What Can Psychiatry Learn from Worms, Flies, Bees and Fish&Quest
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Molecular Psychiatry (2011) 16, 7–16 & 2011 Macmillan Publishers Limited All rights reserved 1359-4184/11 www.nature.com/mp FEATURE REVIEW Big ideas for small brains: what can psychiatry learn from worms, flies, bees and fish? T Burne1,2, E Scott3, B van Swinderen1, M Hilliard1, J Reinhard1, C Claudianos1, D Eyles1,2 and J McGrath1,2,4 1Queensland Brain Institute, University of Queensland, St Lucia, Australia; 2Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Wacol, Queensland, Australia; 3School of Biomedical Sciences, University of Queensland, St Lucia, Australia and 4Department of Psychiatry, University of Queensland, St Lucia, Queensland, Australia While the research community has accepted the value of rodent models as informative research platforms, there is less awareness of the utility of other small vertebrate and invertebrate animal models. Neuroscience is increasingly turning to smaller, non-rodent models to understand mechanisms related to neuropsychiatric disorders. Although they can never replace clinical research, there is much to be learnt from ‘small brains’. In particular, these species can offer flexible genetic ‘tool kits’ that can be used to explore the expression and function of candidate genes in different brain regions. Very small animals also offer efficiencies with respect to high-throughput screening programs. This review provides a concise overview of the utility of models based on worm, fruit fly, honeybee and zebrafish. Although these species may have small brains, they offer the neuropsychiatric research community opportunities to explore some of the most important research questions in our field. Molecular Psychiatry (2011) 16, 7–16; doi:10.1038/mp.2010.35; published online 30 March 2010 Keywords: animal model; psychiatry; C. elegans; Drosophila; Apis; Danio Introduction goal. However, animal models provide an experi- mental platform that allows researchers to focus on Although clinical studies remain central to psychia- more substrate-pure, neurobiological correlates of tric research, experiments based on non-human clinical syndromes.7,8 animal models provide an essential tool to explore a Essentially, neuroscience aims to understand how wide range of important research questions. Apart animals sense, interpret and respond to the world from the use of animals in preclinical psychopharma- around them and to internal cues. To explore these cology, which has a long and distinguished track issues, we need to understand (a) the component record,1–3 various animal models have been devel- parts of the brain (for example, neural circuits, oped to explore candidate risk factors associated cells, neurotransmitters, proteins, genes), (b) how with neuropsychiatric disorders, and to learn more these components interact to generate information about pathways implicated in the clinical syndrome. processing capacity (for example, perception, atten- Transgenic mice, in particular, have contributed to tion, learning, memory), and (c) how individual significant advances in our understanding of how animals live within ecological niches, and interact genes that have been linked to clinical disorders within groups of animals (for example, rearing, social impact on brain development and adult brain func- behavior). Trying to unravel the mechanisms con- tion.4–6 Over the last decade or so, the psychiatric tributing to a neuropsychiatric syndrome is a daunt- research community has become more comfortable ing task, as the final surface-level phenotype is a in the acceptance that animal models do not need to higher order derivative of many underlying factors. recapitulate the full phenotype of clinical disorders to The instructions for building a brain accumulate be valuable. Although some aspects of neurological across the lifespan and incorporate information from disorders can be more readily modeled in animals many categories of observation (for example, heritable (for example, the motor features of Parkinson’s and factors, everyday background and infrequent environ- Huntington’s disease), reproducing symptoms such as mental exposures). delusions and hallucinations seems an unrealistic Dealing with biological complexity is daunting enough, but when much of this complexity remains Correspondence: Professor J McGrath, Queensland Brain Insti- hidden and poorly understood, as is the case with tute, University of Queensland, St Lucia 4076, Australia. E-mail: [email protected] brain functioning, the task can be overwhelming. Received 3 August 2009; revised 28 January 2010; accepted 16 From a clinical perspective, one strategy is to divide February 2010; published online 30 March 2010 the tasks into different categories of clinical