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Common data elements (CDEs) are becoming more common as more areas of preclinical research have generated CDEs. Herein we provide an overview of the progress to date in generating CDEs for preclinical epilepsy research. Currently there are CDEs that have been developed for Physiology (in vivo), Behavior, Pharmacology, and Electroencephalography (EEG). Together the CDEs and methodologic considerations associated with these CDEs are laid out in consecutive manuscripts published in Epilepsia Open, each describing CDEs for their respective topic area. In addition to the overview of progress for the 4 subjects, core characteristics (Core CDEs) are described and explained. Data collection using a case report form (CRF) is described, and considerations that are involved in using the CDEs and CRFs are discussed.
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Preclinical pharmacology studies in animal models of seizures and epilepsy have provided a platform to identify more than 20 antiseizure drugs in recent decades. To minimize variability in lab-to-lab studies and to harmonize approaches to data collection and reporting methodology in pharmacologic evaluations of the next generation of therapies, we present common data elements (CDEs), case report forms (CRFs), and this companion manuscript to help with the implementation of methods for studies in established preclinical seizure and epilepsy models in adult rodents. The development of and advocacy for CDEs in preclinical research has been encouraged previously by both clinical and preclinical groups. It is anticipated that adoption and implementation of these CDEs in preclinical studies may help standardize approaches to minimize variability and increase the reproducibility of preclinical studies. Moreover, they may provide a methodologic framework for pharmacology studies in atypical animal models or models in development, which may ultimately promote novel therapy development. In the present document, we refer selectively to animal models that have a long history of preclinical use, and in some cases, are clinically validated.
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The provided companion has been developed by the Behavioral Working Group of the Joint Translational Task Force of the International League Against Epilepsy (ILAE) and the American Epilepsy Society (AES) with the purpose of assisting the implementation of Preclinical Common Data Elements (CDE) for studying and for reporting neurobehavioral comorbidities in rodent models of epilepsy. Case Report Forms (CRFs) are provided, which should be completed on a per animal/per test basis, whereas the CDEs are a compiled list of the elements that should be reported. This companion is not designed as a list of recommendations, or guidelines for how the tests should be run-rather, it describes the different types of assessments, and highlights the importance of rigorous data collection and transparency in this regard. The tests are divided into 7 categories for examining behavioral dysfunction on the syndrome level: deficits in learning and memory; depression; anxiety; autism; attention deficit/hyperactivity disorder; psychosis; and aggression. Correspondence and integration of these categories into the National Institute of Mental Health (NIMH) Research Domain Criteria (RDoC) is introduced. Developmental aspects are addressed through the introduction of developmental milestones. Discussion includes complexities, limitations, and biases associated with neurobehavioral testing, especially when performed in animals with epilepsy, as well as the importance of rigorous data collection and of transparent reporting. This represents, to our knowledge, the first such resource dedicated to preclinical CDEs for behavioral testing of rodents.
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Electroencephalography (EEG) is commonly used in epilepsy and neuroscience research to study brain activity. The principles of EEG recording such as signal acquisition, digitization, and conditioning share similarities between animal and clinical EEG systems. In contrast, preclinical EEG studies demonstrate more variability and diversity than clinical studies in the types and locations of EEG electrodes, methods of data analysis, and scoring of EEG patterns and associated behaviors. The TASK3 EEG working group of the International League Against Epilepsy/American Epilepsy Society (ILAE/AES) Joint Translational Task Force has developed a set of preclinical common data elements (CDEs) and case report forms (CRFs) for recording, analysis, and scoring of animal EEG studies. This companion document accompanies the first set of proposed preclinical EEG CRFs and is intended to clarify the CDEs included in these worksheets. We provide 7 CRF and accompanying CDE modules for use by the research community, covering video acquisition, electrode information, experimental scheduling, and scoring of EEG activity. For ease of use, all data elements and input ranges are defined in supporting Excel charts (Appendix S1).
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OBJECTIVE: Common data elements (CDEs) are currently unavailable for mobile health (mHealth) in epilepsy devices and related applications. As a result, despite expansive growth of new digital services for people with epilepsy, information collected is often not interoperable or directly comparable. We aim to correct this problem through development of industry-wide standards for mHealth epilepsy data. METHODS: Using a group of stakeholders from industry, academia, and patient advocacy organizations, we offer a consensus statement for the elements that may facilitate communication among different systems. RESULTS: A consensus statement is presented for epilepsy mHealth CDEs. SIGNIFICANCE: Although it is not exclusive, we believe that the use of a minimal common information denominator, specifically these CDEs, will promote innovation, accelerate scientific discovery, and enhance clinical usage across applications and devices in the epilepsy mHealth space. As a consequence, people with epilepsy will have greater flexibility and ultimately more powerful tools to improve their lives.
