Brenda A. Eales

The degree of lateralization of paw usage (handedness) in the mouse is defined by three major phenotypes

Lateralization of paw usage in the laboratory mouse may be a useful model system in which to assess the genetic and developmental cause of asymmetry of hand usage. With a set number of paw reaches from a centrally placed food tube, individual mice from an inbred strain will exhibit a reliable number of left and right paw reaches. For a single inbred strain, there are approximately equal numbers of left-pawed and right-pawed mice, but strain differences have been reported in the degree of lateralization of paw preference. We reported a preliminary strain survey in which the strains appeared to fall into two groups of highly lateralized and weakly lateralized paw preference (Biddleet al., 1993). We review here our expanded survey of genetically different strains and stocks of the laboratory mouse, including different species and subspecies. The major genetic trait is the degree of lateralization of paw preference and the strain differences appear to fall into three major classes of highly lateralized, weakly lateralized, and ambilateral preference. The trait exhibits both additivity and dominance in preliminary reciprocal crosses, depending on which strain pairs are used. The wide difference between strains that have highly lateralized and ambilateral paw preference suggests specific genetic tools that could be used to begin a genetic dissection of the causes of this trait. Preliminary assessment of the size of the corpus callosum in three strains with significantly different degrees of lateralization suggests that genetically determined deficiencies and absence of this structure are not the direct cause of the strain differences in the trait of degree of lateralization. In the expanded survey, some strains appear to exhibit a directional deviation from equal numbers of mice with left and right paw usage. Therefore, direction of paw usage may not be a genetically neutral trait, but replicate assessments and genetic tests are needed to confirm this.

Learning of paw preference in mice is strain dependent, gradual and based on short-term memory of previous reaches

We studied the dynamics of paw preference learning in unbiased symmetrical test chambers where mice, Mus musculus, could freely choose which paw to use. When compared to nonlearner model mice, three strains exhibited different degrees of learning within and between two training sessions 1 week apart. While paw preference was probabilistic, positive autocorrelation between paw choices made by individual mice in a training session showed that bias in paw preference changed gradually with successive paw reaches and was concordant between sessions. Within a session, the degree of positive autocorrelation between consecutive paw choices differed between strains and decreased faster with increasing lag between reaches in stronger than in weak learners, suggesting that the degree of learning is the genetic variable in mice. We propose that strong biases in individual mice result from weak biases that appear by chance early in training and increase by a positive feedback mechanism because of learning during training. This explains how individual mice of each strain were strongly biased when there was almost no bias at the population level. The decrease in autocorrelation with lag shows that constitutive behaviours play a minor role and, hence, paw preference can adapt to environmental changes. We conclude that paw preference learning in mice is genetically dependent on past experience, changes gradually within training sessions, and is based on short-term memory; it also has long-term effects, provided there is time for memory consolidation.

Dynamic Agent-Based Model of Hand-Preference Behavior Patterns in the Mouse

Using a new agent-based model that mimics the learning process in hand-reaching behavior of individual mice, we show that mouse hand preference is probabilistic, dependent on the environment and prior learning. We quantify the learning capabilities of three inbred strains and show that population distributions of hand preference emerge from the properties of individual mice. The model informs our understanding of gene—environment interactions because it accommodates genotypic differences in learning and memory abilities, and environmental biases. We tuned each strain’s model to match their experimental hand-preference distributions in unbiased worlds and, by comparing simulations and experiments, identified and quantified a constitutive left-bias in hand preference of one strain. The models, tuned for unbiased worlds, match experimental measures in left- and right-biased worlds and in biased worlds after previous training. New measures quantitatively assess this matching, revealing that two strains, previously considered non-learners of hand preference, actually have significant learning ability and we confirm this with new experiments. Model mice match the kinetics of hand-preference learning of one strain and predict the limits of learning. We conclude that genetically evolved hand-preference behavior in mice is inherently probabilistic to provide robustness and allow constant adaptability to ever-changing environments.

Predictability and randomness of paw choices are critical elements in the behavioural plasticity of mouse paw preference

Lateralized paw usage of mice, Mus musculus, is a learned behaviour, based on a gradual reinforcement of randomly occurring weak asymmetries in paw choice early in training. The reinforcement relies on strain-dependent, short-term and long-term memory. We characterized the skills of information accumulation by quantifying the predictability of each reach of initially naive mice from past behaviour in two training sessions of 50 reaches, separated by a 1-week interval. We studied six mouse strains, including 9XCA and BTBR with absent corpus callosum and severely reduced hippocampal commissure, and compared them to a null model with random, unbiased paw preference. We found that each paw choice was based on a limited, strain-specific number of previous choices. Also, there was a limited, strain-specific degree of predictability of each choice. Consequently, there was a strain-specific degree of randomness that was not lost with training. After 1 week for consolidation of memory of learned biases, paw choices became more predictable and made use of fewer previous choices, except in 9XCA and BTBR; nevertheless, a degree of randomness remained. We conclude that paw choices are regulated by short-term memory of a small number of previous choices and by long-term memory that affects future behaviour patterns and decreases, but does not remove, the usage of short-term memory. Both short-term and long-term memory skills are strain dependent. Importantly, a degree of randomness is not removed by training and this may be a critical element for behavioural plasticity in paw preference in changing environments, supplying constant adaptability in paw preferences.

Biological Limits of Hand Preference Learning Hiding Behind the Genes

Biological limits of learning are the cto our understanding of learning and memory. We are conducting a detailed investigation of structure and function of gene regulatory networks in a biological system of learning and memory. We use a simple system of hand reaching in laboratory mice and assess the regulation of the limit of hand preference learning. In this chapter, we describe hand-reaching behavior of mice and the discovery that it is a complex adaptive behavior in which future preference is genotypically dependent on past experience. We define the key elements that led to the collaborative development of a stochastic agent-based model. Simulation with the model mimics hand-reaching behavior and successfully predicts dynamics and kinetics of the learning and memory process in different genotypes of mice. Therefore, a mouse receives information from the act of reaching and uses it to inform the choice of the next hand reach; the model shows the structure of the behavior and the biological limits of hand preference learning hiding behind the genes. We use three different mouse strains as prototypes to illustrate the constructive path that predicts the adaptive behavioral phenotype from specified genotype. We believe that promises made by the power of genetic analysis will be kept by the discovery that simplicity resides in gene regulatory networks that give rise to learning and memory in adaptive behaviors.