Of mice and marbles: Novel perspectives on burying behavior as a screening test for psychiatric illness

Abstract

Burying forms part of the normal behavioral routine of rodents, although its expression is species-specific. However, it has been suggested that aberrant burying behavior, of which marble-burying (MB) is an example, may represent neophobic and/or compulsive-like behavior. In the present investigation, we assessed MB in an established animal model of obsessive-compulsive disorder (OCD)-namely, spontaneous stereotypy in the deer mouse-to establish whether high (H) stereotypy is associated with neophobia and/or another compulsive endophenotype, i.e. MB, as compared to nonstereotypical (N) controls. A three-trial, one-zone MB test was performed over three consecutive evenings both before and after chronic treatment with high-dose (50 mg/kg/ day) oral escitalopram. Neophobia was measured via the number of marbles buried during the first pre-and posttreatment MB trials, and compulsive-like behavior via the number of marbles buried over all pre-and posttreatment MB trials. The data from the present study support earlier findings that burying is a normal behavioral routine (inherent burying behavior, IBB) that is expressed by all deer mice, irrespective of stereotypical cohort, and is not associated with either neophobia or compulsiveness. Indeed, chronic escitalopram treatment, which is similarly effective in treating clinical anxiety and OCD, as well as in attenuating H behavior, failed to influence IBB. Although 11 % of the animals presented with a unique burying endophenotype (high burying behavior), escitalopram also failed to attenuate said behavior, necessitating further investigation as to its relevance. In conclusion, MB cannot be regarded as a measure of anxiety-like or compulsive behavior in the deer mouse model of OCD.Keywords Marble-burying . Obsessive-compulsive disorder . Neophobia . Deer mouse . Animal model . Escitalopram Burying, burrowing, and digging form part of the normal behavioral repertoire of rodents, in both the wild and the laboratory (Deacon, 2006;Smithers, 1983). These strain-specific behaviors are mostly aimed at searching for food, burying both noxious and harmless objects, and building adequate nurseries capable of protecting individuals against predators and providing suitable environments to breed (Smithers, 1983). Evidently, burying and digging are expressed in relatively nonanxiogenic scenarios (e.g., nesting, hoarding, foraging), as well as under anxiogenic circumstances (e.g., burying of noxious objects, confronting predators).Defensive burying (Pinel & Treit, 1978) can be defined as the process of moving loose bedding material vertically upward and over potentially harmful stimuli or sources of aversive stimulation (e.g., a shock prod). Due to the stressprovoking nature of an electric shock, defensive burying has been used as a measure of avoidance-dependent anxiety in a Electronic supplementary material The online version of this article

Obsessive-compulsive disorder: Insights from animal models

“…H deer mice do not present with altered marble burying behavior, a measure of compulsivity or anxiety (neophobia), compared to non-stereotypic (N) mice (Wolmarans et al, 2016a). In fact, all deer mice exhibit a level of inherent burying behavior, thereby dissociating severity of stereotypy with anxiety.…”

“…Environmental enrichment partially suppresses the expression of stereotypy, also prompting delayed presentation (Hadley et al, 2006; Powell et al, 1999), indicating that confinement stress is more a triggering factor than an etiological determinant, and since compulsions can be distinguished from rigid motor patterns on the basis of thoughtfulness (Eilam et al, 2006), deer mouse stereotypy can be regarded as flexible. Also deer mouse stereotypy appears to be associated with social deficits, is independent of anxiety and presents with symptom heterogeneity with regard to other forms of compulsive-like behavior that has value for studying the obsessive-compulsive interface of OCD (Section 4.3; Wolmarans et al, 2016a,b,c). As in OCD (Evans et al, 2004; Husted et al, 2006; Markarian et al, 2010) and as emphasized in the earlier two models (Sections 2 and 3), high stereotypic (H) deer mice also present with frontal cortical pathology, e.g., disordered redox balance (Guldenpfennig et al, 2011) and altered cyclic adenosine-monophosphate (cAMP)-phosphodiesterase (PDE) signaling (Korff et al, 2009).…”

“…In fact, all deer mice exhibit a level of inherent burying behavior, thereby dissociating severity of stereotypy with anxiety. Moreover, a characteristically different within-species form of high burying behavior is evident in certain animals, although neither inherent nor high burying behavior responds to chronic SSRI treatment (Wolmarans et al, 2016a). Since chronic SSRI treatment is effective in OCD and anxiety, as well as in attenuating deer mouse stereotypy (Korff et al, 2008, 2009; Wolmarans et al, 2013), we conclude that anxiety is not a driving force for perseverative behavior in the deer mouse, which may be in line with the recent DSM-5 reclassification of OCD.…”

Central norepinephrine transmission is required for stress-induced repetitive behavior in two rodent models of obsessive-compulsive disorder

“…Some advances in understanding the neurobiology of OCD have come from genetic and behavioral models of the disease, which have various degrees of face, construct, and predictive validity (Ahmari et al 2015;Fineberg et al 2011;Joel 2006;Ting and Feng 2011;Witkin 2008). The nestlet shredding (NS) and marble burying (MB) tasks are two rodent models of repetitive, compulsive behaviors that may be useful for testing novel pharmacotherapies for OCD (Angoa-Pérez et al 2013;Li et al 2006;Wolmarans et al 2016). In these tasks, repetitive behaviors (digging for MB; shredding for NS) are elicited by cage-change stress and do not habituate even after repeated daily exposures to marbles or nestlets (Thomas et al 2009;Witkin 2008).…”

“…Digging and nest building are normal rodent behaviors that are augmented by stress (Deacon 2006;Kedia and Chattarji 2014;Schultz 1972;Umathe et al 2008). The fact that these behaviors do not habituate lends face validity to both tasks and distinguishes them from canonical models of novelty-induced anxiety (Handley 1991;Witkin 2008;Wolmarans et al 2016). The construct validities of MB and NS are supported by studies using mice with genetic 5-HT depletion (Tph2-/-).…”