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Strain differences in performance of alternation patterns between C57BL/6 and CF1 mice
Abstract
Recombinant DNA technology has facilitated animal models that could be used to investigate candidate gene contributions to acquisition and retention. In practice, researchers focus on genetics or simple behaviors, rarely combining both or investigating genetic contributions to complex behaviors. We investigated inbred C57BL/6 and outbred CF1 mice’s ability to perform single-alternation and double-alternation patterns. C57BL/6 mice performed better, especially on double-alternation patterns. We also observed sex differences in the inbred C57BL/6 strain for the double alternation pattern. This suggests paradigms for investigating complex behaviors can be useful in uncovering strain differences and contributions of candidate genes to learning, retention, and performance.
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Inbreeding refers to mating of related individuals. It results in a decline in survival and reproduction (reproductive fitness), known as inbreeding depression, in most species of plants and animals. Outbreeding refers to matings between individuals from different populations, subspecies, or species. Outbreeding can result in a decline in reproductive fitness known as outbreeding depression, but this is less common than inbreeding depression. Inbreeding in small populations typically increases extinction risk, especially for species that do not normally inbreed. Outbreeding between populations with chromosomal incompatibilities or those that are adapted to different environmental conditions can also increase extinction risk. Restoring gene flow between isolated populations can reverse inbreeding depression. This article discusses the conservation implications of inbreeding and outbreeding depression.
Mice that overexpress the human mutant amyloid precursor protein (hAPP) show learning deficits, but the apparent lack of a relationship between these deficits and the progressive βamyloid plaque formation that the hAPP mice display is puzzling. In the water maze1, hAPP mice are impaired before and after amyloid plaque deposition2-7. Here we show, using a new watermaze training protocol, that PDAPP mice8 also exhibit a separate age-related deficit in learning a series of spatial locations. This impairment correlates with β-amyloid plaque burden and is shown in both cross-sectional and longitudinal experimental designs. Cued navigation and object-recognition memory are normal. These findings indicate that Aβ overexpression and/or Aβ plaques are associated with disturbed cognitive function and, importantly, suggest that some but not all forms of learning and memory are suitable behavioural assays of the progressive cognitive deficits associated with Alzheimer's-disease-type pathologies.
Rats (
Rattus norvegicus) were tested on a 4-arm radial maze for several trials each day over a period of 16 days. On each trial, a rat climbed a barrier to enter each arm and pushed a cover off the food cup at the end of each arm. Within each daily sequence of trials, entries into arms of the maze were rewarded or nonrewarded according to patterns that differed between arms, and the assignment of reward patterns to arms varied randomly between days for each S. Plots of mean rank of arm entry against trial-by-trial reward patterns showed that Ss learned to track at least 2 patterns at the same time. Ss accurately tracked patterns that contained long runs of reward and nonreward (Exp 1), patterns that followed a simple alternation rule (Exp 2), and patterns that followed an increasing or decreasing monotonic rule (Exp 3). However, patterns that were structurally complex or quasi-random were tracked poorly or not at all. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Choosing the best genetic strains of mice for developing a new knockout or transgenic mouse requires extensive knowledge of the endogenous traits of inbred strains. Background genes from the parental strains may interact with the mutated gene, in a manner which could severely compromise the interpretation of the mutant phenotype. The present overview summarizes the literature on a wide variety of behavioral traits for the 129, C57BL/6, DBA/2, and many other inbred strains of mice. Strain distributions are described for open field activity, learning and memory tasks, aggression, sexual and parental behaviors, acoustic startle and prepulse inhibition, and the behavioral actions of ethanol, nicotine, cocaine, opiates, antipsychotics, and anxiolytics. Using the referenced information, molecular geneticists can choose optimal parental strains of mice, and perhaps develop new embryonic stem cell progenitors, for new knockouts and transgenics to investigate gene function, and to serve as animal models in the development of novel therapeutics for human genetic diseases.
Synaptotagmin (Syt) IV is a synaptic vesicle protein. Syt IV expression is induced in the rat hippocampus after systemic kainic acid treatment. To examine the functional role of this protein in vivo, we derived Syt IV null [Syt IV(-/-)] mutant mice. Studies with the rotorod revealed that the Syt IV mutants have impaired motor coordination, a result consistent with constitutive Syt IV expression in the cerebellum. Because Syt IV is thought to modulate synaptic function, we also have examined Syt IV mutant mice in learning and memory tests. Our studies show that the Syt IV mutation disrupts contextual fear conditioning, a learning task sensitive to hippocampal and amygdala lesions. In contrast, cued fear conditioning is normal in the Syt IV mutants, suggesting that this mutation did not disrupt amygdala function. Conditioned taste aversion, which also depends on the amygdala, is normal in the Syt IV mutants. Consistent with the idea that the Syt IV mutation preferentially affects hippocampal function, Syt IV mutant mice also display impaired social transmission of food preference. These studies demonstrate that Syt IV is critical for brain function and suggest that the Syt IV mutation affects hippocampal-dependent learning and memory, as well as motor coordination.
