Translational Neuroscience Research Research Articles

Translational Research in Bipolar Disorders

Translational Research in Bipolar Disorders

Molecular psychiatry of zebrafish.

Due to their well-characterized neural development and high genetic homology to mammals, zebrafish (Danio rerio) have emerged as a powerful model organism in the field of biological psychiatry. Here, we discuss the molecular psychiatry of zebrafish, and its implications for translational neuroscience research and modeling CNS disorders. In particular, we outline recent genetic and technological developments allowing for in-vivo examinations, high-throughput screening and whole-brain analyses in larval and adult zebrafish. We also summarize the application of these molecular techniques to the understanding of neuropsychiatric disease, outlining the potential of zebrafish for modeling complex brain disorders, including attention-deficit/hyperactivity disorder (ADHD), aggression, post-traumatic stress and substance abuse. Critically evaluating the advantages and limitations of larval and adult fish tests, we suggest that zebrafish models become a rapidly emerging new field in modern biological psychiatry research.

Enacting the 'neuro' in practice: translational research, adhesion and the promise of porosity.

This article attends to the processes through which neuroscience and the neuro are enacted in a specific context: a translational neuroscience research group that was the setting of an ethnographic study. The article therefore provides a close-up perspective on the intersection of neuroscience and translational research. In the scientific setting we studied, the neuro was multiple and irreducible to any particular entity or set of practices across a laboratory and clinical divide. Despite this multiplicity, the group’s work was held together through the ‘promise of porosity’ – that one day there would be translation of lab findings into clinically effective intervention. This promise was embodied in the figure of the Group Leader whose expertise spanned clinical and basic neurosciences. This is theorized in terms of a contrast between cohesion and adhesion in interdisciplinary groupings. We end by speculating on the role of ‘vivification’ – in our case mediated by the Group Leader – in rendering ‘alive’ the expectations of interdisciplinary collaboration.

Gaining translational momentum: More zebrafish models for neuroscience research

Zebrafish (Danio rerio) are rapidly becoming a popular model organism in translational neuroscience and biological psychiatry research. Here we discuss conceptual, practical and other related aspects of using zebrafish in this field ("from tank to bedside"), and critically evaluate both advantages and limitations of zebrafish models of human brain disorders. We emphasize the need to more actively develop zebrafish models for neuroscience research focusing on complex traits.

The contemporary challenges and clinician-scientists' perspective in translational medicine neuroscience research ‘/INS;new pathways of discovery’/INS;: From bench to bedside

The contemporary challenges and clinician-scientists' perspective in translational medicine neuroscience research ‘/INS;new pathways of discovery’/INS;: From bench to bedside

Behavioral effects of bidirectional modulators of brain monoamines reserpine and d-amphetamine in zebrafish

Brain monoamines play a key role in the regulation of behavior. Reserpine depletes monoamines, and causes depression and hypoactivity in humans and rodents. In contrast, d-amphetamine increases brain monoamines' levels, and evokes hyperactivity and anxiety. However, the effects of these agents on behavior and in relation to monoamine levels remain poorly understood, necessitating further experimental studies to understand their psychotropic action. Zebrafish (Danio rerio) are rapidly emerging as a promising model organism for drug screening and translational neuroscience research. Here, we have examined the acute and long-term effects of reserpine and d-amphetamine on zebrafish behavior in the novel tank test. Overall, d-amphetamine (5 and 10mg/L) evokes anxiogenic-like effects in zebrafish acutely, but not 7 days later. In contrast, reserpine (20 and 40mg/L) did not evoke overt acute behavioral effects, but markedly reduced activity 7 days later, resembling motor retardation observed in depression and/or Parkinson's disease. Three-dimensional ‘temporal’ (X, Y, time) reconstructions of zebrafish locomotion further supports these findings, confirming the utility of 3D-based video-tracking analyses in zebrafish models of drug action. Our results show that zebrafish are highly sensitive to drugs bi-directionally modulating brain monoamines, generally paralleling rodent and clinical findings. Collectively, this emphasizes the potential of zebrafish tests to model complex brain disorders associated with monoamine dysregulation.

Innovative solutions to novel drug development in mental health

There are many new advances in neuroscience and mental health which should lead to a greater understanding of the neurobiological dysfunction in neuropsychiatric disorders and new developments for early, effective treatments. To do this, a biomarker approach combining genetic, neuroimaging, cognitive and other biological measures is needed. The aim of this article is to highlight novel approaches for pharmacological and non-pharmacological treatment development. This article suggests approaches that can be taken in the future including novel mechanisms with preliminary clinical validation to provide a toolbox for mechanistic studies and also examples of translation and back-translation. The review also emphasizes the need for clinician-scientists to be trained in a novel way in order to equip them with the conceptual and experimental techniques required, and emphasizes the need for private-public partnership and pre-competitive knowledge exchange. This should lead the way for important new holistic treatment developments to improve cognition, functional outcome and well-being of people with neuropsychiatric disorders.

