Marble burying as compulsive behaviors in male and female mice

An increasing number of investigators utilize the marble-burying assay despite the paucity of information available regarding what underlies the behavior. We tested the possibility that a genetic component underlies marble burying in mice and if there is a genetic correlation with other anxiety-like traits. Since findings reported in the literature indicate that marble-burying behavior reflects an anxiety-like response, we explored the assumption that the novel nature of a marble induces this anxiety. Finally, we investigated how the natural response of a mouse to dig relates to the marble-burying phenomenon. We examined ten different inbred mouse strains to determine if marble-burying behavior is genetically regulated and correlated with anxiety-like traits in two other assays. We employed multiple variants of the "traditional" marble-burying assay to address how issues such as the novelty of marbles and digging behavior contribute to marble burying. Marble-burying behavior varied across strain and did not correlate with anxiety measures in other assays. Multiple tests conducted to reduce the novelty of marbles failed to alter burying behavior. Additionally, digging behavior correlated with marble burying, and the presence of marbles did not significantly impact the digging response. Our results indicate that mouse marble burying is genetically regulated, not correlated with other anxiety-like traits, not stimulated by novelty, and is a repetitive behavior that persists/perseveres with little change across multiple exposures. Marble burying is related to digging behavior and may in fact be more appropriately considered as an indicative measure of repetitive digging.

Advances in neuroimaging techniques over the past two decades have allowed scientists to investigate the neurocircuitry of anxiety disorders. Such research has implicated the orbitofrontal cortex (OFC). Characterizing the role of OFC in anxiety disorders, however, is principally complicated by two factors-differences in underlying pathophysiology across the anxiety disorders and heterogeneity in function across different OFC sub-territories. Contemporary neurocircuitry models of anxiety disorders have primarily focused on amygdalo-cortical interactions. The amygdala is implicated in generating fear responses, whereas cortical regions, specifically the medial OFC (mOFC) and the ventromedial prefrontal cortex (vmPFC), are implicated in fear extinction. In contrast to mOFC, anterolateral OFC (lOFC) has been associated with negative affects and obsessions and thus dysfunctional lOFC may underlie different aspects of certain anxiety disorders. Herein, we aim to review the above-mentioned theories and provide a heuristic model for conceptualizing the respective roles of mOFC and lOFC in the pathophysiology and treatment of anxiety disorders. We will also review the role of the OFC in fear extinction and the implications of this role to the pathophysiology of anxiety disorders.

Autism spectrum disorder (ASD) is diagnosed by two core behavioral criteria, unusual reciprocal social interactions and communication, and stereotyped, repetitive behaviors with restricted interests. Excitatory/inhibitory imbalance is a prominent hypothesis for the etiology of autism. The selective GABAB receptor agonist R-baclofen previously reversed social deficits and reduced repetitive behaviors in a mouse model of Fragile X syndrome, and Arbaclofen improved some clinical symptoms in some Fragile X and ASD patients. To evaluate R-baclofen in a broader range of mouse models of ASD, we tested both the R-baclofen enantiomer and the less potent S-baclofen enantiomer in two inbred strains of mice that display low sociability and/or high repetitive or stereotyped behaviors. R-baclofen treatment reversed social approach deficits in BTBR T+ Itpr3tf/J (BTBR), reduced repetitive self-grooming and high marble burying scores in BTBR, and reduced stereotyped jumping in C58/J (C58), at nonsedating doses. S-baclofen produced minimal effects at the same doses. These findings encourage investigations of R-baclofen in other preclinical model systems. Additional clinical studies may be warranted to further evaluate the hypothesis that the GABAB receptor represents a promising pharmacological target for treating appropriately stratified subsets of individuals with ASD.