Research reportProcedural learning and cognitive flexibility in a mouse model of restricted, repetitive behaviour
Introduction
Restricted, repetitive behaviours (e.g., stereotypy, compulsions, restricted interests) are common behavioural phenotypes of autism and related neurodevelopmental disorders [21], [46]. These behaviours are considered abnormal because they are stigmatizing, preclude or disrupt goal-directed actions, limit interaction with the environment, and on occasion are self-injurious. Despite their prevalence and clinical significance, specific pathophysiological mechanisms that mediate the development and expression of these behaviours have yet to be identified.
To study the underlying neurobiological basis of repetitive behaviours, several categories of relevant animal models are available. These categories include stereotypy associated with central nervous system insults, pharmacologically induced stereotypy, and stereotypy induced by rearing animals in restricted environments [22]. The preponderance of what we know about the neurobiology of repetitive behaviour comes from studies of drug-induced stereotyped behaviour. This literature supports perturbations of cortico-basal ganglia circuitry as mediating repetitive behaviour [6], [12], [14], [20], [41], [48], [49].
Our lab has used a model of spontaneous stereotypy associated with environmental restriction. This model uses deer mice (Peromyscus maniculatus), which show persistent, high rates of vertical jumping or backward somersaulting when housed under standard laboratory conditions. Early exposure to environmentally complex settings significantly attenuates the development of such behaviours [13], [32], [33]. Such attenuation has been associated with structural and functional brain changes occurring selectively in areas included in cortico-basal ganglia circuitry [43], [44], [45]. More direct tests by our group of the involvement of this circuitry have supported its importance [34], [35].
If spontaneous, persistent stereotypy in deer mice reflects disrupted cortico-basal ganglia circuitry, then other functional domains (e.g., cognitive function) relying on similar brain regions should also be perturbed. Moreover, such altered functioning should be associated with levels of stereotypy. The role of the striatum in cognition (e.g., procedural learning or stimulus-response learning), distinct from hippocampally dependent learning and memory, is increasingly appreciated [29], [52], [55]. The double dissociation of these mnemonic systems has been supported by lesion studies in spatial and cue versions of Morris water maze tasks [25], [28] and win-shift and win-stay radial-arm maze tasks [17], [27]. In addition, as rats learned a new stimulus-response contingency, task-specific dynamic changes in neural firing patterns within the striatum have been demonstrated [1], [15], further supporting the role of the striatum in procedural learning.
Other domains of cognitive function, which require intact cortico-basal ganglia circuitry, include cognitive flexibility, a subcomponent of executive function. Damage in subregions of the frontal cortex (dorsolateral prefrontal cortex and orbitofrontal cortex) causes difficulty in shifting a response or switching strategies when the stimulus-response contingency changes [3], [4], [18], [36], [51].
There is some evidence in both the clinical and animal literature supporting an association between repetitive motor behaviour and these forms of cognitive function. For example, spontaneously stereotypic blue and marsh tits [10], Orange-winged Amazon parrots [11], bank voles [9], and bears [50] exhibited a perseverative response pattern in a gambling task or in reversal or extinction of stimulus-response learning. A similar relationship was demonstrated by Lopez et al. [23] in adults with autism, whose scores on the executive function task that indexed cognitive rigidity were positively correlated with severity of restricted, repetitive behaviour. Executive function deficits have been recognized in individuals with autism for some time but previously not related to repetitive behaviour. Little is known about the relationship between procedural or implicit learning and repetitive motor behaviour, although there is some evidence that children with obsessive-compulsive disorder (OCD) and tic disorders may have deficits in this form of learning [24], [38].
To investigate the association between spontaneous stereotypy and cognitive programs mediated by cortico-basal ganglia circuitry, the present experiment examined procedural learning and cognitive flexibility in deer mice. We hypothesized that mice exhibiting high rates of stereotypy would show impaired performance in a simple T-maze task as well as in the reversal of the learned task contingency. Moreover, we hypothesized that environmental enrichment would result in improved performance on these cognitive tasks in addition to attenuating repetitive motor behaviour.
Section snippets
Subjects
Fifty-nine deer mice (P. maniculatus) were originally designated for this experiment, but during the period from weaning to the completion of the experiment, two mice died for unknown reasons and five mice were excluded. Data from 52 mice (23 male and 29 female; 3–7 months old) were used for analysis. Subjects were obtained from the breeding colony maintained in our laboratory, and at weaning (day 21) were randomly assigned to either standard cage (SC) or enriched environment (EE) housing
Stereotypy assessment
Stereotypy scores ranged from 38 to 2394 responses per hour for all animals. There was a significant housing effect on stereotypy score with EE mice (n = 25) exhibiting significantly lower rates of stereotypy than SC mice (n = 27). The EE condition decreased the average per hour stereotypy score by 550 (F(1,9) = 9.00, p = 0.02, Fig. 1) compared to SC mice. This p-value was from the type III tests, indicating that housing condition significantly affected stereotypy score even after sex and litter were
Discussion
We examined hypothesized impairments in cortico-striatally mediated cognitive processes in deer mice housed in different conditions and displaying different rates of stereotypy. In agreement with our previous findings (e.g., ref. [13]), deer mice reared in the EE condition developed significantly lower rates of stereotypy compared to mice reared in SC.
It has been repeatedly demonstrated that memory dependent on the hippocampus improves in animals following exposure to EE [5], [19], [31], [37],
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