research Big ideas for small brains T Burne et al 8 (for example, functional and structural neuroimaging, animal models with differing levels of neuronal gene association studies), and then to ‘drill down’ complexity, and especially by using these models in into these domains looking for mechanisms that combination, we can refine our questions relating to may underpin the disorder of interest. Hopefully, biological function. In addition, the neuroscience and the different categories of research will converge on genetic ‘took kits’ now available for several of these mechanisms related to pathogenesis. Another strategy species allow the opportunity to dissect some of the is to use clues from clinical research in animal models molecular and cellular architecture underpinning to simplify the research question and build experi- neuropsychiatric syndromes. mental research platforms based on a range of non- human species. For example, the anatomical descrip- Caenorhabditis elegans tion of the C. elegans nervous system, with its 302 neurons and roughly 5000 synapses, is complete at The hermaphrodite of the nematode C. elegans is the cellular level.9 Many of these neurons are also comprised of 959 somatic cells, 302 of which are linked to discrete behaviors.10 While still complex, neurons. This simple nervous system is one of the the neuroscience research community is more likely best characterized at the cellular and molecular level to gain traction on the hidden layers of complexity among metazoan. The lineage, position and morpho- underpinning neuropsychiatric disorders using logy of each neuron have been determined, and all animal models with ‘small brains’.11–13 the neuronal connections have been resolved by The aim of this paper is to provide a concise serial reconstruction with electron microscopy.14,15 overview of how animal models such as worm, fruit Neuronal functionality and wiring are almost invar- fly, honeybee and zebrafish can inform psychiatric iant among animals, and the chemical properties of research (see Figure 1). We argue that these models C. elegans neurons are similar to those of mammalian provide efficiencies that are particularly attractive for neurons with synapses relying on neurotransmitters high-throughput research platforms. By examining such as acetylcholine, glutamate, dopamine, seroto- Figure 1 Examples of experimental features associated with each of the four species. Upper left, Drosophila melanogaster— electrophysiology is used to record from an awake behaving fly. Upper right, Apis mellifera—bees leave the research hive to forage and explore the environment outside the laboratory. Lower left, Caenorhabditis elegans—green fluorescent protein highlighting the mechanosensory neurons in a freely moving worm. Lower right, Danio rerio—swimming is used as a behavioral readout for various tasks in zebrafish. Molecular Psychiatry Big ideas for small brains T Burne et al 9 nin and GABA. The precise characterization at the and single cell resolution to study development and single cell level, combined with powerful molecular function. For example, the entire set of 26 GABAergic and genetic tools, rapid life cycle and ease of neurons can be highlighted with green fluorescent manipulation, have allowed important biological protein using the promoter of the gene encoding questions to be answered in this model organism. for the GABA biosynthetic enzyme, unc-25.21 Of particular relevance is the discovery of the Similarly, the eight dopaminergic neurons can be conserved genes and mechanisms regulating pro- visualized using the promoter of the dopamine trans- grammed cell death, which led to the Nobel Prize in porter dat-1,22 and the 12 serotonergic neurons using 2004 for Sydney Brenner, Robert Horvitz and John the promoter of the tryptophan hydroxylase tph-1.23 Sulston. Similarly, research based on C. elegans was Using these or similar specific promoters, the critical in the discovery of gene silencing by double- expression of particular genes can be targeted to stranded RNA (RNA interference or RNAi) by Craig classes of neurons to study the function of their Mello and Andy Fire (Nobel prize in 2006), as well as encoded protein. This approach has been employed the development of the green fluorescent protein, that to define the conserved role of human homologs in had its eukaryotic start in C. elegans by Martin Chalfie C. elegans.18,24 (Nobel Prize in 2008). More recently, research in the Despite the simplicity of its nervous system, worm allowed the discovery of microRNAs for which C. elegans shows an interesting repertoire of well- the C. elegans scientists Victor Ambros and Gary defined behaviors. With their sensory systems exqui- Ruvkun were awarded the Lasker prize in 2008. sitely developed, worms are able to find food sources, Classical