Further evidence for ClockΔ19 mice as a model for bipolar disorder mania using cross-species tests of exploration and sensorimotor gating

Abstract

Bipolar disorder (BD) is a pervasive neuropsychiatric disorder characterized by episodes of mania and depression. The switch between mania and depression may reflect seasonal changes and certainly can be affected by alterations in sleep and circadian control. The circadian locomotor output cycles kaput (CLOCK) protein is a key component of the cellular circadian clock. Mutation of the Clock gene encoding this protein in Clock△19 mutant mice leads to behavioral abnormalities reminiscent of BD mania. To date, however, these mice have not been assessed in behavioral paradigms that have cross-species translational validity. In the present studies of Clock△19 and wildtype (WT) littermate mice, we quantified exploratory behavior and sensorimotor gating, which are abnormal in BD manic patients. We also examined the saccharin preference of these mice and their circadian control in different photoperiods. Clock△19 mice exhibited behavioral alterations that are consistent with BD manic patients tested in comparable tasks, including hyperactivity, increased specific exploration, and reduced sensorimotor gating. Moreover, compared to WT mice, Clock△19 mice exhibited a greater preference for sweetened solutions and greater sensitivity to altered photoperiod. In contrast with BD manic patients however, Clock△19 mice exhibited more circumscribed movements during exploration. Future studies will extend the characterization of these mice in measures with cross-species translational relevance to human testing.

Modeling bipolar disorder in mice by increasing acetylcholine or dopamine: chronic lithium treats most, but not all features

“…Startle and PPI testing were examined in eight startle chambers (SR-LAB, San Diego Instruments, USA), using an experimental session as described previously (van Enkhuizen et al 2013c). Each chamber consists of a Plexiglas cylinder, 5 cm in diameter, resting on a platform in a ventilated sound-attenuating outer box.…”

“…Indeed, animal models being used to reproduce a BD-like phenotype are usually specific only to the manic phase of the disorder (Gould et al 2001; Roybal et al 2007; van Enkhuizen et al 2013a). These models typically reproduce aspects of hyperactivity (Shaldubina et al 2002), with some measuring impaired risk-taking (Young et al 2011b), and increased reward seeking (van Enkhuizen et al 2013c). An awareness exists for the necessity to model the full spectrum of BD (depression and mania) in animals in order to find novel treatments for the full disorder (Machado-Vieira et al 2004), but the complexity of the matter has prevented such an outcome as yet (Young and Dulcis 2015).…”

“…Furthermore, dysfunctional sensorimotor gating of the startle reflex as measured by reduced prepulse inhibition (PPI) has been observed in manic patients with BD (Perry et al 2001), but not in depressed subjects (Perry et al 2004; Quednow et al 2006), suggesting that dysfunctional PPI is state dependent (Kohl et al 2013). These PPI deficits can be recreated in rodents (Geyer et al 2002) and have been observed in rodent models of BD mania (van Enkhuizen et al 2013c), including mice challenged with GBR12909 (Kwek and van den Buuse 2013). …”

Animal models of bipolar mania: The past, present and future

“…Recent efforts have begun to develop and employ translational approaches providing cross-species validation of behavioral phenotypes relevant to BD (Henry et al, 2010, van Enkhuizen et al, 2013b). Impaired sensorimotor gating and hyperactivity are core features of acutely manic patients, which can also be readily assessed in rodent models.…”

Variants in Ion Channel Genes Link Phenotypic Features of Bipolar Illness to Specific Neurobiological Process Domains

“…BD patients have an increased nocturnal temperature and blunted thyroid-stimulating hormone secretion [127,128]. ClockΔ19 mutant mice show behaviors of increased locomotion, disrupted circadian rhythm, and decreased sensorimotor gating similar to mania [129]. …”