Galanin is a neuropeptide with multiple inhibitory actions on neurotransmission and memory. In Alzheimer's disease (AD), increased galanin-containing fibers hyperinnervate cholinergic neurons within the basal forebrain in association with a decline in cognition. We generated transgenic mice (GAL-tg) that overexpress galanin under the control of the dopamine beta-hydroxylase promoter to study the neurochemical and behavioral sequelae of a mouse model of galanin overexpression in AD. Overexpression of galanin was associated with a reduction in the number of identifiable neurons producing acetylcholine in the horizontal limb of the diagonal band. Behavioral phenotyping indicated that GAL-tgs displayed normal general health and sensory and motor abilities; however, GAL-tg mice showed selective performance deficits on the Morris spatial navigational task and the social transmission of food preference olfactory memory test. These results suggest that elevated expression of galanin contributes to the neurochemical and cognitive impairments characteristic of AD.
3 test-sophisticated white rabbits, 2 male and 1 female, were trained on the double alternation problem in the Wisconsin General Test Apparatus. All 3 animals mastered the problem to the criterion of 80% correct responses over 50 consecutive sequences of responses. The performance of the rabbits was compared with results recorded by other workers for cats and raccoons.
The negatively accelerated, gradually increasing learning curve is an artifact of group averaging in several commonly used basic learning paradigms (pigeon autoshaping, delay- and trace-eye-blink conditioning in the rabbit and rat, autoshaped hopper entry in the rat, plus maze performance in the rat, and water maze performance in the mouse). The learning curves for individual subjects show an abrupt, often step-like increase from the untrained level of responding to the level seen in the well trained subject. The rise is at least as abrupt as that commonly seen in psychometric functions in stimulus detection experiments. It may indicate that the appearance of conditioned behavior is mediated by an evidence-based decision process, as in stimulus detection experiments. If the appearance of conditioned behavior is taken instead to reflect the increase in an underlying associative strength, then a negligible portion of the function relating associative strength to amount of experience is behaviorally visible. Consequently, rate of learning cannot be estimated from the group-average curve; the best measure is latency to the onset of responding, determined for each subject individually.
Numerous investigators have examined the hypothesis that males and females learn or perform differentially on various tasks. However, many of the behavioural investigations with nonhuman animals (e.g., rats) have used paradigms that do not permit the exploration of complex learning and memory between the sexes. To this end, we explored the ability of male versus female mice to learn three different patterns in succession in three separate experiments: single alternation (e.g., right, left, right, left), double alternation (e.g., right, right, left, left), and runs (e.g., 123, 234, 345, 456, 567, 678, 781, 812, where digits represent locations within a circular array in the counterclockwise direction). We hypothesized that sex differences, if they existed, would be most likely to appear as the pattern to be learned became more complex (required more rules to capture how elements relate to one another). The results indicated that mice can learn all three pattern types, but learning was more difficult as pattern complexity increased. Males learned the runs pattern significantly more quickly than females did; no significant differences were found between males and females for acquisition of the single-alternation or double-alternation patterns. These results suggest that sex differences in serial pattern learning within rodents are not unique to rats and are more likely to be seen during acquisition of more complex patterns.
Inbreeding refers to mating of related individuals. It results in a decline in survival and reproduction (reproductive fitness) in inbred progeny, known as inbreeding depression, in most species of plants and animals. Outbreeding refers to matings between individuals from different populations, subspecies, or species. Outbreeding can result in a decline in reproductive fitness known as outbreeding depression, but this is less common than inbreeding depression. Inbreeding in small populations typically increases extinction risk, especially for species that do not normally inbreed. Outbreeding between populations with chromosomal incompatibilities or those that are adapted to different environmental conditions can also increase extinction risk. Restoring gene flow between isolated populations can reverse inbreeding depression (genetic rescue). Provided the risk of outbreeding depression is low, most attempts at genetic rescue are likely to result in greatly improved population fitness.
