The influence of visual ability on learning and memory performance in 13 strains of mice

We calculated visual ability in 13 strains of mice (129SI/Sv1mJ, A/J, AKR/J, BALB/cByJ, C3H/HeJ, C57BL/6J, CAST/EiJ, DBA/2J, FVB/NJ, MOLF/EiJ, SJL/J, SM/J, and SPRET/EiJ) on visual detection, pattern discrimination, and visual acuity and tested these and other mice of the same strains in a behavioral test battery that evaluated visuo-spatial learning and memory, conditioned odor preference, and motor learning. Strain differences in visual acuity accounted for a significant proportion of the variance between strains in measures of learning and memory in the Morris water maze. Strain differences in motor learning performance were not influenced by visual ability. Conditioned odor preference was enhanced in mice with visual defects. These results indicate that visual ability must be accounted for when testing for strain differences in learning and memory in mice because differences in performance in many tasks may be due to visual deficits rather than differences in higher order cognitive functions. These results have significant implications for the search for the neural and genetic basis of learning and memory in mice.     

Emergence of a cue strategy preference on the water maze task in aged C57B6 x SJL F1 hybrid mice

The effects of age on cue learning, spatial reference memory, and strategy preference were assessed in B6 × SJL F1 mice by using the Morris water maze. This mouse strain is of particular interest because it is the background strain for a common transgenic model of Alzheimer's disease, the Tg2576 mouse, which develops plaques and other neurobiological markers of pathology beginning at 8 mo and increasing in severity with advanced age. In the current study, 12- and 23-mo-old C57B6 × SJL F1 mice were serially trained in cue and place versions of the Morris water maze task. At the completion of training, mice received a strategy probe test in which place (hidden) and cue (visible) strategies were in competition. Cue and spatial learning ability was maintained between 12 and 23 mo of age; however, on the strategy preference probe test, the 23-mo-old mice exhibited a significant bias toward the selection of a cue strategy. There was no relationship between strategy preference in the probe test and spatial learning ability, but the 23-mo-old mice did exhibit a strong trend toward shorter latencies during visible platform training, possibly reflecting the enhanced function of striatal-based neural systems in aging. These data demonstrate that 23-mo-old C57B6 × SJL F1 mice are capable of effective place learning, but if a place strategy is pitted against the use of a cue strategy, the use of a cue strategy predominates in the aged mice. The strategy preference observed here may reflect an emergence of differential processing in underlying brain circuitry with age in the B6 × SJL F1 mouse strain.     

Strain-dependent differences in LTP and hippocampus-dependent memory in inbred mice

Many studies have used "reverse" genetics to produce "knock-out" and transgenic mice to explore the roles of various molecules in long-term potentiation (LTP) and spatial memory. The existence of a variety of inbred strains of mice provides an additional way of exploring the genetic bases of learning and memory. We examined behavioral memory and LTP expression in area CA1 of hippocampal slices prepared from four different inbred strains of mice: C57BL/6J, CBA/J, DBA/2J, and 129/SvEms-+(Ter?)/J. We found that LTP induced by four 100-Hz trains of stimulation was robust and long-lasting in C57BL/6J and DBA/2J mice but decayed in CBA/J and 129/SvEms-+(Ter?)/J mice. LTP induced by one 100-Hz train was significantly smaller after 1 hr in the 129/SvEms-+(Ter?)/J mice than in the other three strains. Theta-burst LTP was shorter lasting in CBA/J, DBA/2J, and 129/SvEms-+(Ter?)/J mice than in C57BL/6J mice. We also observed specific memory deficits, among particular mouse strains, in spatial and nonspatial tests of hippocampus-dependent memory. CBA/J mice showed defective learning in the Morris water maze, and both DBA/2J and CBA/J strains displayed deficient long-term memory in contextual and cued fear conditioning tests. Our findings provide strong support for a genetic basis for some forms of synaptic plasticity that are linked to behavioral long-term memory and suggest that genetic background can influence the electrophysiological and behavioral phenotypes observed in genetically modified mice generated for elucidating the molecular bases of learning, memory, and LTP.     

