Learning performance varies with brain weight in heterogeneous mouse lines.

Three lines of unselected heterogeneous stocks of mice—Fuller HET, Roderick SEL 19B, and Roderick SEL 16C—were tested for learning and activity in active avoidance acquisition and extinction, water-maze discrimination learning and reversal learning, operant discrimination, and passive avoidance acquisition tasks. Ambulation in the open field was also measured. Small to moderate correlations between brain weight and learning measures were obtained for all tasks except passive avoidance. A moderate correlation between brain weight and activity was found only in the open field (r?=?.39). Partialing out differences in operant level and body weight had little effect on the magnitude of the correlations between brain weight and learning performance. When ambulation in the open field was partialed out, however, all correlations between brain weight and learning performance decreased. Previous research, as summarized in T. H. Roderick et al (1976), suggested a positive relation between brain weight and learning scores across mammalian orders and species. The present results extend this relation to within-species variation in brain size and emphasize the limitations of estimating genetic associations between brain and behavior from comparisons between small numbers of inbred strains or selected lines. (24 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

An association between granule cell density in the dentate gyrus and two-way avoidance conditioning in the house mouse.

In 2 experiments, 102 hybrid male mice (C57BL/6J and C58/J stock) with genetically associated variations in the number and density of granule cells in the dentate gyrus were tested for open-field activity, spatial maze learning, and 2-way avoidance conditioning. The number of granule cells was not associated with any behavior. Only avoidance conditioning was related to granule cell density, which had a negative correlation with performance on the shuttlebox task. This result was replicated in 2 genetically different stocks of mice. Density of the more caudal portion of the dentate was associated with early stages of avoidance learning, whereas the more rostral portion was associated with later stages. Results are discussed in relation to theories of functional dissociation within the hippocampus. (38 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Strain distribution of mice in discriminated Y-maze avoidance learning: Genetic and procedural differences.

The current study was conducted to characterize discriminated avoidance learning in mice by using a Y-maze task. In Experiment 1, the task parameters were manipulated, including the amount of time spent in the start arm, the amount of time to make the avoidance response, and the intertrial interval (ITI) using C57?×?SJL F1 hybrid mice. Avoidance performance was significantly improved with longer times to avoid the shock and longer ITIs. In Experiment 2, mice from 4 inbred strains (BALB/cByJ, DBA/2J, C57BL/6J, and SJL/J), an F1 hybrid (C57?×?SJL), and 1 outbred strain (CD1) were tested with various ITIs. Strain differences were observed in avoidance learning, with BALB, DBA, C57?×?SJL and CD1 mice showing significantly better avoidance learning than C57 mice, which were better than SJL mice. These data demonstrate that Y-maze performance is significantly influenced by the genetic background of the mouse and the parameters of the task. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dissociation of multiple behavioral effects between olfactory bulbectomized C57Bl/6J and DBA/2J mice

The behavioral effects of bulbectomy and subsequent antidepressant treatment in two mice strains were compared on measures of open field behavior and passive and active avoidance 2 and 4 weeks after surgery. After bulbectomy, both strains displayed elevated locomotion in open field, corrected by antidepressants. Enhanced rearing was decreased by antidepressants in C57Bl/6J, but not in DBA/2J mice. Passive avoidance, being intact 2 weeks after surgery in both strains, was strongly impaired 4 weeks after bulbectomy in C57Bl/6J mice, with antidepressants restoring the performance. Active avoidance acquisition and retention were also dramatically disturbed in C57Bl/6J mice 2 and 4 weeks after surgery, and antidepressants had recuperative effect. In contrast, bulbectomized DBA/2J mice didn't show any significant passive or active avoidance deficits, and antidepressant treatment seemed to have no effect on their learning ability. The observed strain differences suggest that bulbectomy may produce quite diverse neurophysiological and neurochemical alterations in two strains.     

Septal lesions and behavior: Effects of presurgical rearing and strain of mouse.

In 2 experiments a total of 64 black C57BL/10J and 64 albino SJL/J male mice were reared in either enriched social cages or restricted individual cages from 25 days of age until they underwent septal or control surgery 1 mo later. Enrichment differentially altered septal or control behavior as measured by fluid consumption of water, saccharin, and quinine; performance on a rotorod; and the acquisition of an active avoidance task. The interactions of presurgical history with brain damage were manifested differently in the 2 strains of mice. The importance of attending more to genetic and presurgical history in attempts to define the effects of brain damage on behavior and to determine the function of brain structures is discussed. (25 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Genotype-dependent effects of septal lesions on different types of learning in the mouse.