In two experiments, mice learned 24-element serial patterns. In Experiment 1, patterns either were perfectly structured or had a single violation element and were either phrased by temporal pauses or unphrased. In Experiment 2, the same violation pattern of Experiment 1 was phrased by temporal cues, visual cues, or a combination of the two. For mice, as for rats and humans in earlier studies, pattern structure predicted pattern learning difficulty and also the nature and relative frequency of errors. Mice, like rats and humans, also found a violation element especially difficult to learn and at that point in the pattern made errors consistent with the structure of the remainder of the pattern. However, in both experiments, phrasing interfered with responding correctly on the element after the phrasing cue. In a third experiment, mice were able to use temporal intervals and, to a lesser degree, visual stimuli as discriminative cues to control spatial responses in the same apparatus used in earlier studies. The results support the view that mice are sensitive to pattern organization but may have difficulty using phrasing cues in the context of serial patterns.
Previous studies of double alternation learning have failed to demonstrate learning of extended double alternation sequences by nonprimate Ss. The present study investigates whether such learning can be induced by manipulations of the training procedure. Pigeons (N = 6) were trained on a double alternation procedure with continuous trial presentations. A new double alternation sequence began after each error so that the length of a sequence was a function of the accuracy of performance. All Ss learned the double alternation pattern for the first four positions of the sequence, but none learned consistently to emit longer sequences. The degree of learning was a function of several procedural variables, particularly the use of an appropriate correction procedure.
The cAMP-responsive element-binding protein (CREB) has been implicated in the activation of protein synthesis required for long-term facilitation, a cellular model of memory in Aplysia. Our studies with fear conditioning and with the water maze show that mice with a targeted disruption of the alpha and delta isoforms of CREB are profoundly deficient in long-term memory. In contrast, short-term memory, lasting between 30 and 60 min, is normal. Consistent with models claiming a role for long-term potentiation (LTP) in memory, LTP in hippocampal slices from CREB mutants decayed to baseline 90 min after tetanic stimulation. However, paired-pulse facilitation and posttetanic potentiation are normal. These results implicate CREB-dependent transcription in mammalian long-term memory.
In many experiments, rats have evidenced extreme difficulty mastering alternation patterns. In three experiments, we explored rats’ ability to learn double alternation patterns and possible reasons behind their past difficulties with such patterns. In Experiment 1, rats learned single and double alternation patterns. In the second and third experiment, we explored the role of correction and interference from stimulus set size on rats’ learning of double alternation patterns. Our results showed that rats easily learned both single and double alternation patterns and that stimulus set size had no noticeable effect on learning double alternation patterns. Findings additionally evidenced that correction played an important role in rats’ learning double alternation patterns.
This study was designed to determine whether deficits in adult serial pattern learning caused by adolescent nicotine exposure persist as impairments in asymptotic performance, whether adolescent nicotine exposure differentially retards learning about pattern elements that are inconsistent with "perfect" pattern structure, and whether there are sex differences in rats' response to adolescent nicotine exposure as assessed by a serial multiple choice task. The current study replicated the results of our initial report (Fountain, Rowan, Kelley, Willey, & Nolley, 2008) using this task by showing that adolescent nicotine exposure (1.0mg/kg/day nicotine for 35days) produced a specific cognitive impairment in male rats that persisted into adulthood at least a month after adolescent nicotine exposure ended. In addition, sex differences were observed even in controls, with additional evidence that adolescent nicotine exposure significantly impaired learning relative to same-sex controls for chunk boundary elements in males and for violation elements in females. All nicotine-induced impairments were overcome by additional training so that groups did not differ at asymptote. An examination of the types of errors rats made indicated that adolescent nicotine exposure slowed learning without affecting rats' cognitive strategy in the task. This data pattern suggests that exposure to nicotine in adolescence may have impaired different aspects of adult stimulus-response discrimination learning processes in males and females, but left abstract rule learning processes relatively spared in both sexes. These effects converge with other findings in the field and reinforce the concern that adolescent nicotine exposure poses an important threat to cognitive capacity in adulthood.