Genetic differences in response to novelty and spatial memory using a two-trial recognition task in mice

A two-trial memory task, based on a free-choice exploration paradigm in a Y-maze, was previously developed to study recognition processes in Sprague-Dawley rats. Because this paradigm avoids the use of electric shock or deprivation that may have nonspecific effects and does not require learning of a rule, it may be particularly useful for studying memory in mice. Four inbred strains (Balb/cByJ, DBA/2J, C57BL/6J, and SJL/J), an F1 hybrid (C57BL/6 x SJL/J), and one outbred strain (CD1) were used to validate this task in mice and to characterize a strain distribution in response to novelty and working memory. Exploration was measured with a short (2 min) intertrial interval (ITI) between acquisition and retrieval, while memory was examined with longer intervals (30 min, 1 h, and 2 h). A study of the time course of the response to novelty revealed varying degrees of preference and/or habituation to novelty among the different strains, with CD1 exhibiting a very high response to novelty and others showing lower (C57 x SJL hybrids) to complete absence (SJL) of exploration of novelty. Memory span, assessed with increasing ITIs, varied widely among strains from 30 min (C57 x SJL hybrids) to at least 2 h (C57 and BALB). Such demonstrated sensitivity to a wide range of behavioral phenotypes supports the use of this spatial memory task as an effective tool for the study of genetic influences on the response to novelty and recognition processes in mice.     

High-fat diets impair spatial learning in the radial-arm maze in mice

It has been suggested that hyperglycemia and insulin resistance triggered by energy-dense diets can account for hippocampal damage and deficits of cognitive behaviour. We wonder if the impairment of learning and memory processes detected in diet-induced obese (DIO) mice is linked to diet composition itself. With this purpose we have evaluated learning performance in mice undergoing a short-term high-fat (HF) treatment, which leads to a pre-obese state characterized by increased adiposity without significant changes of glucose and insulin plasma levels. C57BL/6J mice were fed either a HF (45 kcal% from fat) or control diet (10 kcal% from fat) during 8 weeks. Learning performance was evaluated by using the four-arm baited version of the eight-arm radial maze test (RAM). Mice were trained to learn the RAM protocol and then memory was tested at different time-points. Time spent to consume food placed in baited arms and errors committed to find them were measured in all sessions. DIO mice significantly spent more time in learning the task and made a greater number of errors than controls. Moreover, retention tests revealed that both working and total memory errors were also more numerous in DIO mice. The current results show that short-term DIO impairs spatial learning and suggest that impairment of hippocampal learning elicited by HF diets might be perceptible before metabolic alterations linked to obesity develop.     

Trace and contextual fear conditioning is enhanced in mice lacking the α4 subunit of the GABAA receptor

The GABA_AR α4 subunit is highly expressed in the dentate gyrus region of the hippocampus at predominantly extra synaptic locations where, along with the GABA_AR δ subunit, it forms GABA_A receptors that mediate a tonic inhibitory current. The present study was designed to test hippocampus-dependent and hippocampus-independent learning and memory in GABA_AR α4 subunit-deficient mice using trace and delay fear conditioning, respectively. Mice were of a mixed C57Bl/6J X 129S1/X1 genetic background from α4 heterozygous breeding pairs. The α4-knockout mice showed enhanced trace and contextual fear conditioning consistent with an enhancement of hippocampus-dependent learning and memory. These enhancements were sex-dependent, similar to previous studies in GABA_AR δ knockout mice, but differences were present in both males and females. The convergent findings between α4 and δ knockout mice suggests that tonic inhibition mediated by α4βδ GABA_A receptors negatively modulates learning and memory processes and provides further evidence that tonic inhibition makes important functional contributions to learning and behavior.     

Strain and sex differences on olfactory discrimination learning in C57BL/6J and DBA/2J inbred mice (Mus musculus)

In this study, the authors explored potential strain and sex differences in nonspatial cognitive ability. Beginning around 90 days of age, male and female C57BL/6J (C57) and DBA/2J (DBA) inbred mice (Mus musculus) were tested on a task of simple odor discrimination learning with 3 repeated reversals. Males learned the task more readily than females, and DBA mice learned the task more readily than C57 mice. All differences became evident after repeated testing. Similarity of perseveration measures indicated the differences were not due to inhibitory deficits. Instead, a phase analysis localized differences to a transitional period of reversal learning. Females increased transitional errors that more likely indicated adaptive sampling strategies than memory failures. C57 females used this strategy indiscriminately, but DBA females sampled as a function of environmental uncertainty.     