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Elementos de Datos Comunes/normas , Epilepsia , Neurología/normas , Telemedicina/normas , Terminología como Asunto , HumanosRESUMEN
The major objective of preclinical translational epilepsy research is to advance laboratory findings toward clinical application by testing potential treatments in animal models of seizures and epilepsy. Recently there has been a focus on the failure of preclinical discoveries to translate reliably, or even to be reproduced in different laboratories. One potential cause is a lack of standardization in preclinical data collection. The resulting difficulties in comparing data across studies have led to high cost and missed opportunity, which in turn impede clinical trials and advances in medical care. Preclinical epilepsy research has successfully brought numerous antiseizure treatments into the clinical practice, yet the unmet clinical needs have prompted the reconsideration of research strategies to optimize epilepsy therapy development. In the field of clinical epilepsy there have been successful steps to improve such problems, such as generation of common data elements (CDEs) and case report forms (CRFs and standards of data collection and reporting) by a team of leaders in the field. Therefore, the Translational Task Force was appointed by the International League Against Epilepsy (ILAE) and the American Epilepsy Society (AES), in partnership with the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institutes of Health (NIH) to define CDEs for animal epilepsy research studies and prepare guidelines for data collection and experimental procedures. If adopted, the preclinical CDEs could facilitate collaborative epilepsy research, comparisons of data across different laboratories, and promote rigor, transparency, and impact, particularly in therapy development.
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Comités Consultivos , Elementos de Datos Comunes/normas , Epilepsia/diagnóstico , Epilepsia/terapia , Investigación Biomédica Traslacional/normas , Animales , Recolección de Datos , Modelos Animales de Enfermedad , Humanos , Cooperación Internacional , National Institute of Neurological Disorders and Stroke (U.S.) , Sociedades Científicas/normas , Investigación Biomédica Traslacional/métodos , Estados UnidosRESUMEN
The mossy fiber (MF) pathway is critical to hippocampal function and influenced by gonadal hormones. Physiological data are limited, so we asked whether basal transmission and long-term potentiation (LTP) differed in slices of adult male and female rats. The results showed small sex differences in basal transmission but striking sex differences in opioid receptor sensitivity and LTP. When slices were made from females on proestrous morning, when serum levels of 17ß-estradiol peak, the nonspecific opioid receptor antagonist naloxone (1 µm) enhanced MF transmission but there was no effect in males, suggesting preferential opioid receptor-dependent inhibition in females when 17ß-estradiol levels are elevated. The µ-opioid receptor (MOR) antagonist Cys2,Tyr3,Orn5,Pen7-amide (CTOP; 300 nm) had a similar effect but the δ-opioid receptor (DOR) antagonist naltrindole (NTI; 1 µm) did not, implicating MORs in female MF transmission. The GABAB receptor antagonist saclofen (200 µm) occluded effects of CTOP but the GABAA receptor antagonist bicuculline (10 µm) did not. For LTP, a low-frequency (LF) protocol was used because higher frequencies elicited hyperexcitability in females. Proestrous females exhibited LF-LTP but males did not, suggesting a lower threshold for synaptic plasticity when 17ß-estradiol is elevated. NTI blocked LF-LTP in proestrous females, but CTOP did not. Electron microscopy revealed more DOR-labeled spines of pyramidal cells in proestrous females than males. Therefore, we suggest that increased postsynaptic DORs mediate LF-LTP in proestrous females. The results show strong MOR regulation of MF transmission only in females and identify a novel DOR-dependent form of MF LTP specific to proestrus.
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Hipocampo/citología , Potenciación a Largo Plazo/fisiología , Fibras Musgosas del Hipocampo/fisiología , Receptores Opioides/metabolismo , Caracteres Sexuales , Sinapsis/fisiología , Animales , Baclofeno/análogos & derivados , Baclofeno/farmacología , Bicuculina/análogos & derivados , Bicuculina/farmacología , Espinas Dendríticas/metabolismo , Espinas Dendríticas/ultraestructura , Ciclo Estral/efectos de los fármacos , Femenino , Antagonistas de Receptores de GABA-A/farmacología , Potenciación a Largo Plazo/efectos de los fármacos , Masculino , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Somatostatina/análogos & derivados , Somatostatina/farmacologíaRESUMEN
Experience-dependent plasticity shapes postnatal development of neural circuits, but the mechanisms that refine dendritic arbors, remodel spines, and impair synaptic activity are poorly understood. Mature brain-derived neurotrophic factor (BDNF) modulates neuronal morphology and synaptic plasticity, including long-term potentiation (LTP) via TrkB activation. BDNF is initially translated as proBDNF, which binds p75(NTR). In vitro, recombinant proBDNF modulates neuronal structure and alters hippocampal long-term plasticity, but the actions of endogenously expressed proBDNF are unclear. Therefore, we generated a cleavage-resistant probdnf knockin mouse. Our results demonstrate that proBDNF negatively regulates hippocampal dendritic complexity and spine density through p75(NTR). Hippocampal slices from probdnf mice exhibit depressed synaptic transmission, impaired LTP, and enhanced long-term depression (LTD) in area CA1. These results suggest that proBDNF acts in vivo as a biologically active factor that regulates hippocampal structure, synaptic transmission, and plasticity, effects that are distinct from those of mature BDNF.