Why research sex differences and similarities?

Why research sex differences and similarities?

Towards a Comprehensive Catalog of Zebrafish Behavior 1.0 and Beyond

Zebrafish (Danio rerio) are rapidly gaining popularity in translational neuroscience and behavioral research. Physiological similarity to mammals, ease of genetic manipulations, sensitivity to pharmacological and genetic factors, robust behavior, low cost, and potential for high-throughput screening contribute to the growing utility of zebrafish models in this field. Understanding zebrafish behavioral phenotypes provides important insights into neural pathways, physiological biomarkers, and genetic underpinnings of normal and pathological brain function. Novel zebrafish paradigms continue to appear with an encouraging pace, thus necessitating a consistent terminology and improved understanding of the behavioral repertoire. What can zebrafish 'do', and how does their altered brain function translate into behavioral actions? To help address these questions, we have developed a detailed catalog of zebrafish behaviors (Zebrafish Behavior Catalog, ZBC) that covers both larval and adult models. Representing a beginning of creating a more comprehensive ethogram of zebrafish behavior, this effort will improve interpretation of published findings, foster cross-species behavioral modeling, and encourage new groups to apply zebrafish neurobehavioral paradigms in their research. In addition, this glossary creates a framework for developing a zebrafish neurobehavioral ontology, ultimately to become part of a unified animal neurobehavioral ontology, which collectively will contribute to better integration of biological data within and across species.

What is an emotion in the first place? Time to sort things out

Event Abstract Back to Event What is an emotion in the first place? Time to sort things out Peter Walla1, 2* 1 University of Newcastle, School of Psychology, Australia 2 Centre for Translational Neuroscience and Mental Health Research, Australia Research on emotion has a long history, and yet, we still don’t understand how exactly it contributes to guiding behaviour and how it interacts with cognition, not even do we have an agreeable definition of emotion in the first place. There is accumulating scientific evidence that supports the idea to more clearly define what and what should not be labelled an emotion. By taking various different simultaneous measures while study participants view emotional material it turns out that the same set of stimuli causes different patterns of results depending on the measure and its sensitivity. These different findings mirror the fact that emotion-related processing happens on various different levels and thus deserves a more sophisticated terminology. Various different data are presented that support an emotion-model that defines emotion as the behavioural output of affective information processing (see Walla & Panksepp, 2013). Also, affective processing is separate from cognitive processing and it evolved before language came into existence. Thus, it is hard to find words for deep and raw affective content, which in turn means that survey-based investigations about emotion-related information may not necessarily tell us the entire truth. The fields for implications are enormous and span from basic neuroscience over clinical domains to even consumer neuroscience and marketing. References Peter Walla and Jaak Panksepp (2013). Neuroimaging Helps to Clarify Brain Affective Processing Without Necessarily Clarifying Emotions, Novel Frontiers of Advanced Neuroimaging, Prof. Kostas Fountas (Ed.), ISBN: 978-953-51-0923-5, InTech, DOI: 10.5772/51761. Available from: http://www.intechopen.com/books/novel-frontiers-of-advanced-neuroimaging/neuroimaging-helps-to-clarify-brain-affective-processing-without-necessarily-clarifying-emotions Keywords: Emotions, affective processing, brain imaging, Self Report, Models, Biological Conference: ASP2013 - 23rd Annual meeting of the Australasian Society for Psychophysiology, Wollongong, Australia, 20 Nov - 22 Nov, 2013. Presentation Type: Keynote Address Topic: Emotion Citation: Walla P (2013). What is an emotion in the first place? Time to sort things out. Conference Abstract: ASP2013 - 23rd Annual meeting of the Australasian Society for Psychophysiology. doi: 10.3389/conf.fnhum.2013.213.00033 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 05 Nov 2013; Published Online: 05 Nov 2013. * Correspondence: Prof. Peter Walla, University of Newcastle, School of Psychology, Newcastle, New South Wales, Australia, peter.walla@webster.ac.at Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Peter Walla Google Peter Walla Google Scholar Peter Walla PubMed Peter Walla Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Unique and potent effects of acute ibogaine on zebrafish: The developing utility of novel aquatic models for hallucinogenic drug research