Transient activation of the CA3 Kappa opioid system in the dorsal hippocampus modulates complex memory processing in mice

The hippocampus plays a central role in various forms of complex learning and memory. Opioid peptides and receptors are abundant in the hippocampus. These peptides are co-released with glutamate from mossy fiber- and lateral perforant path-synapses. In this study, we evaluated the functional relevance of the CA3 Kappa opioid receptors (KOR) by transient pharmacological activation or inactivation using single bilateral intrahippocampal microinjections of a selective agonist (U50,488H, 1 or 2.5 nmol), a selective antagonist (nor-binaltorphimine, norBNI 5 nmol) or a mixture of both. C57Bl/6J mice were tested in a fear conditioning paradigm (FC) or in a modified version of the water maze task thought to reveal how flexibly animals can learn and manipulate spatial information (WM). In FC, the agonist (2.5 nmol) decreased context-induced (but not tone-induced) freezing whereas norBNI had no effect. The impairment caused by the agonist U50,488H was blocked by the injection of norBNI, suggesting that overstimulation of CA3-KOR impairs the acquisition and consolidation of contextual fear-related memory. In the WM task, mice were trained repeatedly each day to find a hidden platform. After having reached this goal, the platform position was changed the next day for a new task. U50,488H injection before the last task abolished the previously acquired ability to find rapidly a new platform location, whereas adding norBNI reversed this impairment. Thus, in the mouse, even partial and topographically restricted activation of CA3-KOR entails impairments in two different hippocampus-dependent tasks, indicating functional relevance of the kappa opioid system.     

Genetic influences on digging behaviors in mice (Mus musculus) in laboratory and seminatural settings

Digging behaviors of several inbred strains of laboratory mice and some of their crosses were examined in three contexts. In laboratory burrow boxes, C57BL/6Abg mice constructed more sophisticated burrow systems than did BALB/cAbg mice. Their F1 hybrids built burrow systems more complex than either parental strain. The same pattern of genetic influence was observed in an outdoor pen. In an escape task that required digging, BALB/c mice escaped more quickly than did C57BL/6 mice; their F1 hybrids showed dominance toward the BALB/c phenotype. These results indicate that behavioral polymorphisms in digging behavior, which may relate to habitat selection, have a genetic basis. The dominance and overdominance toward the better digging parental strain in each type of task suggest the possible evolutionary importance of these digging behaviors.     

嵌套范式下视空工作记忆对基于规则类别学习

基于COVIS模型与认知加工阶段假设,通过2个实验探讨嵌套范式下, 视空工作记忆对基于规则类别学习的影响。实验1采用类别学习中嵌套视空工作记忆的范式,结果发现视空工作记忆削弱基于规则类别学习成绩,与COVIS模型预测相一致。实验2则采用视空工作记忆中嵌套类别学习任务的范式,结果却发现视空工作记忆对基于规则类别学习的影响消失。实验结果表明嵌套范式下视空工作记忆的位置影响基于规则类别学习,初步验证了类别学习存在多个认知加工阶段的假设,视空工作记忆主要影响基于规则类别学习中规则的发现和检验阶段。     

Learning and memory deficits in mice lacking protease activated receptor-1

The roles of serine proteases and protease activated receptors have been extensively studied in coagulation, wound healing, inflammation, and neurodegeneration. More recently, serine proteases have been suggested to influence synaptic plasticity. In this context, we examined the role of protease activated receptor 1 (PAR1), which is activated following proteolytic cleavage by thrombin and plasmin, in emotionally motivated learning. We were particularly interested in PAR1 because its activation enhances the function of NMDA receptors, which are required for some forms of synaptic plasticity. We examined several baseline behavioral measures, including locomotor activity, expression of anxiety-like behavior, motor task acquisition, nociceptive responses, and startle responses in C57Bl/6 mice in which the PAR1 receptor has been genetically deleted. In addition, we evaluated learning and memory in these mice using two memory tasks, passive avoidance and cued fear-conditioning. Whereas locomotion, pain response, startle, and measures of baseline anxiety were largely unaffected by PAR1 removal, PAR1-/- animals showed significant deficits in a passive avoidance task and in cued fear conditioning. These data suggest that PAR1 may play an important role in emotionally motivated learning.     