Tested 80 C57BL/6J, DBA/2J, and SEC/1ReJ mice with septal or control lesions for exploratory behavior, shuttle-box avoidance learning, discriminated avoidance, and maze-learning ability. Control DBA and SEC Ss normally displayed low levels of exploratory behavior and efficient avoidance and maze learning. High exploratory activity and low avoidance and maze learning were characteristically shown by C57 controls. All strains with septal lesions increased levels of exploratory and avoidance behaviors. In contrast, following septal lesions the 3 strains performed more poorly in discriminated-avoidance and maze learning. It is concluded that differences in septal function-e.g., in level of response inhibition-do not substantially account for the learning differences evident between these strains. (19 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A single pre-training glucose injection induces memory facilitation in rodents performing various tasks: contribution of acidic fibroblast growth factor

Effects of a pre-training intraperitoneal glucose injection on learning and memory were tested using two tasks: passive avoidance and Morris water maze. In the former task, mice that had received glucose 2 h prior (but not 1, 3, or 5 h prior) to a trial that combined acquisition with passive avoidance of foot shock showed a significantly increased retention latency when tested 24 h later. Thus, this effect was time-dependent, and it was also found to be dose-dependent by further experiment. In contrast, 2-deoxy-D-glucose and fructose had no such effect. In the Morris water maze task, glucose injection 2 or 3 h before a block of trials enhanced the spatial memory performance of mice. These glucose-induced memory-facilitation effects were abolished by an intracerebroventricular injection of anti-acidic fibroblast growth factor antibody 30 min before the glucose injection, suggesting a critical role for endogenous acidic fibroblast growth factor in this facilitatory effect. Furthermore, continuous intracerebroventricular infusion of acidic fibroblast growth factor in rats significantly increased retention latency (when tested repeatedly on successive days using a passive avoidance task). Our earlier studies demonstrated that brain acidic fibroblast growth factor is produced in the ependymal cells of the cerebroventricular system, and is released into the cerebrospinal fluid following either a meal or a (intraperitoneal or intracerebroventricular) glucose injection. This released acidic fibroblast growth factor also diffuses into the brain parenchyma, and is taken up by neurons in the hippocampus, hypothalamus, and elsewhere in the brain some 2 h after the meal or glucose injection. These and the present findings indicate (i) that pre-training glucose injection improves memory performance, and (ii) that acidic fibroblast growth factor, especially by its action within the hippocampus, is involved in this enhancement process.     

The role of performance factors in the active avoidance-conditioning deficit in autoimmune mice.

Prior studies with autoimmune mice demonstrated deficits in 2-way active avoidance conditioning that correlated with the degree of autoimmunity. In this study, autoimmune female NZB?×?NZW F1 hybrid (B/W) mice were tested in shock-motivated discrimination learning, 1-way avoidance conditioning, and a modified 2-way avoidance task and compared to nonautoimmune female NZW mice. The discrimination and 1-way conditioning results indicated that B/W mice can learn shock-motivated tasks that involve minimal fatigue and no conflict. B/W mice were also able to learn the 2-way avoidance task when it was made easier by increasing conditioned-stimulus cue salience, clarifying contingencies, and increasing trial spacing to decrease possible cognitive, emotional, and physical fatigue. Thus, poor performance in 2-way avoidance appears to be a consequence of altered attention, motivation, or emotionality and can be overcome by altering task parameters. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Impairment of acquisition of learning by inhibitors of RNA or protein synthesis

The effects of inhibitors of RNA or protein synthesis (cycloheximide, puromycin and actinomycin D) on acquisition of learning in mice were investigated using various types of shock avoidance tasks. Mice having uniform and superior learning ability were used as subjects. Drugs were injected into the lateral ventricle 1 hr before training for avoidance tasks in three different shapes of maze and in a one-way shuttle box and for those based on light-dark discrimination. In all cases of training, the drugs were found to impair the acquisition of learning. The impairment was pronounced in a relatively complicated task such as H-maze learning as compared to a simple task such as T-maze learning. The drugs never affected the performance of pretrained animals. During the discussion, the acquisition of learning would be related to some specific process of RNA and protein synthesis in the brain.     

