Melanin concentrating hormone modulates oxytocin-mediated marble burying

Abstract

Repetitive and perseverative behaviors are common features of a number of neuropsychiatric diseases such as Angelman’s syndrome, Tourette’s syndrome, obsessive-compulsive disorder, and autism spectrum disorders. The oxytocin system has been linked to the regulation of repetitive behavior in both animal models and humans, but many of its downstream targets have still to be found. We report that the melanin-concentrating hormone (MCH) system is a target of the oxytocin system in regulating one repetitive behavior, marble burying. First we report that nearly 60% of MCH neurons express oxytocin receptors, and demonstrate using rabies mediated tract tracing that MCH neurons receive direct pre-synaptic input from oxytocin neurons. Then we show that MCH receptor knockout (MCHR1KO) mice and MCH ablated animals display increased marble burying response while central MCH infusion decreases it. Finally, we demonstrate the downstream role of the MCH system on oxytocin mediated marble burying by showing that central infusions of MCH and oxytocin alone or together reduce it while antagonizing the MCH system blocks oxytocin-mediated reduction of this behavior. Our findings reveal a novel role for the MCH system as a mediator of the role of oxytocin in regulating marble-burying behavior in mice.

A critical inquiry into marble-burying as a preclinical screening paradigm of relevance for anxiety and obsessive–compulsive disorder: Mapping the way forward

“…Finally, neuropeptide Y receptors, specifically the Y2 and Y4 receptors, seem to modulate anxiety-like behavior, in that Y2-and Y4-KO mice have been demonstrated to present with anxiolytic responses in the MBT as well as in other anxiety tests (Tasan et al, 2009). Mice lacking the melanin-concentrating hormone receptor (MCHR) also display increased MBA (Sanathara et al, 2018), findings that were further corroborated by pharmacological interventions in the same study. Together, these findings suggest that genetic KO models do indeed provide an interesting avenue for further research, but that the aforementioned genetic KO investigations are subject to many of the methodological constraints highlighted throughout this review.…”

“…Furthermore, significantly bolstered marble-burying was also found in prior-stressed animals (Dey et al, 2016). Increased marble-burying has also been reported in animals injected with diphtheria toxin (Sanathara et al, 2018). Since the investigation by Kedia and Chattarji employed MBA to measure the manifestations of induced anxiety (that is to say, as a measure of induced anxiety) in animals, it cannot be concluded that the presence of marbles in test arenas per se contributed to the experienced level of anxiety; rather, it may be an accurate predictor of anxiogenic manipulation, albeit variably so (cf.…”

“…In fact, it has been shown that marble-burying persists over repeated exposure, even when avoidance of the marbles is possible and after animals have been habituated to the presence of marbles in their home cage environments for extended periods (Njung'e & Handley, 1991b;Thomas et al, 2009). Moreover, the facts that marble-burying correlates poorly with the outcomes of other classical experimental tests of anxiety (Sanathara et al, 2018;Savy et al, 2015;Thomas et al, 2009; although see also Greene-Schloesser et al, 2011) and that it is subject to significant between-strain variation (Angoa-Pérez, Kane, Briggs, Francescutti, & Kuhn, 2013;Egashira et al, 2013;Nicolas et al, 2006;Thomas et al, 2009) further suggest that marble-burying as it is normally carried out in the lab-that is, not based on individual differences in behavior, but rather to characterize group differences in supposed abnormal burying behavior, mostly following drug intervention-represents an inherent, rather than a neophobic or anxiety-related, behavioral phenotype. As such, the MBT has since been employed to model the purported behavioral manifestations of OCD-that is, seemingly purposeless repetition Gaikwad, Parle, Kumar, & Gaikwad, 2010;Iijima, Kurosu, & Chaki, 2010;Taylor et al, 2017;Umathe, Bhutada, Dixit, & Shende, 2008;Umathe et al, 2012); in most cases, however, this approach is also unjustified, as will be explained.…”

“…In addition to different strains being used, a number of genetically modified strains have also been characterized with respect to burying behavior. Since these studies are numerous and mostly included the MBT only as one of a number of behavioral experiments (Angoa-Pérez et al, 2013;Balemans et al, 2010;Burne, McGrath, Eyles, & Mackay-Sim, 2005;Duangdao, Clark, Okamura, & Reinscheid, 2009;Egashira, Tanoue, et al, 2007;Gavioli, Rizzi, Marzola, Zucchini, & Regoli, 2007;Lähdesmäki et al, 2002;Mosienko et al, 2012;Sanathara et al, 2018;Shmelkov et al, 2010;Tasan et al, 2009;Yamada et al, 2002), we will only highlight some key findings here. Tryptophan hydroxylase 2 (TPH2) knockout (KO) mice, which present with no detectable brain levels of 5-HT, demonstrate bolstered MBA in a 1Z paradigm as compared to their wild-type counterparts (Angoa-Pérez et al, 2013).…”

“…Oxytocin administration also reduces the behavior, since many MCH neurons express oxytocin receptors that influence their activity levels. Finally, blockade of the MCH receptor with antagonist GW803430 prevents the attenuating actions of both the aforementioned hormones (Sanathara et al, 2018). Oxytocin has been linked to anxious behavior (Neumann & Landgraf, 2012).…”