Novel behavioral and pharmacological characterization of spontaneous stereotypy in the deer mouse
Abstract
Obsessive-compulsive disorder (OCD) is a psychiatric condition that is characterized by two main symptom cohorts, namely recurrent inappropriate thoughts (obsessions) and seemingly purposeless repetitive motor actions (compulsions). Furthermore, OCD is a clinically heter-ogeneous condition, presenting with different within- and between patient symptom pheno-types. Although OCD is classified as an obsessive-compulsive (OC) spectrum disorder, while anxiety is very often a co-presenting symptom, it is debated whether anxiety plays a role in its pathology. However, central to the diagnosis of OCD is the time-consuming nature of symptoms that interferes with the normal social and occupational routines of patients. More-over, 70% of cases, irrespective of the symptom cohort diagnosed, respond to chronic but not sub-chronic high dose treatment with the selective serotonin reuptake inhibitors (SSRIs), e.g. escitalopram.
Validated animal models play a crucial role in acquiring new knowledge pertaining to the pa-thology and pharmacology of psychiatric illness, and OCD is no exception. The current study continues the validation process of the deer mouse (Peromyscus maniculatus bairdii) model of OCD and builds on previous work done in our laboratory. Deer mice that are bred and housed in confinement naturally develop two main forms of stereotypical behavior, namely vertical jumping and pattern running. Furthermore, based on the intensity and time-consum-ing nature of these behaviors, it can be categorized into levels of severity, namely high (H) and non- (N)-stereotypic cohorts. The seemingly purposeless and repetitive nature of these be-haviors mimics the compulsions that characterize human OCD and constitutes the basis for face validity of the model. However, given the heterogeneous nature of OCD, the main focus of the current investigation was aimed at broadening the face validity of deer mouse behavior by 1) characterizing the social interactivity between animals from the same and different co-horts, 2) establishing if novelty-induced anxiety (viz. neophobia) may play a role in the mani-festation of H stereotypy, 3) determining whether deer mouse stereotypy is representative of multiple OC phenotypes, and 4) if such differences do exist, are they responsive to chronic escitalopram treatment.
As patients with OCD demonstrate altered social competence in relationships with normal peers, we characterized the within and between cohort social behavior of H and N deer mice. However, in an attempt to observe the social interactions of H and N animals towards one another in the presence of an animal from a different cohort, we developed a novel three-animal social interaction paradigm. As such, we determined that treatment-naive H deer mice display more within cohort interaction, compared to N controls. Furthermore, H animals interact more with one another in the presence of an N animal while N animals also group together in the presence of an H animal. Moreover, chronic treatment with oral escitalopram significantly increased the sociability of H animals towards one another and towards N ani-mals, while the social interactivity of N animals remained unaltered.
In an attempt to establish if neophobia-related anxiety may be associated with the expression of H stereotypy, we subjected animals to the marble-burying (MB) test. The test is based on the theory that neophobia will be associated with increased burying behavior on the first, but not subsequent MB trials. As such, data from the current investigation demonstrates that all deer mice display inherent burying behavior that is not sensitive to chronic treatment with escitalopram and therefore fails to demonstrate a neophobia-like component underlying H stereotypy. This result is in line with literature proposing that MB resembles normal and investigative, rather than pathological behavior.
As previous studies propose both aberrant MB and nest-building (NB) behavior to resemble OC behavior in different putative animal models of OCD, we aimed to determine whether such behavior may be expressed by deer mice, thereby resembling symptom heterogeneity in the deer mouse model of OCD. Although we identified aberrant (viz. high) MB behavior in 11% of animals from both stereotypical cohorts, chronic escitalopram treatment failed to at-tenuate this behavior. However, 30% of all animals of both cohorts, displayed unique large nest building (LNB) behavior. Furthermore, chronic treatment with escitalopram significantly affected LNB, decreasing the average daily and total nesting scores to levels akin to that ex-pressed by the larger group. Although we could not demonstrate an OC construct underlying MB, we were able to provide evidence for the putative face and predictive validity of aberrant NB in deer mice. The latter supports the notion that deer mouse stereotypy is indeed het-erogeneous with multiple symptom presentation.
Taken together, the results from the current study strengthens the face and predictive validity of the deer mouse model of OCD and confirm the model’s status as a prominent, useful and robust animal model of OCD. Not only is altered and treatment sensitive sociability impli-cated in the behavior of H animals, but the model also provides a useful pre-clinical platform to investigate the heterogeneous nature of OCD and its response to treatment, as well as future explorative studies into its neurobiology
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