drugs. Cocaine enhanced retention in the C57 strain and impaired it in the DBA strain, and MK-801 potentiated the effects of cocaine in both strains. Furthermore, pretreatment with SCH 23390 completely antagonized the potentiation of the effects of cocaine exerted by MK-801. In the second set of experiments mice belonging to these same two strains were injected posttraining with vehicle or with the D2 DA receptor antagonist (-)-sulpiride and then with saline, cocaine (5 mg/kg), MK-801 (0.1 mg/kg), or with a combination of these two drugs. Pretreatment with the D2 DA receptor antagonist completely antagonized in both strains the potentiation of the effect of cocaine exerted by MK-801. The results of the present research show that the noncompetitive NMDA receptor antagonist MK-801 enhances the effect of cocaine on retention performance in C57 and DBA mice and that dopaminergic mechanisms are involved in this potentiation.     

Brief reaching training with “sticky mittens” in preterm infants: Randomized controlled trial

ObjectiveTo examine whether a brief reaching training with sticky mittens was effective to improve reaching behavior in newly reaching preterm infants.MethodsIn this randomized controlled trial, twenty four 5-month-old (±16-week-old corrected age) preterm infants were randomly allocated into experimental or control groups. Infants were assessed three times in a single session: pretraining (immediately before training), posttraining (immediately after training), and retention (4 min after the posttraining). During training, infants in the experimental group wore open fingers Velcro covered mittens. Training consisted of one 4-minute session of stimulated reaching using Velcro covered toys. Controls did not receive the training. During assessments, infants were placed in a baby chair and toys without Velcro were offered at their midline for 2 min. Number of total reaches, proximal adjustments and distal adjustments of reaching were primary outcomes. Grasping was a secondary outcome.ResultsGroups were similar in the pretraining. In the posttraining, trained infants performed greater amount of total reaches and bimanual reaches than untrained infants. Greater amount of bimanual reaches in trained infants was maintained in the retention test. Distal adjustments and grasping outcome were not influenced by the training.ConclusionsA brief-term training with open fingers sticky mittens benefited reaching behavior and favored retention of increased bimanual reaches in newly reaching late preterm infants. However, it was not sufficient to influence hand openness and early grasping.     

Ontogeny of cholinergic mediation of behaviors in the rat.

In a series of six experiments, cholinergic mediation of behavior was studied in immature rats. It was found that although scopolamine disrupted discriminative choice behavior in both 15- and 23-day-old rat pups, it increased latency to choice in 15-day-olds and decreased latency to choice in 23-day-olds. This disruption of discriminated choice behavior was not due to differential shock thresholds or differences in locomotor activity between drug-treated and control animals, nor was it specific to a T-maze shock-escape discrimination task. These results suggest that central cholinergic mediation of different behaviors may mature at different rates.     

Effects of repetitive motor training on movement representations in adult squirrel monkeys: role of use versus learning

Current evidence indicates that repetitive motor behavior during motor learning paradigms can produce changes in representational organization in motor cortex. In a previous study, we trained adult squirrel monkeys on a repetitive motor task that required the retrieval of food pellets from a small-diameter well. It was found that training produced consistent task-related changes in movement representations in primary motor cortex (M1) in conjunction with the acquisition of a new motor skill. In the present study, we trained adult squirrel monkeys on a similar motor task that required pellet retrievals from a much larger diameter well. This large-well retrieval task was designed to produce repetitive use of a limited set of distal forelimb movements in the absence of motor skill acquisition. Motor activity levels, estimated by the total number of finger flexions performed during training, were matched between the two training groups. This experiment was intended to evaluate whether simple, repetitive motor activity alone is sufficient to produce representational plasticity in cortical motor maps. Detailed analysis of the motor behavior of the monkeys indicates that their retrieval behavior was highly successful and stereotypical throughout the training period, suggesting that no new motor skills were learned during the performance of the large-well retrieval task. Comparisons between pretraining and posttraining maps of M1 movement representations revealed no task-related changes in the cortical area devoted to individual distal forelimb movement representations. We conclude that repetitive motor activity alone does not produce functional reorganization of cortical maps. Instead, we propose that motor skill acquisition, or motor learning, is a prerequisite factor in driving representational plasticity in M1.