On the Digital Psychopharmacology of Valproic Acid in Mice

Abstract

Antiepileptic drugs (AEDs) require daily ingestion for maximal seizure prophylaxis. Adverse psychiatric consequences of AEDs present as: (i) reversible changes in mood, anxiety, anger and/or irritability that often necessitate drug discontinuation, and (ii) autism and/or cognitive/psychomotor delays following fetal exposure. Technical advances in quantifying naturalistic rodent behaviors may provide sensitive preclinical estimates of AED psychiatric tolerability and neuropsychiatric teratogenicity. In this study, we applied instrumented home-cage monitoring to assess how valproic acid (VPA, dissolved in sweetened drinking water) alters home-cage behavior in adult C57BL/6J mice and in the adult offspring of VPA-exposed breeder pairs. Through a pup open field assay, we also examined how prenatal VPA exposure impacts early spontaneous exploratory behavior. At 500-600 mg/kg/d, chronic VPA produced hyperphagia and increased wheel-running without impacting sleep, activity and measures of risk aversion. When applied to breeder pairs of mice throughout gestation, VPA prolonged the latency to viable litters without affecting litter size. Two-weeks old VPA-exposed pups displayed open field hypoactivity without alterations in thigmotaxis. As adults, prenatal VPA-exposed mice displayed active state fragmentation, hypophagia and increased wheel running, together with subtle alterations in home-cage dyadic behavior. Together, these data illustrate how automated home-cage assessments of spontaneous behavior capture an ethologically centered psychopharmacological profile of enterally administered VPA that is aligned with human clinical experience. By characterizing the effects of pangestational VPA exposure, we discover novel murine expressions of pervasive neurodevelopment. Incorporating such rigorous assessments of psychological tolerability may inform the design of future AEDs with improved neuropsychiatric safety profiles, both for patients and their offspring.

Measuring Behavior in the Home Cage: Study Design, Applications, Challenges, and Perspectives

“…Additionally, to be in line with animal welfare regulations 1 , the design of HCMS should crucially promote species-specific natural behavior. Whenever possible, such systems should be furnished with familiar bedding (Blom et al, 1996), chow and drinking water identical to those of vivarium conditions (Jankovic et al, 2019;Bass et al, 2020). Additionally, environmental enrichment by means of additional substrates and objects allows to expand the range of behaviors that the animals can express (Wolfer et al, 2004;Baumans, 2005).…”

“…This may be related to infradian rhythms or the cumulative effects of social isolation itself. In one study employing PhenoTyper cages studying sociallyisolated C57BL/6J mice during an 8 day recording period, 1 www.na3rsc.org total daily distances gradually declined with similar gradual increases in total daily sleep (defined behaviorally) as well as feeding and licking times (Bass et al, 2020). Providing greater environmental enrichment may ameliorate such phenotypic drifts.…”

“…These include running wheels (de Visser et al, 2005(de Visser et al, , 2007 which provide an avenue to clarify whether changes in measures of horizontal displacement (hypo-vs. hyperactivity) extend to measures of voluntary exercise. Since wheel access may be sufficient to ameliorate several aspects of neuropsychiatric symptomatology in rodent models (Guo et al, 2020), a single day of wheel access can be incorporated into a home-cage based battery of behavioral testing (Bass et al, 2020) using detachable running wheels for the PhenoTyper. To prevent the effects that may come about from social isolation, several recent reports demonstrate the feasibility of studying rodents in pairs or larger groups using RFID-based individual identification, which can be applied to home-cages (Alexandrov et al, 2015;de Chaumont et al, 2019;Peleh et al, 2019Peleh et al, , 2020.…”

“…To prevent the effects that may come about from social isolation, several recent reports demonstrate the feasibility of studying rodents in pairs or larger groups using RFID-based individual identification, which can be applied to home-cages (Alexandrov et al, 2015;de Chaumont et al, 2019;Peleh et al, 2019Peleh et al, , 2020. Without RFID chips, or fluorescent markers (Shemesh et al, 2013), infrared video recordings are somewhat limited in their ability to distinguish between individual subjects within a group (Bass et al, 2020), and therefore report on measures that pertain to the group as a whole (e.g., total distances of the pair, mean proximity between subjects of the pair). Thus, a suitable home cage for HCMS studies is one that provides food, water, shelter and bedding, and optionally other enrichment objects.…”

“…It still requires habituation after the subjects are transferred from the vivarium. The habituation phase depends on several factors including the subjects' strain (Loos et al, 2014;Bass et al, 2020; see ''Reducing Human Interference and Controlling for the Effects of Habituation'' Section) .…”