Memory of a choice direction in a T maze as measured by spontaneous alternation in mice: Effects of intertrial interval and reward

Spontaneous alternation in a T maze was studied as a one trial learning paradigm in mice of the BALB/c strain. In the first experiment the combined effects of time interval between the first and second trial (intertrial interval: ITI), food deprivation and feeding given during the first trial, were shown to affect performance. Thus, on the one hand, the percentage of spontaneous alternation decreased as ITI increased; on the other hand, food reward dramatically improved spontaneous alternation for the 24-h ITI, but had no significant effect for 30-sec and 1-h ITI. Since the effect of feeding might be due either to an increase of arousal, thus favoring input of informations associated with the first choice, or to an improvement in memory consolidation, a second experiment was aimed at testing the effect of food given after the first trial. It was shown that, as in the first experiment, post-trial feeding improved spontaneous alternation on the second trial given 24 hours later with a temporal gradient of effect less than 30 min. These results clearly showed that the reinforcement of run to one side (first trial) increased the tendency to go to the other side 24 hours later. It is concluded that reinforcement might have two distinct effects: (i) according to SR theory, reinforcement increases conditioned responses and (ii), as shown here, acts on memory processes by preventing memory traces from fading. The fact that this last effect was only observed for long ITI suggests that short-term or transient memory and long-term memory are two relatively independent processes.     

Effects of physical fatigue in mice on learning performance in a water maze

We investigated the effects of physical fatigue produced by swimming exercise on learning the Morris water maze in BALB/c mice. We measured the escape latency in the maze immediately after the swimming exercise. The control group was soaked in the water but not fatigued. For easier tasks, like one with an obvious cue flag, the escape latency was not changed by exercise fatigue. However, escape latency was increased after exercise fatigue for more difficult tasks of spatial learning. These results appear to suggest that physical fatigue impaired learning performance. The effects of swimming exercise fatigue on learning efficiency were then investigated. Mice were continuously fatigued during the spatial learning period. This increased escape latency between the first and third sessions. The results suggest that learning efficiency was impaired by exercise fatigue. This system may be useful for screening new foods used to enhance brain function during exercise.     

Effect of L-asparaginase on retention of maze learning in mice

Long-term memory impairment has been described previously in mice receiving inhibitors of protein synthesis. In the present work, the enzyme L-asparaginase was injected into mice by an intrathecal or by an intraperitoneal route and produced a significant impairment of memory. Glutamine and asparagine prevented the effect of asparaginase when injected by the intraperitoneal route.     

Pre-natal administration of diazepam improves radial maze learning in mice

A number of studies have found that the peri-natal exposure of rodents to diazepam alters their adult behaviour. Adult male mice, treated with diazepam or appropriate controls during pregnancy, were examined in terms of their ability to learn a radial maze. Those animals receiving diazepam prior, but not after birth, learnt the maze significantly more rapidly. The results are discussed in terms of the possible involvement of the hippocampus in this influence of diazepam.     

Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice

The National Institute on Aging's Interventions Testing Program was established to evaluate agents that are purported to increase lifespan and delay the appearance of age-related disease in genetically heterogeneous mice. Up to five compounds are added to the study each year and each compound is tested at three test sites (The Jackson Laboratory, University of Michigan, and University of Texas Health Science Center at San Antonio). Mice in the first cohort were exposed to one of four agents: aspirin, nitroflurbiprofen, 4-OH-alpha-phenyl-N-tert-butyl nitrone, or nordihydroguaiaretic acid (NDGA). Sample size was sufficient to detect a 10% difference in lifespan in either sex,with 80% power, using data from two of the three sites. Pooling data from all three sites, a log-rank test showed that both NDGA (p=0.0006) and aspirin (p=0.01) led to increased lifespan of male mice. Comparison of the proportion of live mice at the age of 90% mortality was used as a surrogate for measurement of maximum lifespan;neither NDGA (p=0.12) nor aspirin (p=0.16) had a significant effect in this test. Measures of blood levels of NDGA or aspirin and its salicylic acid metabolite suggest that the observed lack of effects of NDGA or aspirin on life span in females could be related to gender differences in drug disposition or metabolism. Further studies are warranted to find whether NDGA or aspirin, over a range of doses,might prove to postpone death and various age-related outcomes reproducibly in mice.     

Bayesian cue integration as a developmental outcome of reward mediated learning

Average human behavior in cue combination tasks is well predicted by bayesian inference models. As this capability is acquired over developmental timescales, the question arises, how it is learned. Here we investigated whether reward dependent learning, that is well established at the computational, behavioral, and neuronal levels, could contribute to this development. It is shown that a model free reinforcement learning algorithm can indeed learn to do cue integration, i.e. weight uncertain cues according to their respective reliabilities and even do so if reliabilities are changing. We also consider the case of causal inference where multimodal signals can originate from one or multiple separate objects and should not always be integrated. In this case, the learner is shown to develop a behavior that is closest to bayesian model averaging. We conclude that reward mediated learning could be a driving force for the development of cue integration and causal inference.     