An indole alkaloid, ibogaine is the principal psychoactive component of the iboga plant, used by indigenous peoples in West Africa for centuries. Modulating multiple neurotransmitter systems, the drug is a potent hallucinogen in humans, although its psychotropic effects remain poorly understood. Expanding the range of model species is an important strategy for translational neuroscience research. Here we exposed adult zebrafish (Danio rerio) to 10 and 20mg/L of ibogaine, testing them in the novel tank, light–dark box, open field, mirror stimulation, social preference and shoaling tests. In the novel tank test, the zebrafish natural diving response (geotaxis) was reversed by ibogaine, inducing initial top swimming followed by bottom dwelling. Ibogaine also attenuated the innate preference for dark environments (scototaxis) in the light–dark box test. While it did not exert overt locomotor or thigmotaxic responses in the open field test, the drug altered spatiotemporal exploration of novel environment, inducing clear preference of some areas over others. Ibogaine also promoted ‘mirror’ exploration in the mirror stimulation test, disrupted group cohesion in the shoaling test, and evoked strong coloration responses due to melanophore aggregation, but did not alter brain c-fos expression or whole-body cortisol levels. Overall, our results support the complex pharmacological profile of ibogaine and its high sensitivity in zebrafish models, dose-dependently affecting multiple behavioral domains. While future investigations in zebrafish may help elucidate the mechanisms underlying these unique behavioral effects, our study strongly supports the developing utility of aquatic models in hallucinogenic drug research. High sensitivity of three-dimensional phenotyping approaches applied here to behavioral effects of ibogaine in zebrafish provides further evidence of how 3D reconstructions of zebrafish swimming paths may be useful for high-throughput pharmacological screening.

The Developing Utility of Zebrafish Models for Cognitive Enhancers Research

Whereas cognitive impairment is a common symptom in multiple brain disorders, predictive and high-throughput animal models of cognition and behavior are becoming increasingly important in the field of translational neuroscience research. In particular, reliable models of the cognitive deficits characteristic of numerous neurobehavioral disorders such as Alzheimer’s disease and schizophrenia have become a significant focus of investigation. While rodents have traditionally been used to study cognitive phenotypes, zebrafish (Danio rerio) are gaining popularity as an excellent model to complement current translational neuroscience research. Here we discuss recent advances in pharmacological and genetic approaches using zebrafish models to study cognitive impairments and to discover novel cognitive enhancers and neuroprotective mechanisms.

Translational Neurodegeneration, a platform to share knowledge and experience in translational study of neurodegenerative diseases

Translational Neurodegeneration, a platform to share knowledge and experience in translational study of neurodegenerative diseases

Plasticity of corticospinal neural control after locomotor training in human spinal cord injury.

Spinal lesions substantially impair ambulation, occur generally in young and otherwise healthy individuals, and result in devastating effects on quality of life. Restoration of locomotion after damage to the spinal cord is challenging because axons of the damaged neurons do not regenerate spontaneously. Body-weight-supported treadmill training (BWSTT) is a therapeutic approach in which a person with a spinal cord injury (SCI) steps on a motorized treadmill while some body weight is removed through an upper body harness. BWSTT improves temporal gait parameters, muscle activation patterns, and clinical outcome measures in persons with SCI. These changes are likely the result of reorganization that occurs simultaneously in supraspinal and spinal cord neural circuits. This paper will focus on the cortical control of human locomotion and motor output, spinal reflex circuits, and spinal interneuronal circuits and how corticospinal control is reorganized after locomotor training in people with SCI. Based on neurophysiological studies, it is apparent that corticospinal plasticity is involved in restoration of locomotion after training. However, the neural mechanisms underlying restoration of lost voluntary motor function are not well understood and translational neuroscience research is needed so patient-orientated rehabilitation protocols to be developed.

The neurochemical profile quantified by in vivo 1H NMR spectroscopy

Proton NMR spectroscopy is emerging from translational and preclinical neuroscience research as an important tool for evidence based diagnosis and therapy monitoring. It provides biomarkers that offer fingerprints of neurological disorders even in cases where a lesion is not yet observed in MR images. The collection of molecules used as cerebral biomarkers that are detectable by (1)H NMR spectroscopy define the so-called "neurochemical profile". The non-invasive quality of this technique makes it suitable not only for diagnostic purposes but also for therapy monitoring paralleling an eventual neuroprotection. The application of (1)H NMR spectroscopy in basic and translational neuroscience research is discussed here.

Ketamine as a Novel Antidepressant: From Synapse to Behavior

Recent reports of a rapid antidepressant effect of the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine, even in treatment-resistant populations, have spurred translational therapeutic and neuroscience research aimed at elucidating ketamine's mechanism of action. This article provides a concise overview of research findings that pertain to the effects of low-dose ketamine at the cellular, neurocircuitry, and behavioral levels and describes an integrated model of the action of ketamine in the treatment of depression.

Current molecular imaging of spinal tumors in clinical practice.