Separation of taste-aversion-prone and taste-aversion-resistant rats through selective breeding: Implications for individual differences in conditionability and aversion-therapy alcoholism treatment.

Reports on the ongoing development of rat strains suitable for studies of biological bases of individual differences in taste aversion (TA) conditionability. Sprague-Dawley-derived rats were selectively bred over 7 generations as strong or weak learners of a TA to saccharin induced by intraperitoneal injections of cyclophosphamide (12.5 or 15 mg/kg). Efficiency of aversion acquisition was a selectable propensity, as indicated by progressively divergent strain separation that attained significance in the 2nd selected generation. Ss were also studied with respect to shock-motivated environmental avoidance (SMEA), but efficiency of SMEA performance was not a selection factor. Results show an unexpected trend across generations indicative of a within-strain reversal of TA and SMEA learning efficiency. Continuation of this reversal in subsequent generations could have important implications for studies of genetic contributions to different learning capacities and for the selection of biologically appropriate noxious stimuli for aversive therapy treatments of various target problems, sush as alcoholism. (35 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Novel environment induced inhibition of corticosterone secretion: physiological evidence for a suprachiasmatic nucleus mediated neuronal hypothalamo-adrenal cortex pathway

The effects of two cognition enhancers on avoidance impairment induced by the tricyclic antidepressant amitriptyline were assessed during shuttle-box avoidance acquisition and in previously trained mice of the DBA/2 strain. The nootropic agent piracetam (50, 100 or 200 mg/kg, i.p.) had slight or no effect in mice receiving amitriptyline (5 or 10 mg/kg, i.p.). Conversely, the acetylcholinesterase inhibitor tacrine (0.5, 1, 2 or 3 mg/kg, i.p.) prevented the avoidance impairment induced by 5 mg/kg amitriptyline on shuttle-box avoidance acquisition as well as on a previously learned avoidance response. The avoidance disrupting action produced by 10 mg/kg of the antidepressant drug was not affected by the anticholinesterase drug. The preventing action of tacrine seems specifically related to the avoidance impairment induced by amitriptyline, since the acetylcholinesterase inhibitor did not reduce, but enhanced the avoidance impairing action of the neuroleptic chlorpromazine. Taken together, the results indicate that amitriptyline-induced avoidance impairment, and the related preventing action of tacrine, may be ascribed to drug effects on the performance of the avoidance response, rather than to interferences with learning processes.     

Evidence for multiple pathologic and protective mechanisms of murine cerebral malaria

Murine cerebral malaria (CM) induced by Plasmodium berghei ANKA kills susceptible mice within 24 to 48 h of onset of symptoms and is characterized by the production of inflammatory cytokines in the brain. C57BL/6J mice are sensitive to lethal CM, while A/J mice are resistant. These strains of mice were immunized with an adjuvant vaccine of killed whole-blood-stage parasites. The immunization protected C57BL/6 mice from lethal CM following virulent challenge. The same immunization increased the incidence of lethal CM in A/J mice challenged similarly. Histopathologic examination of the brains of mice from these studies revealed two distinct types of lesions. Type I CM is acute in onset; usually lethal; and characterized by widespread microglial activation, endothelial cell damage, and microvascular disruption in the brain. Type II CM is characterized by intense, but focal, mononuclear cell inflammation without endothelial cell damage or microvascular destruction. Animals with type II lesions were clinically normal and protected from type I lesions. Available clinical, epidemiological, and biochemical evidence suggests that type I and type II lesions might exist in human CM as well.     