Repeated acquisition and performance chamber for mice: a paradigm for assessment of spatial learning and memory

Molecular genetic manipulation of the mouse offers the possibility of elucidating the function of individual gene products in neural systems underlying learning and memory. Many extant learning paradigms for mice rely on negative reinforcement, involve simple problems that are relatively rapidly acquired and thus preclude time-course assessment, and may impose the need to undertake additional experiments to determine the extent to which noncognitive behaviors influence the measures of learning. To overcome such limitations, a multiple schedule of repeated acquisition and performance was behaviorally engineered to assess learning vs rote performance within-behavioral test session and within-subject utilizing an apparatus modified from the rat (the repeated acquisition and performance chamber; RAPC). The multiple schedule required mice to learn a new sequence of door openings leading to saccharin availability in the learning component during each session, while the sequence of door openings for the performance component remained constant across sessions. The learning and performance components alternated over the course of each test session, with different auditory stimuli signaling which component was currently in effect. To validate this paradigm, learning vs performance was evaluated in two inbred strains of mice: C57BL/6J and 129/SvJ. The hippocampal dependence of this measure was examined in lesioned C57BL/6J mice. Both strains exhibited longer latencies and higher errors in the learning compared to the performance component and evidenced declines in both measures across the trials of each session, consistent with an acquisition phenomenon. These same measures showed little or no evidence of change in the performance component. Whereas three trials per session were utilized with C57BL/65 mice in each component, behavior of 129/SvJ mice could only be sustained for two trials per component per session, demonstrating differences in testing capabilities between these two strains under these experimental conditions and thus precluding the ability to make systematic strain comparisons of learning capabilities. Hippocampal lesions in C57BL/6J mice resulted in substantially longer latencies and increased errors in the learning but not the performance component, demonstrating the importance of this region to spatial learning as measured in the RAPC. In aggregate, this positive reinforcement-based operant paradigm to evaluate murine spatial learning detects strain differences and hippocampal dependence and permits explicit differentiation of the impact of noncognitive contributions to learning measures on a within-subject, within-session basis.     

Long-term effects of prior cocaine exposure on Morris water maze performance

Cocaine addiction is associated with long-term cognitive alterations including deficits on tests of declarative/spatial learning and memory. To determine the extent to which cocaine exposure plays a causative role in these deficits, adult male Long-Evans rats were given daily injections of cocaine (30 mg/kg/day x 14 days) or saline vehicle. Three months later, rats were trained for 6 sessions on a Morris water maze protocol adapted from Gallagher, Burwell, and Burchinal [Gallagher, M., Burwell, R., & Burchinal, M. (1993). Severity of spatial learning impairment in aging: development of a learning index for performance in the Morris water maze. Behavioral Neuroscience, 107, 618-626]. Rats given prior cocaine exposure performed similarly to controls on training trials, but searched farther from the platform location on probe trials interpolated throughout the training sessions and showed increased thigmotaxis. The results demonstrate that a regimen of cocaine exposure can impair Morris water maze performance as long as 3 months after exposure. Although the impairments were not consistent with major deficits in spatial learning and memory, they may have resulted from cocaine-induced increases in stress responsiveness and/or anxiety. Increased stress and anxiety would be expected to increase thigmotaxis as well as cause impairments in searching for the platform location, possibly through actions on ventral striatal dopamine signaling.     