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Factor Neurotrófico Derivado del Encéfalo/genética , Hipocampo/metabolismo , Plasticidad Neuronal/fisiología , Transmisión Sináptica/fisiología , Alelos , Animales , Factor Neurotrófico Derivado del Encéfalo/química , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Células Cultivadas , Técnicas de Sustitución del Gen , Hipocampo/anatomía & histología , Hipocampo/citología , Depresión Sináptica a Largo Plazo , Ratones , Unión Proteica , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Receptor trkB/metabolismo , Receptores de Factor de Crecimiento Nervioso/química , Receptores de Factor de Crecimiento Nervioso/metabolismo , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismoRESUMEN
Androgens have dramatic effects on neuronal structure and function in hippocampus. However, androgen depletion does not always lead to hippocampal impairment. To address this apparent paradox, we evaluated the hippocampus of adult male rats after gonadectomy (Gdx) or sham surgery. Surprisingly, Gdx rats showed increased synaptic transmission and long-term potentiation of the mossy fiber (MF) pathway. Gdx rats also exhibited increased excitability and MF sprouting. We then addressed the possible underlying mechanisms and found that Gdx induced a long-lasting upregulation of MF BDNF immunoreactivity. Antagonism of Trk receptors, which bind neurotrophins, such as BDNF, reversed the increase in MF transmission, excitability, and long-term potentiation in Gdx rats, but there were no effects of Trk antagonism in sham controls. To determine which androgens were responsible, the effects of testosterone metabolites DHT and 5α-androstane-3α,17ß-diol were examined. Exposure of slices to 50 nm DHT decreased the effects of Gdx on MF transmission, but 50 nm 5α-androstane-3α,17ß-diol had no effect. Remarkably, there was no effect of DHT in control males. The data suggest that a Trk- and androgen receptor-sensitive form of MF transmission and synaptic plasticity emerges after Gdx. We suggest that androgens may normally be important in area CA3 to prevent hyperexcitability and aberrant axon outgrowth but limit MF synaptic transmission and some forms of plasticity. The results also suggest a potential explanation for the maintenance of hippocampal-dependent cognitive function after androgen depletion: a reduction in androgens may lead to compensatory upregulation of MF transmission and plasticity.
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Región CA3 Hipocampal/fisiología , Potenciación a Largo Plazo/fisiología , Fibras Musgosas del Hipocampo/fisiología , Transmisión Sináptica/fisiología , Testosterona/deficiencia , Factores de Edad , Animales , Masculino , Vías Nerviosas/fisiología , Orquiectomía , Ratas , Ratas Endogámicas F344 , Testosterona/metabolismoRESUMEN
Research suggests that the use and abuse of marijuana can be especially harmful if it occurs during adolescence, a period of vast developmental changes throughout the brain. Due to the localization of cannabinoid receptors within the limbic system and the established effects of cannabinoids on emotional states and anxiety levels of rats and humans, we studied the sex- and dose-related effects of Δ9-tetrahydrocannabinol (THC, the main psychoactive component in marijuana) on behavior and anxiety during spontaneous withdrawal. Male and female Sprague Dawley rats were administered 2, 7.5 or 15 mg/kg THC or vehicle from postnatal day 35-41 (approximating mid-adolescence in humans). Locomotor activity and anxiety-related behaviors were measured during drug administration and abstinence. THC caused significant dose-dependent locomotor depression during drug administration. Locomotor depression initially abated upon drug cessation, but re-emerged by the end of the abstinence period and was greater in female than male rats. We found sensitization to the locomotor-depressing effects of THC in middle- and high-dose rats and the subsequent development of tolerance in high-dose rats. The high dose of THC increased anxiety-like behaviors while the low dose decreased anxiety-like behaviors during drug administration, with females more sensitive to the anxiogenic effects of THC than males. During abstinence, females were again especially sensitive to the anxiogenic effects of THC. This study demonstrates sexually-dimorphic effects of THC on anxiety-related behaviors and locomotor activity during and after THC administration during adolescence. This information may be useful in the development of therapeutic approaches for the treatment of marijuana withdrawal in adolescents.