A concussive-like brain injury model in mice (II): selective neuronal loss in the cortex and hippocampus

The modeling of human concussive brain injury (CBI) in the laboratory has been challenging. In the present study, we developed an experimental CBI model in mice using a novel weight-drop device. Various injury levels were examined by adjusting the height of the falling weight (diameter 10 mm, length 20 cm, weight 21 g). At a height of 50 cm, the impact resulted in a mortality rate of 46.7% with a skull fracture rate of 28.6%. At a height of 25 cm, however, the impact produced a concussive-like brain injury (CLBI) to the mice without skull fracture. A series of pathophysiological and neurobehavioral responses was evaluated at this injury level. The CLBI mice lost muscle tone and righting reflex response immediately following the trauma and recovered from the latter within a short duration of 1.6 +/- 0.32 min (mean +/- SE). Brain edema formation started at 12 h, reached a maximum at 24 h and recovered 48 h. Typically edema was found in the neocortex, hippocampus, and cerebellum, but not in the brain stem. Deficits in the feeding behaviors lasted for 2 days, accompanied by lower body weight persisting for 5 days. The body weight growth rate for 24 h returned to the control levels by the third day postinjury. Learning and memory were evaluated at the end of 1-3 weeks after the trauma using a water-finding task. At 1 week, exploratory behaviors were slightly inhibited while learning and memory were profoundly impaired. Interestingly, the learning and memory deficits lasted for 2 weeks while recovering to the control levels by 3 weeks. No motor disability was found in the CLBI mice during the 3-week evaluations. These results indicate that the weight-drop impact produced graded injury to the brain, and at the injury level of 25 cm it produced a CLBI in the mice in which the characteristics of transient loss of neurobehavioral responses, short duration of brain edema, and long-lasting learning and memory deficits are similar to those of human CBI.     

The uterine environment enhances cognitive competence

Genetically identical mouse embryos were transferred into same-strain uteri (transfer controls) or into hybrid uteri. A third group was not transferred. When adult, the mice were given a series of behavioral tests. In-strain transfer controls differed from non-transfer mice only on two activity measures, and did not differ on any cognitive variable. In contrast, mice reared in hybrid uteri were found to be superior to in-strain transfer mice on discrimination learning. Lashley maze learning and Morris maze learning; they also showed better adaptation in an avoidance learning shuttlebox. To our knowledge this is the first study showing that the uterine environment can have a general enhancing effect upon cognitive competence across a broad range of behaviors.     

Genetic analysis of avoidance, maze, and wheel-running behaviors in the mouse.

Conducted a genetic analysis of avoidance, maze learning, and wheel-running activity in 1,573 SEC/1ReJ, DBA/2J, and C57BL/6J strain mice and their F1, F2, and F3 progenies. Results show that the mode of inheritance in a given behavioral measure depends on the crosses considered. Thus, a given allele may be dominant in a given hybrid combination and recessive in another combination. The significant genetic correlations between these 3 behavioral measures suggest that these traits could be influenced by some of the same genes. The estimates of heritability are larger for avoidance than for activity, suggesting that the latter trait is more related to fitness. (36 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of cycloheximide administered in conjunction with nicotine on retention of a passive avoidance task in mice.

Studied retention of a passive avoidance task in mice given either cycloheximide (30 mg/kg or 100 mg/kg sc) or cycloheximide in combination with nicotine (1.0 mg/kg, ip). Two similar experiments were conducted: In the 1st experiment, the effects of these drugs were studied in 45 inbred C57Bl/6J mice. In the 2nd experiment, the effects of these drugs were studied in 113 genetically heterogenous mice. Cycloheximide was found to have a deleterious effect on retention of the passive avoidance task. Larger doses of cycloheximide were found to be necessary to disrupt memory in heterogenous than C57Bl/6J Ss. Nicotine, when administered in conjunction with cycloheximide, abolished the memory disruptive effects of cycloheximide. Results are discussed in terms of a time-dependent consolidation model of memory storage. (36 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of reduced myristoylated alanine-rich C kinase substrate expression on hippocampal mossy fiber development and spatial learning in mutant mice: transgenic rescue and interactions with gene background