Spatial learning induces differential changes in calcium/calmodulin-stimulated (ACI) and calcium-insensitive (ACII) adenylyl cyclases in the mouse hippocampus

Several lines of evidence indicate that Ca2+/calmodulin-stimulated isoforms of adenylyl cyclase (AC) are involved in long-term potentiation and in certain forms of learning. Recently, we found that training in different types of learning task differentially activates Ca2+-sensitive versus Ca2+-insensitive AC activities in certain brain regions, indicating that AC species other than those stimulated by Ca2+/calmodulin may play an important role in learning processes (Guillou, Rose, & Cooper, 1999). Here, we report the effects of spatial reference memory training in a radial arm maze on the levels of AC1 and AC2 mRNA in the dorsal hippocampus of C57BL/6 mice. Acquisition of the task was associated with a learning-specific and time-dependent increase of AC1 mRNA expression selectively in subfields CA1-CA2. In contrast, AC2 mRNA levels were either reduced or not reliably affected depending on the stage of acquisition. Moreover, no significant changes in AC expression were observed either in the dorsal hippocampus of mice trained in a non-spatial (procedural) version of the task or in cortical regions of mice learning the spatial or procedural task. The regional specificity of these effects indicates that the formation of spatial and non-spatial memory requires distinct contributions from Ca2+-sensitive and Ca2+-insensitive AC in the hippocampus. It is suggested that downregulation of AC2 throughout all hippocampal subfields may play a permissive role during the acquisition of spatial learning whereas an upregulation of AC1 specifically in subfield CA1, may be critical to accurately encode, store or use spatial information.     

NK(3) receptor agonism promotes episodic-like memory in mice

The mammalian tachykinins are a family of closely related peptides including substance P, neurokinin A, neurokinin B and, recently, also hemokinin-1. They are present in the peripheral and central nervous systems, and bind to three known neurokinin (NK) receptors, the NK(1)-, NK(2)- and NK(3) receptors. In both rodents and humans, NK(3) receptors are expressed in brain structures which have been associated with learning and memory. Evidence for a role of NK(3) receptors in learning and memory has been found in NK(3) receptor knockout mice. Here, we investigated the influence of the NK(3) receptor agonist, senktide (0.1, 0.2 and 0.4 mg/kg), on the performance of C57BL/6 mice in a recently developed episodic-like memory task. Since a promnestic effect of senktide was expected, we employed an experimental protocol that provided sub-optimal learning conditions for episodic-like memory. The results indicate that senktide promotes episodic-like memory in mice in a dose-dependent manner, providing, for the first time, evidence for an involvement of NK(3) receptors in episodic-like memory.     

Substance P facilitation of memory: effects in an appetitively motivated learning task

Food deprived, heterogeneous strain (HS/IBG) mice were trained on two different discrimination tasks for food reinforcement. In one experiment animals were trained to make spatial discriminations in a T maze. Immediately after training they were given subcutaneous injections of either substance P (1 ng/g) or vehicle. Twenty-four hours later the animals were given reversal training in the same maze. The results showed that substance P-treated animals took significantly longer to acquire the reversal habit than did control mice. In a second experiment, animals were trained to make visual discriminations in a T maze. Immediately after reaching acquisition criterion animals were injected with either substance P (1 ng/g) or vehicle. Different groups of mice were retrained on the same task either 1, 2, 3, or 7 days after original learning. Savings scores were calculated and, at every interval, substance P-treated mice retained the task better than control animals. One interpretation of these data is that substance P-treated mice remembered the original task significantly better than vehicle-injected control animals.     

Genetic background differences and nonassociative effects in mouse trace fear conditioning

Fear conditioning, including variants such as delay and trace conditioning that depend on different neural systems, is widely used to behaviorally characterize genetically altered mice. We present data from three strains of mice, C57/BL6 (C57), 129/SvlmJ (129), and a hybrid strain of the two (F(1) hybrids), trained on various versions of a trace fear-conditioning protocol. The initial version was taken from the literature but included unpaired control groups to assess nonassociative effects on test performance. We observed high levels of nonassociative freezing in both contextual and cued test conditions. In particular, nonassociative freezing in unpaired control groups was equivalent to freezing shown by paired groups in the tests for trace conditioning. A number of pilot studies resulted in a new protocol that yielded strong context conditioning and low levels of nonassociative freezing in all mouse strains. During the trace-CS test in this protocol, freezing in unpaired controls remained low in all strains, and both the C57s and F(1) hybrids showed reliable associative trace fear conditioning. Trace conditioning, however, was not obtained in the 129 mice. Our findings indicate that caution is warranted in interpreting mouse fear-conditioning studies that lack control conditions to address nonassociative effects. They also reveal a final set of parameters that are important for minimizing such nonassociative effects and demonstrate strain differences across performance in mouse contextual and trace fear conditioning.     

