Sequential super-stereotypy of an instinctive fixed action pattern in hyper-dopaminergic mutant mice: a model of obsessive compulsive disorder and Tourette's

Abstract

Background: Excessive sequential stereotypy of behavioral patterns (sequential super-stereotypy) in Tourette's syndrome and obsessive compulsive disorder (OCD) is thought to involve dysfunction in nigrostriatal dopamine systems. In sequential super-stereotypy, patients become trapped in overly rigid sequential patterns of action, language, or thought. Some instinctive behavioral patterns of animals, such as the syntactic grooming chain pattern of rodents, have sufficiently complex and stereotyped serial structure to detect potential production of overly-rigid sequential patterns. A syntactic grooming chain is a fixed action pattern that serially links up to 25 grooming movements into 4 predictable phases that follow 1 syntactic rule. New mutant mouse models allow gene-based manipulation of brain function relevant to sequential patterns, but no current animal model of spontaneous OCD-like behaviors has so far been reported to exhibit sequential super-stereotypy in the sense of a whole complex serial pattern that becomes stronger and excessively rigid. Here we used a hyper-dopaminergic mutant mouse to examine whether an OCD-like behavioral sequence in animals shows sequential super-stereotypy. Knockdown mutation of the dopamine transporter gene (DAT) causes extracellular dopamine levels in the neostriatum of these adult mutant mice to rise to 170% of wild-type control levels.

Results: We found that the serial pattern of this instinctive behavioral sequence becomes strengthened as an entire entity in hyper-dopaminergic mutants, and more resistant to interruption. Hyper-dopaminergic mutant mice have stronger and more rigid syntactic grooming chain patterns than wild-type control mice. Mutants showed sequential super-stereotypy in the sense of having more stereotyped and predictable syntactic grooming sequences, and were also more likely to resist disruption of the pattern en route, by returning after a disruption to complete the pattern from the appropriate point in the sequence. By contrast, wild-type mice exhibited weaker forms of the fixed action pattern, and often failed to complete the full sequence.

Conclusions: Sequential super-stereotypy occurs in the complex fixed action patterns of hyper-dopaminergic mutant mice. Elucidation of the basis for sequential super-stereotypy of instinctive behavior in DAT knockdown mutant mice may offer insights into neural mechanisms of overly-rigid sequences of action or thought in human patients with disorders such as Tourette's or OCD.

Figure 1

Prototypical syntactic grooming chain pattern. Choreograph shows mouse movements of the left/right paws over the face (time proceeds from left to right). Lines deviating above/below the horizontal axis show the trajectory height of left/right paws. Large black box denotes bout of body licking, and placement of asterisk in box shows which left/right side flank was chosen by the mouse to initiate body licking. Phase I: series of ellipse-shaped strokes tightly around the nose. Left and right paws often take alternating turns as the major/minor trajectory. Phase II: series of unilateral strokes, each made by one paw, that reach up the mystacial vibrissae to below the eye. Mice often make hybrid Phase I/II strokes, in that one paw makes a Phase II unilateral stroke while the remaining paw makes a smaller Phase I type ellipse. Phase III: series of bilateral strokes made by both paws simultaneously. Paws reach back and upwards, ascending usually high enough to pass over the ears, before descending together over the front of the face. Phase IV (strong or classic form): sustained bout of body licking, preceded by postural cephalocaudal transition to move mouth and tongue from facial and paw grooming to body grooming. Mouse-typical pattern modified from Berridge (1990). See Additional movie file 1 for examples of syntactic grooming chains by DAT-KD mutant mice.

Figure 2

Sequential super-stereotypy of syntactic pattern. Cumulative rates of full pattern completion by DAT-KD mutant (dark symbols) and wild-type mice (open symbols) for each type of syntactic chain (Perfect, Insertion of unpredicted component, Phase Reversal, Phase Skip, Substitution of paw lick for Terminal Phase IV component). Choreographs at bottom show example for each type of syntactic chain. Mutant mice have higher rates of syntactic completion for all forms of the chain that terminate in the strong form of Phase IV, body licking, which characterizes the prototypical Phase IV for all rodents. Wild-type mice use a weak form of Phase IV (paw lick substitution) to terminate a substantial proportion of their syntactic chains. All mice show less pattern completion when grooming in the laboratory (top) than when grooming in their home cage (bottom), but mutant mice show more rigid sequential patterns than wild-type mice while grooming in both environments. * p < 0.05; ** p < 0.01.

Figure 3

Sample choreographs of actual syntactic chains. Both mutant mice and wild-type mice emit every type of syntactic chain described in the text (Perfect, Insertion of unpredicted component, Phase Reversal, Phase Skip, and Substitution of paw lick for Terminal Phase IV).

Figure 4

Initiation of stereotyped syntactic chain pattern. Rates of initiation of syntactic chains are slightly higher for mutant mice, especially while grooming in the laboratory, measured cumulatively across the entire observation period (top). In more detail, initiation rates are broken down as occurring either early versus late in grooming bouts (bottom). All mice tend to start the stereotyped sequential pattern more often early in a grooming bout. Mutant mice are even more likely than wild-type mice to start the pattern in an early grooming bout, both in home and laboratory environments. ** p < 0.01.

Figure 5

General amount and bout features of grooming behavior. Cumulative time spent in grooming behavior during observation (total duration), Duration of individual bouts of grooming, and the Number of bouts of grooming emitted during observation session. Mutant mice tend to spend more time in grooming than wild-type mice, and to have longer grooming bouts, in the home environment. Mutant mice tend to emit a greater number of fragmented bouts when grooming in the laboratory environment. These general features of grooming enhancement in mutant mice are flexible and context-dependent, in contrast to the greater mutant rigidity of sequential pattern that is constant across both environments (shown in Figure 2). * p < 0.05; ** p < 0.01.