The myristoylated alanine-rich C kinase substrate (MARCKS) is a prominent protein kinase C (PKC) substrate in brain that is expressed highly in hippocampal granule cells and their axons, the mossy fibers. Here, we examined hippocampal infrapyramidal mossy fiber (IP-MF) limb length and spatial learning in heterozygous Macs mutant mice that exhibit an approximately 50% reduction in MARCKS expression relative to wild-type controls. On a 129B6(N3) background, the Macs mutation produced IP-MF hyperplasia, a significant increase in hippocampal PKCepsilon expression, and proficient spatial learning relative to wild-type controls. However, wild-type 129B6(N3) mice exhibited phenotypic characteristics resembling inbred 129Sv mice, including IP-MF hypoplasia relative to inbred C57BL/6J mice and impaired spatial-reversal learning, suggesting a significant contribution of 129Sv background genes to wild-type and possibly mutant phenotypes. Indeed, when these mice were backcrossed with inbred C57BL/6J mice for nine generations to reduce 129Sv background genes, the Macs mutation did not effect IP-MF length or hippocampal PKCepsilon expression and impaired spatial learning relative to wild-type controls, which now showed proficient spatial learning. Moreover, in a different strain (B6SJL(N1), the Macs mutation also produced a significant impairment in spatial learning that was reversed by transgenic expression of MARCKS. Collectively, these data indicate that the heterozygous Macs mutation modifies the expression of linked 129Sv gene(s), affecting hippocampal mossy fiber development and spatial learning performance, and that MARCKS plays a significant role in spatial learning processes.     

Phlorizin, a competitive inhibitor of glucose transport, facilitates memory storage in mice

Posttraining intraperitoneal administration of phlorizin (3.0-300.0 microg/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 microg/kg) on retention were time dependent, and the administration of phlorizin (30.0 microg/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 microg/kg). These findings indicate that phlorizin influenced memory storage, but not memory retrieval. Finally, the simultaneous administration of phlorizin (3. 0-300.0 microg/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.     

The influence of nimodipine and MK-801 on the brain free arachidonic acid level and the learning ability in hypoxia-exposed rats

1. The influence of voltage dependent calcium channel blocker (VDCC), nimodipine and N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 on the brain free arachidonic acid (FAA) level and on the learning ability in hypoxia-exposed rats was examined. 2. Some animals were decapitated after cerebral hypoxia had been obtained and the brain FAA level was determined by gas chromatography. The other animals were trained in a passive avoidance procedure and were exposed to hypoxic conditions immediately after the learning trial response had been acquired. A passive avoidance retention test was performed 24 hours later. 3. Various doses of nimodipine (0.03; 0.1; 0.3 and 1.0 mg/kg) and MK-801 (0.03; 0.1 and 0.3 mg/kg) had been injected 30 minutes before biochemical or behavioral procedures started. 4. It was found that hypoxia strongly increased the brain FAA level and impaired the retention of the passive avoidance response. 5. Pretreatment with 0.3 mg/kg and 1.0 mg/kg of nimodipine prevented the brain FAA accumulation. It has also been shown that all tested doses of nimodipine significantly improved the retention deficit in the animals exposed to hypoxia. 6. Neither the one of tested doses of MK-801 influenced significantly the increase of the brain FAA level and/or passive avoidance behavior in hypoxic animals. 7. These results confirm the hypothesis that the brain FAA accumulation and cognitive impairment, caused by hypoxia, are maybe associated with disturbances in calcium homeostasis and that nimodipine may be useful in ameliorating the hypoxia-induced brain tissue damage. Blocade of NMDA receptor-channel complex by MK-801 was not sufficient to prevent hypoxia-induced neuronal damage.     

Differential effects of prefrontal lesions and combined prefrontal and limbic lesions on subsequent learning performance in the cat.

15 cats were given lesions in either the prefrontal cortex alone (n?=?7) or in the prefrontal cortex, anterior thalamus, mamillary bodies, and subiculum (n?=?8) before being tested in the acquisition of visual-reversal, delayed-alternation, and 2-way active-avoidance tasks. Lesioned Ss were compared to 6 unoperated and 4 sham-operated controls. As an extension of E. Irle and H. J. Markowitsch's (see record 1984-19842-001) study, in which triple limbic lesions failed to impair learning behavior of cats, the present study examined the effects of a lesion in the 4th brain structure (in addition to the original triple lesions). Results indicate that, compared with controls, Ss with prefrontal lesions were impaired in the acquisition of the avoidance task. In contrast, Ss with combined lesions were unimpaired in the acquisition of the visual-reversal task, facilitated in the acquisition of the avoidance task, but impaired in the acquisition of the delayed-alternation task. The superior performance Ss with combined lesions is interpreted as due to a lesion-induced functional shift acting on intact brain structures which, prior to massive limbic lesions, remained inhibited. (56 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)