A Necessity for MAP Kinase Activation in Mammalian Spatial Learning

Although the biochemical mechanisms underlying learning and memory have not yet been fully elucidated, mounting evidence suggests that activation of protein kinases and phosphorylation of their downstream effectors plays a major role. Recent findings in our laboratory have shown a requirement for the mitogen-activated protein kinase (MAPK) cascade in hippocampal synaptic plasticity. Therefore, we used an inhibitor of MAPK activation, SL327, to test the role of the MAPK cascade in hippocampus-dependent learning in mice. SL327, which crosses the blood-brain barrier, was administered intraperitoneally at several concentrations to animals prior to cue and contextual fear conditioning. Administration of SL327 completely blocked contextual fear conditioning and significantly attenuated cue learning when measured 24 hr after training. To determine whether MAPK activation is required for spatial learning, we administered SL327 to mice prior to training in the Morris water maze. Animals treated with SL327 exhibited significant attenuation of water maze learning; they took significantly longer to find a hidden platform compared with vehicle-treated controls and also failed to use a selective search strategy during subsequent probe trials in which the platform was removed. These impairments cannot be attributed to nonspecific effects of the drug during the training phase; no deficit was seen in the visible platform task, and injection of SL327 following training produced no effect on the performance of these mice in the hidden platform task. These findings indicate that the MAPK cascade is required for spatial and contextual learning in mice.     

Active avoidance performance in genetically defined mice

It has been concluded by several investigators that active avoidance performance in mice is primarily influenced or even determined by a single gene. The genetically defined strains C57BL/6 and BALB/c have provided evidence that an aberrant development of pyramidal cells and mossy fiber configuration in the hippocampus of BALB/c mice also is determined by a single gene. As a test of the generality of the single gene influence on avoidance learning, and to examine the relationship of the hippocampal defect to avoidance learning, adult male mice of the inbred progenitor strains C57BL/6ByJ and BALB/cByJ and their seven recombinant inbred strains were tested in a variant of the shuttle-box paradigm used in previous studies. BALB/c were found to acquire the avoidance response at a faster rate than C57BL/6, consistent with most earlier reports, but performances of the recombinant inbred strains failed to dichotomize about the progenitor strains. The rank order of performance scores for the recombinant inbred strains was different from that reported in previous studies. Thus the present data failed to support the interpretation of a single major gene influencing active avoidance learning. It is concluded that avoidance learning and performance cannot be considered as unitary variables and that the interaction of genetic with environmental factors, including the conditions of the specific testing situation, are important considerations in any interpretation of genetic effects. No relationship between the hippocampal lamination defect and avoidance performance was demonstrated.     

Learning-induced axonal remodeling: evolutionary divergence and conservation of two components of the mossy fiber system within Rodentia

Damage to the hippocampal formation results in profound impairments in spatial navigation in rats and mice leading to the widely accepted assumption that the hippocampal cellular and molecular memory mechanisms of both genera are conserved. Recently our group has shown in two rat strains that hippocampal-dependent training in the water maze specifically induces robust 'sprouting' of granule cell suprapyramidal mossy fiber axon terminal fields. Here we sought to investigate whether the pronounced remodeling of adult hippocampal circuitry observed in the rat is also present in the mouse motivated by the thought that subsequent studies using genetically-engineered mice could then be implemented to explore the molecular mechanisms underlying training-dependent axonal growth in adult rodents. However, in contrast to Wistar rats, no changes in the Timm's-stained area of mossy fiber terminal fields (MFTFs) were observed in C57BL/6J or 129Sv/EmsJ inbred wild-type mice after water maze training. Neither extending the duration of training nor scaling down the size of the apparatus was able to induce sprouting in mouse mossy fiber pathways. Though there may be similarities in the ultimate output of the hippocampus of rats and mice as inferred from lesion studies, the current results, as well as differences in learning and memory characteristics between the two genera, suggest that the way in which the component circuitry functions is likely to be different; a not too surprising conclusion given the substantial evolutionary distance between them (>20 million years). The present findings afford an opportunity for uncovering linkages between evolutionarily significant alterations in hippocampal circuitry in relation to genera-specific information storage requirements.