In spite of the generally conceded fact that kinaesthetic processes are of fundamental importance in animal behavior, almost nothing is known that bears specifically upon these processes. Except for Carr's recent extended study of simple alternation no attempt has been made to disentangle the kinaesthetic processes incident to all studies of discrimination from the matrix of other sensory processes in which they are obscured. The present study, first reported in 1918, attempts to determine how much a rat can do in terms of kinaesthesis using the following maze problems: simple alternation; double alternation (twice to the right side of the apparatus, twice to the left side, etc.); and a problem termed the "temporal maze." The present tests ultimately indicated that the rat has practically no capacity to set up habits where the sensory complexes succeed each other merely in time. It is possible that a rat might learn a space maze requiring simple alternation and then run it in terms of kinaesthesis. The animal however easily masters the ordinary maze where the choices may be in any combination. How can it use the kinaesthesis connected with a left turn at one time to initiate a turn to the right and at another moment to initiate a turn to the left? The tests reported here have indicated that this cannot be done unless spatially arranged cues are available. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Complex behaviors such as learning and memory are regulated by multigenic systems. The advent of new animal models created by recombinant DNA technology has provided a set of genetic tools whereby the role of specific candidate genes in acquisition and retention of new information can be examined. These techniques include the creation of null mutant mice. Because of the polygenic nature of complex behaviors, the impact of single gene manipulations will in part depend on the genetic background of the mouse. This review addresses the relationship of endogenous strain differences in complex learning performance using a number of learning and memory paradigms to the analyses of null mutants. Limitations to the current technology and possible future advances are discussed. © 1997 Wiley-Liss, Inc.
Rats were trained over a number of sessions on an eight-arm radial maze with eight trials on each session. Each of four arms
on the maze contained a different pattern formed by sequences of reward (two pellets) or nonreward (no pellets) over successive
trials within sessions. The patterns were single alternation, double alternation, and two patterns in which four rewards or
four nonrewards were preceded and followed by two nonrewards or two rewards, respectively. The other four arms on the maze
served as control arms and always contained one pellet. It was found that rats tracked all of these patterns when they were
required to climb over barriers to enter and leave arms. However, rats showed no ability to extrapolate patterns beyond the
training trials. These findings, and a further analysis of arm-choice stereotypy, led to the conclusion that rats tracked
by using a trial-number strategy.
Morris water maze data are most commonly analyzed using repeated measures analysis of variance in which daily test sessions are analyzed as an unordered categorical variable. This approach, however, may lack power, relies heavily on post hoc tests of daily performance that can complicate interpretation, and does not target the nonlinear trends evidenced in learning data. The present project used Monte Carlo simulation to compare the relative strengths of the traditional approach with both linear and nonlinear mixed effects modeling that identifies the learning function for each animal and condition. Both trend-based mixed effects modeling approaches showed much greater sensitivity to identifying real effects, and the nonlinear approach provided uniformly better fits of learning trends. The common practice of removing a rat from the maze after 90 s, however, proved more problematic for the nonlinear approach and produced an underestimate of y-axis intercepts.
Inbred mouse strains differ in genetic makeup and display diverse learning and memory phenotypes. Mouse models of memory impairment can be identified by examining hippocampus-dependent memory in multiple strains. These mouse models may be used to establish the genetic, molecular, and cellular correlates of deficits in learning or memory. In this article, we review research that has characterized hippocampal learning and memory in inbred mouse strains. We focus on two well-established behavioral tests, contextual fear conditioning and the Morris water maze (MWM). Selected cellular and molecular correlates of good and poor memory performance in inbred strains are highlighted. These include hippocampal long-term potentiation, a type of synaptic plasticity that can influence hippocampal learning and memory. Further methods that might help to pinpoint the anatomical loci, and genetic and cellular/molecular factors that contribute to memory impairments in inbred mice, are also discussed. Characterization of inbred mouse strains, using multidisciplinary approaches that combine cellular, genetic, and behavioral techniques, can complement directed mutagenesis to help identify molecular mechanisms for normal and abnormal memory functions.
The existence of sex differences in the standard rat and mouse models of learning and memory is a controversial and contested topic in the literature. The present meta-analysis of radial maze and water maze experiments was conducted to assess the reliablility and magnitude of sex effects in the standard rodent models of learning and memory. Data were culled from published and unpublished sources. Findings indicate large reliable male advantages for rats in radial maze and water maze protocols. Significant strain differences were also identified. In each paradigm, protocol variations were associated with differential sex effects. For the water maze, smaller male advantages were associated with pretraining regimens and for the radial maze, larger significant male advantages were observed in protocols that included unbaited arms (combined reference and working memory protocols). Mouse studies exhibited a different pattern of sex effects; small female advantages were evident in the water maze, but small male advantages were evident in the radial maze. Together these findings establish the reliability of male advantages in spatial working and reference memory for rats across strains, protocols, ages and rearing environments. The findings also support an important species dichotomy between rats and mice that should be considered when transitioning from rat to mouse models. In light of these results, the biological evidence supporting theoretical explanations of sex differences is reviewed and evaluated.