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.

In many childhood-onset genetic epilepsies, seizures are accompanied by neurobehavioral impairments and motor disability. In the Stargazer mutant mouse, genetic disruptions of Cacng2 result in absence-like spike-wave seizures, cerebellar gait ataxia and vestibular dysfunction, which limit traditional approaches to behavioral phenotyping. Here, we combine videotracking and instrumented home-cage monitoring to resolve the neurobehavioral facets of the murine Stargazer syndrome. We find that despite their gait ataxia, stargazer mutants display horizontal hyperactivity and variable rates of repetitive circling behavior. While feeding rhythms, circadian or ultradian oscillations in activity are unchanged, mutants exhibit fragmented bouts of behaviorally defined “sleep”, atypical licking dynamics and lowered sucrose preference. Mutants also display an attenuated response to visual and auditory home-cage perturbations, together with profound reductions in voluntary wheel-running. Our results reveal that the seizures and ataxia of Stargazer mutants occur in the context of a more pervasive behavioral syndrome with elements of encephalopathy, repetitive behavior and anhedonia. These findings expand our understanding of the function of Cacng2.

Disability in patients with epilepsy (PWE) is multifactorial: beyond seizure frequency/severity, PWE are prone to a range of neuropsychiatric, cognitive, and somatic comorbidities that significantly impact quality of life. In this study, we explored how variations in epilepsy severity and the burden of self-reported somatic/neuropsychiatric symptoms are associated with disruptions to 24h activity patterns (rest-activity rhythms, RARs), determined through wrist accelerometry/actigraphy. Continuous multiday recordings were obtained from 59 adult patients with focal epilepsy (44% male, ages 18-72), who contemporaneously provided responses to a range of validated psychometric instruments to measure the burden of anxiety, depression, sleepiness, and somatic symptoms. As a comparator, we conducted a similar psychometric-actigraphic correlation in 1761 subjects of Hispanic origin (35% male, ages 18-65) from the Study of Latinos (SOL) Sueño Ancillary Study. RARs were analyzed via a sigmoidally-transformed cosine model (quantifying RAR amplitude, steepness, acrophase and robustness) and non-parametric measures to estimate RAR stability, fragmentation, and sleep. Compared with age- and sex-matched SOL subjects, RARs from PWE subjects featured a significantly diminished amplitude, a wider rest phase and significantly more total daily sleep. Within PWE, similar RAR distortions were associated with seizure intractability and/or anticonvulsant polytherapy. In contrast, high anxiety, depression, and somatic symptom scores were associated with diminished RAR robustness and a delayed acrophase. We applied the complete SOL Sueño database to train logistic regression models to dichotomously classify anxiety, depression and sleepiness symptoms using age, sex, body mass index and a range of non-collinear RAR parameters. When tested on PWE, these models predicted prevalent anxiety and depression symptoms with modest success (accuracy ∼70%) but failed to predict subjective sleepiness. Together, these results demonstrate that RAR features may vary with depression and anxiety symptoms in ambulatory patients with focal epilepsy, potentially offering a set of objective wearable-derived endpoints to adjunct routine clinical care and drug/device treatment trials. With larger actigraphic-psychometric datasets in PWE, we may identify RAR signatures that can more precisely distinguish between variations in seizure risk, the burden of anticonvulsant therapy and prevalent mood/anxiety symptoms.

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Background The continued emergence of side-effects caused by synthetic drugs underscores the need for plant-based drugs in human medicine. Medicinal rhizomatous crops are a “goldmine for modern drugs”, and include such species as Gloriosa superba L. and Colchicum autumnale L., the producers of colchicine, a plant-based medicine. The natural isomer of bioactive colchicine is used to effectively treat major diseases such as cancer, cardiovascular disease, and gout. The medicinal properties of colchicine are well characterized, however, almost nothing is known about its biosynthesis. The paucity of information on the colchicine biosynthetic pathway is a significant barrier to biomanufacturing of this biomedicine. A comparative transcriptome study of G. superba and C. autumnale serves as a sequence resource to aid with identification of this biomedicine pathway and rhizome development genes for synthetic biotechnology toolbox, which will enable improved colchicine biomanufacturing. Result Transcriptomes of two colchicine synthesizing monocots G. superba and C. autumnale were interrogated to identify putative cDNAs encoding enzymes and transcription factors involved in the colchicine biosynthetic pathway and rhizome development. Mining of the transcriptomes using Blast2GO led to the identification from G. superba and C. autumnale, respectively, of 20 and 29 candidate colchicine biosynthetic genes N-methyltransferases, 3-O-methyltransferases, cytochrome P450s, a class that could catalyze several steps in the pathway, and N-acetyltransferases. Similarly, 19 and 15 candidate rhizome developmental genes, which belongs to several classes including GIGANTEA, CONSTANS, Phytochrome B, Sucrose Synthase), Flowering Locus T, and REVOLUTA. Likewise, about 16 and 12 transcription factors involved in regulating rhizome development and secondary metabolic pathways in rhizomes such as MADS-box, AP2-EREBP, bHLH, MYB, NAC, and WRKY were also found in G. superba and C. autumnale, respectively. Conclusion The predicted genes in G. superba and C. autumnale encode colchicine pathway enzymes that provide fundamental information for plant-based biomedicine engineering in biorhizomes and microorganisms, a potentially important area of synthetic biotechnology. Additionally, increasing our understanding of rhizome functional genomics will lead to improved colchicine biomanufacturing, and generate important knowledge that can be applied to many other medicinal plant species, allowing for the engineered production of additional biomedicines in medicinal rhizomes.