An investigation of habitual behaviour in deer mice (Peromyscus maniculatus bairdii) displaying motor persistence

Abstract

Obsessive-compulsive disorder (OCD)1 is characterized by thematically specific obsessions, i.e. intrusive thoughts and impulses, and/or compulsions, that is highly repetitive behaviors or mental acts. Obsessions and compulsions are time consuming and persistent (lasting for at least one hour daily) and cause a significant degree of distress in the sufferer. OCD is a heterogeneous disorder, meaning that the symptom phenotypes differ with respect to, among others, theme, content, manifestation, severity and treatment response. Four major symptom phenotypes have been described, i.e. contamination/washing, safety/checking, symmetry/ordering, and intrusive thoughts associated with covert mental routines. As many as 25 % of adult OCD patients have already shown noticeable signs of OCD by the age of 14 years. Further, more than half of OCD cases is diagnosed between the ages of 6 – 10 years. Juvenile onset OCD is classified as one of the most occurring mental disorders in children with a prevalence rate of up to 3 %. However, this number might be higher, especially since accurate diagnoses of OCD in young age groups are difficult, likely because many behaviors often shown by children, i.e. rituals and habit-like repetition of certain actions, agree with some of the diagnostic criteria of the condition. Further, it is entirely unknown if and how said normal behaviors in children, will predict and contribute to the development of OCD in some, but not others. In terms of neurobiology, OCD is primarily associated with abnormalities in and dysfunction of the cortico-striatal-thalamo-cortical (CSTC)2 pathways. These anatomical components and their associated pathways play a crucial role in the planning, execution, and termination of goal-directed actions. It is proposed that in OCD, overactivity in the CSTC circuitry may contribute to the excessive behavioral engagement typical of the condition. Specifically, it is believed that a relative hyposerotonergic state may underlie the excessive propagation of executive signals via the CSTC pathways, explaining the response, albeit suboptimally so, of OCD to high-dose treatment with selective serotonin reuptake inhibitors (SSRIs)3. Several neurocognitive theories have been proposed to explain the etiology and development of OCD in different patients. One such theory focuses on the potential role that habit-proneness may play in certain individuals. Broadly viewed, behavior is governed by either goal-directed or habitual processes. Goal-directed behavior usually depends on the value of the specific action’s outcome, is carefully planned and executed, and terminated when the outcome is realized. In contrast, habits are learned and thus

automated, require less attention and fewer cognitive resources. Both response styles are necessary for our normal functioning. However, when the balance between goal-directed and habitual responses becomes dysfunctional, individuals may struggle to switch from habits that are no longer necessary and goal-directed engagement; this is a common neuropsychological endophenotype in OCD1. Against this background, the habit hypothesis of OCD implies that individuals with increased habit-proneness may be at a greater risk of developing OCD. This is important, since it is possible that a lack of understanding of how habits progress to OCD, or how habit-like persistence may promote the expression of compulsive symptomology, contribute to the less-than-optimal treatment outcomes seen in OCD. In other words, different obsessive-compulsive symptom phenotypes, might have unique psychobiological foundations that will arguably show unique responses to different interventions. Considering this, novel treatment options that may target both the cognitive and neurobiological underpinnings of OCD, may be useful. Levetiracetam (LEV)2, may be a promising target for investigation, since this 5-enantiomer of 5-alpha-ethyl-2-oxo-1-pyrrolidine acetamide, clinically prescribed for the treatment of epilepsy, shows promise as a potentially useful cognitive enhancer in both epileptic and healthy cohorts. In this work, its potential as an anti-compulsive agent in a naturalistic model of compulsive-like persistent behaviors was explored. Deer mice (Peromyscus maniculatus bairdii) that are housed under standard laboratory conditions variably present with two distinct compulsive-like behavioral phenotypes, i.e. large nest building (LNB)3 behavior and high motor stereotypy (HS)4. Both respond to chronic, high-dose SSRI5 intervention and are expressed by animals of both sexes. However, the neurocognitive underpinnings of these behaviors remain largely unknown. Thus, the broad aim of this work was to explore the potential relationships between these adult behavioral phenotypes and both early-life and adulthood measures of habit-proneness. We further aimed to investigate whether LNB and HS would respond to LEV, and how their potential associations with increased habit-proneness, would respond to the same intervention. Briefly, 76 juvenile (28-day-old) deer mice of both sexes (ethics approval no.: NWU-00423-21-A5) were assessed for habit-proneness in the Barnes maze (BM)6 and divided into two exposure groups (n = 37-39 per group), i.e. control- (CTRL7; normal drinking water) and LEV (75 mg/kg/day; administered in the

drinking water). After 56 days of uninterrupted CTRL1 or LEV2 exposure, all mice were screened for nesting and stereotypical behavior, and then assessed for working memory in the T-maze. The main findings of the present work were that 1) performance in the BM3 of juvenile P. maniculatus bairdii mice was not related to LNB4 or stereotypy in adulthood; 2) chronic LEV exposure from a juvenile age until adulthood decreased LNB expression without affecting overall nesting scores, but increased CR5 activity; 3) stereotypical expression, notably so CR, and nesting expression were divergent persistent behavioral phenotypes; and 4) LEV exposure generally improved the relationship between working memory and stereotypical engagement.