Energy metabolism measurements in spinal cord tumors, as well as in osseous spinal tumors/metastasis in vivo, are rarely performed only with molecular imaging (MI) by positron emission tomography (PET). This imaging modality developed from a small number of basic clinical science investigations followed by subsequent work that influenced and enhanced the research of others. Apart from precise anatomical localization by coregistration of morphological imaging and quantification, the most intriguing advantage of this imaging is the opportunity to investigate the time course (dynamics) of disease-specific molecular events in the intact organism. Most importantly, MI represents one of the key technologies in translational molecular neuroscience research, helping to develop experimental protocols that may later be applied to human patients. PET may help monitor a patient at the vertebral level after surgery and during adjuvant treatment for recurrent or progressive disease. Common clinical indications for MI of primary or secondary CNS spinal tumors are: (i) tumor diagnosis, (ii) identification of the metabolically active tumor compartments (differentiation of viable tumor tissue from necrosis) and (iii) prediction of treatment response by measurement of tumor perfusion or ischemia. While spinal PET has been used under specific circumstances, a question remains as to whether the magnitude of biochemical alterations observed by MI in CNS tumors in general (specifically spinal tumors) can reveal any prognostic value with respect to survival. MI may be able to better identify early disease and to differentiate benign from malignant lesions than more traditional methods. Moreover, an adequate identification of treatment effectiveness may influence patient management. MI probes could be developed to image the function of targets without disturbing them or as treatment to modify the target's function. MI therefore closes the gap between in vitro and in vivo integrative biology of disease. At the spinal level, MI may help to detect progression or recurrence of metastatic disease after surgical treatment. In cases of nonsurgical treatments such as chemo-, hormone- or radiotherapy, it may better assess biological efficiency than conventional imaging modalities coupled with blood tumor markers. In fact, PET provides a unique possibility to correlate topography and specific metabolic activity, but it requires additional clinical and experimental experience and research to find new indications for primary or secondary spinal tumors.

Emerging Pharmacotherapies for Neurodevelopmental Disorders

A growing and interdisciplinary translational neuroscience research effort for neurodevelopmental disorders (NDDs) is investigating the mechanisms of dysfunction and testing effective treatment strategies in animal models and, when possible, in the clinic. NDDs with a genetic basis have received particular attention. Transgenic animals that mimic genetic insults responsible for disease in man have provided insight about mechanisms of dysfunction, and, surprisingly, have shown that cognitive deficits can be addressed in adult animals. This review will present recent translational research based on animal models of genetic NDDs, as well as pharmacotherapeutic strategies under development to address deficits of brain function for Down syndrome, fragile X syndrome, Rett syndrome, neurofibromatosis-1, tuberous sclerosis, and autism. Although these disorders vary in underlying causes and clinical presentation, common pathways and mechanisms for dysfunction have been observed. These include abnormal gene dosage, imbalance among neurotransmitter systems, and deficits in the development, maintenance and plasticity of neuronal circuits. NDDs affect multiple brain systems and behaviors that may be amenable to drug therapies that target distinct deficits. A primary goal of translational research is to replace symptomatic and supportive drug therapies with pharmacotherapies based on a principled understanding of the causes of dysfunction. Based on this principle, several recently developed therapeutic strategies offer clear promise for clinical development in man.

Arousal from slices to humans

Most psychiatric and neurological disorders exhibit sleep disorders, and in some cases presage the disease. Study of the control of sleep and waking has the potential for making a major impact on a number of disorders, making translational neuroscience research on this area critical. One element of the reticular activating system (RAS) is the pedunculopontine nucleus (PPN), which is the cholinergic arm of the RAS, and projects to the thalamus to trigger thalamocortical rhythms and to the brainstem to modulate muscle tone and locomotion. We developed a research program using brainstem slices containing the PPN to tell us about the cellular and molecular organization of this region. In addition, we developed the P13 midlatency auditory evoked potential, which is generated by PPN outputs, preparation in freely moving rats. This allows the study of PPN cellular and molecular mechanisms at the level of the whole animal. We also study the P50 midlatency auditory evoked potential, which is the human equivalent of the rodent P13 potential, allowing us to study processes detected in vitro, confirmed in the whole animal, and tested in humans. This translational research program led to the discovery of a novel mechanism of sleep-wake control, pointing the way to a number of new clinical applications in the development of novel stimulants and anesthetics.

Building and manipulating neural pathways with microfluidics.

Communication between different brain regions, and between local circuits in the same brain region, is an important area of study for basic and translational neuroscience research. Selective and chronic manipulation of one of the components in a given neural pathway is frequently required for development and plasticity studies. We designed an in vitro platform that captures some of the complexity of mammalian brain pathways but permits easy experimental manipulation of their constituent parts. Organotypic cultures of brain slices were carried out in compartments interconnected by microchannels. We show that co-cultures from cortex and hippocampus formed functional connections by extending axons through the microchannels. We report synchronization of neural activity in co-cultures, and demonstrate selective pharmacological manipulation of activity in the constituent slices. Our platform enables chronic, spatially-restricted experimental manipulation of pre- and post-synaptic neurons in organotypic cultures, and will be useful to investigators seeking to understand development, plasticity, and pathologies of neural pathways.