Preservation of femoral bone thickness in middle age predicts survival in genetically heterogeneous mice

To see whether age-related changes in bone could predict subsequent lifespan, we measured multiple aspects of femur size and shape at 4, 15, and 24 months of age in genetically heterogeneous mice. Mice whose cortical bone became thicker from 4 to 15 months, associated with preservation of the endosteal perimeter, survived longer than mice whose endosteal cavity expanded, at the expense of cortical bone, over this age range. Femur size at age 4 months was also associated with a difference in life expectancy: mice with larger bones (measured by length, cortical thickness, or periosteal perimeter) had shorter lifespans. Femur length, midlife change in cortical bone thickness, and midlife values of CD8 T memory cells each added significant power for longevity prediction. Mice in the upper half of the population for each of these three endpoints lived, on average, 103 days (12%) longer than mice with the opposite characteristics. Thus, measures of young adult bone dimensions, changes as a result of bone remodeling in middle age, and immunological maturation provide partially independent indices of aging processes that together help to determine lifespan in genetically heterogeneous mice.     

Learning to solve a spatial task in a water maze in aggressive and submissive mice

Learning and retention of the spatial memory were studied in mice with alternative under conditions of various experimental protocols. Visible and hidden platform acquisition in a simple model of the water maze was similarly fast both in aggressive and submissive mice, but extinction differed. Retention of the platform location preference persisted in aggressive mice in four testing trials. In submissive mice, extiction of the spatial memory was accompanied with a prolongation of search with parallel production of episodes of "passive drift". Differences in spatial learning between aggressive and submissive mice were revealed in a water maze complicated with partitions. In this case, aggressors were able to learn the position of a hidden platform (in contrast to submissive mice with the dominant response of "passive drift"). During testing the response, aggressive mice longer retained the spatial preference without extinction.     

Computational models of reinforcement learning: the role of dopamine as a reward signal

Reinforcement learning is ubiquitous. Unlike other forms of learning, it involves the processing of fast yet content-poor feedback information to correct assumptions about the nature of a task or of a set of stimuli. This feedback information is often delivered as generic rewards or punishments, and has little to do with the stimulus features to be learned. How can such low-content feedback lead to such an efficient learning paradigm? Through a review of existing neuro-computational models of reinforcement learning, we suggest that the efficiency of this type of learning resides in the dynamic and synergistic cooperation of brain systems that use different levels of computations. The implementation of reward signals at the synaptic, cellular, network and system levels give the organism the necessary robustness, adaptability and processing speed required for evolutionary and behavioral success.     

Neonatal exposure to intermittent hypoxia enhances mice performance in water maze and 8-arm radial maze tasks

Hypoxia has generally been reported to impair learning and memory. Here we established a hypoxia-enhanced model. Intermittent hypoxia (IH) was simulated at 2 km (16.0% O2) or 5 km (10.8% O2) in a hypobaric chamber for 4 h/day from birth to 1, 2, 3, or 4 week(s), respectively. Spatial learning and memory ability was tested in the Morris water maze (MWM) task at ages of postnatal day 36 (P36)-P40 and P85-89, respectively, and in the 8-arm maze task at P60-68. The long-term potentiation (LTP), synaptic density, and phosphorylated cAMP-responsive element-binding protein (p-CREB) level in the hippocampus were measured in mice at P36 under the IH for 4 weeks (IH-4w). The results showed that IH for 3 weeks (IH-3w) and IH-4w at 2 km significantly reduced the escape latencies of mice at P36-40 in the MWM task with significantly enhanced retention, and this spatial enhancement was further confirmed by the 8-arm maze test in mice at P60-68. The improvement in MWM induced by IH-4w at 2 km was still maintained in mice at P85-89. IH-4w at 2 or 5 km significantly increased amplitude of LTP, the number of synapse, and the p-CREB level in the hippocampus of P36 mice. These results indicated that IH (4 h/day) exposure to neonatal mice at 2 km for 3 or 4 weeks enhanced mice spatial learning and memory, which was related to the increased p-CREB, LTP, and synapses of hippocampus in this model.     

Development of a maze test and its application to assess spatial learning and memory in Merino sheep

A maze test was developed to assess spatial memory and learning in Merino sheep. Total time to traverse the maze and times spent in cul de sacs (errors) were used to assess performance. Both total time and errors decreased when the performance of sheep was assessed on three consecutive days, indicating that sheep learnt to traverse the maze. Scopolamine hydrobromide, a drug known to impair memory, was administered to sheep to validate whether the maze could be used to assess deficits in learning and spatial memory. Sheep receiving scopolamine hydrobromide 30 min before maze testing on each of three successive days were significantly slower to complete the maze on day 3 compared to control sheep receiving saline. The results suggested that the maze was measuring spatial memory and therefore might be useful to assess neurological deficits related to spatial memory and learning in sheep in neurological conditions such as Annual Ryegrass Toxicity. Tunicamycins are chemically and toxicologically analogous to the corynetoxins that cause the often fatal neurological disease Annual Ryegrass Toxicity. Exposure to tunicamycins did not affect total time to complete the maze, the number of errors committed or the ability to retain the memory of the maze configuration when tested 6 weeks later. These results, in addition to showing no adverse effect of the tunicamycins, also indicate that sheep have the ability to learn and retain the spatial memory of a relatively complex maze.     

Innate behaviour of mice studied in a double Y maze

A test to study mice innate behaviour was realized. Groups of mice ran a double Y maze and chose one of the four possible exits. The results showed with a high probability level that mice had a very clear preference for a choice rather than the other ones.     

Retarded myogenic cell replication in regenerating skeletal muscles of old mice: an autoradiographic study in young and old BALBc and SJL/J mice

The patterns of skeletal muscle precursor cell replication after crush injury were compared by the use of autoradiographic techniques, in young (4-week-old) and old (39-week-old) BALBc and SJL/J mice. Similar comparisons were made between cut and crush lesions in old BALBc muscle. Muscle precursor cell replication commenced at 18–24 h after injury in both young and old muscles from both strains of mice. In young BALBc muscle the peak of myogenic activity at 60 h was 36 h earlier than in old mice. SJL/J muscle responded more rapidly than did BALBc: in young SJL/J the peak myogenic activity was at 46 h (14 h earlier than in young BALBc muscle), and in old SJL/J muscle the peak activity at 72 h was 24 h earlier than in old BALBc muscle. In all mice (both young and old) myogenic cell replication was substantially reduced by 120 h after injury. A comparison of the timing of muscle precursor cell replication in cut and crush lesions in old BALBc mice revealed a more rapid response in the cut lesion: this difference between the lesions in comparable with data from identical lesion in 6-8-week-old BALBc mice (McGeachie and Grounds 1987). However, the peak of myogenic replication in the older mice in the present study was some 26–36 h later than in the younger 6-8-week-old mice. These experiments show that, whilst muscle precursor cell replication commences at approximately the same time (about 24 h) after injury in young and old mice, the peak level of activity is delayed by some 24–36 h in old mice. In addition, the SJL/J mouse strain responds more rapidly and prolifically to muscle injury than does the BALBc strain.     

Selected contribution: Variation and heritability for the adaptational response to exercise in genetically heterogeneous rats.

Adaptational response to aerobic exercise was artificially selected for across one generation in a founder population of 20 female and 20 male genetically heterogeneous rats (N:NIH). Selection for low and high response was based on the change in treadmill running capacity, assessed by meters (m) run to exhaustion before and after 24 days of modest treadmill running. The training response of the founder population averaged +222 m, with wide variation from a negative gain (-) of -110 m to a positive gain (+) of +430 m. Six pairs of the lowest (+13 m) and highest (+327 m) responders were mated. Mean response to training of the low-line (+242 m) offspring did not differ from the founder. The high-selected line gained 383 m from training, +161 m above the founder population. Narrow sense heritability estimated from regression of offspring on midparent values for response to training was 0.43 (P < 0.007). One generation of selection resulted in a 58% divide between the low and high lines. Selectively bred models of both intrinsic (untrained) and adaptation response can be useful in resolving the genetic basis of variation in aerobic capacity.     

Stromal precursor cell count in the bone marrow of young and old CBA mice

The content of stromal precursor cells in the bone marrow of young (1-4-month-old) and old (24-30-month-old) CBA mice was measured by cloning in primary monolayer cultures. It was found that both the concentration (fibroblast colony forming efficiency) and the total number of stromal precursors in femoral bone marrow markedly increased with aging.     

Two-day radial-arm water maze learning and memory task; robust resolution of amyloid-related memory deficits in transgenic mice

The radial arm water maze (RAWM) contains six swim paths (arms) extending out of an open central area, with an escape platform located at the end of one arm (the goal arm). The goal arm location remains constant for a given mouse. On day 1, mice are trained for 15 trials (spaced over 3 h), with trials alternating between visible and hidden platform. On day 2, mice are trained for 15 trials with the hidden platform. Entry into an incorrect arm is scored as an error. The RAWM has the spatial complexity and performance measurement simplicity of the dry radial arm maze combined with the rapid learning and strong motivation observed in the Morris water maze without requiring foot shock or food deprivation as motivating factors. With two sessions each day, 16 mice can be tested over 2 days.