Year: 2006
Type: editorial
Abstract: Molecular biological approaches have played a key role in our growing understanding of nervous system function in health and disease. However, coupling individual molecular events with the function of distributed neural systems involved in complex behaviors and neuropsychiatric diseases requires the integration of reductionist molecular work with systems neuroscience. Genetic and genomic methods can help provide a systems context for individual molecular changes and also serve as a bridge between human biology and animal or cell models. For example, once genes are identified as causal or susceptibility factors in human disease, the appropriate use of animal or in vitro models will play a key role in clarifying the structural and functional changes occurring at the cellular and neural systems levels. In contrast, when the underlying circuits are well connected to a particular conserved cognitive function or behavior, work in the animal models to define the molecular etiologies can be appropriately translated to humans. With regard to both of these approaches, the manuscripts in this supplement that highlight several presentations from the advanced course ‘Genes and Neurons’ (held in July 2004 at the University of Minho, Braga, Portugal) share a common theme of bridging the gulf between genes and behavior. These papers reflect an area of research that is emerging as one of broad interest to the neuroscience community, as it represents recent advances that bridge the gap between genes, brain and behavior, in many cases using animal models to help shed light on complex human behaviors or cognition and disorders that affect these processes. This ‘Genes and Neurons’ supplement provides a broad overview of this area, covering both fundamental and hot topics, ranging from the basics of mouse behavior and cognition (Sousa, Almeida and Wotjak), genetic approaches to common psychiatric diseases (van Belzen and Heutink), to the MAP kinase (MapK) pathway in memory (Davis and Laroche), the genetics and neurobiology of mental retardation (MR) (Dierssen and Ramakers), the molecular basis of circadian behavior (Oster), a molecular systems level approach to anxiety (Stoppel, Albrecht, Pape and Stork), chromatin remodeling and developmental disorders (Santos and Maciel) and Alzheimer′ Dementia (Grazina and Oliveira). As such, this issue provides an extremely worthwhile and up to date review of these core topics in the molecular genetic basis of cognition and behavior for students and experts alike. In the comprehensively referenced ‘A hitchhiker's guide to behavioral analysis in laboratory rodents', Sousa and colleagues take on the difficult job of providing a template for approaching analysis of relevant behaviors in rats and mice. Several key points are worth noting. Sousa et al. emphasize the importance of using qualitative and quantitative strain differences in genetic mapping, and the challenges of moving from quantitative trait loci (QTLs) to genes, highlighting the development of more sophisticated and innovative analytic methods to facilitate these efforts. They focus on many critical practical issues that can impede proper assessment of behavior in mice, such as handling, training, stable routines and the failure to appreciate interstrain differences. Sousa et al. also appropriately caution us to be wary of over-interpreting molecular lesion studies, such as single-gene knockouts. Similar to anatomical lesion studies of the brain in developing animals, the functions being measured not only reflect the absence of a particular gene but also the potential consequences of environmental factors and molecular or behavioral systems' adaptations to the insult, including the use of alternative strategies not relevant to normal development or function. Lastly, they provide a practical guide for the general assessment of behavior, physical features and cognition in mice. It is clear from this extensive guide that although some of the areas such as motor behavior and memory are well established, several areas of particular relevance to human disease, for example, social behavior (of particular relevance to autism), are far less developed. Furthermore, how aberrancies in native social behaviors in mice correspond to human neurobehavioral disorders is a largely unexplored area. In a parallel introductory chapter, van Belzen and Heutink provide an exceptionally clear and thorough introduction on the use of modern genetic mapping tools to identify genes causing human psychiatric disorders. They move from explaining notions of heritability, the challenge of mapping complex disease genes and endophenotypes to providing concrete examples of approaches that have worked in defining genetic susceptibility factors in complex diseases, such as schizophrenia. Van Belzen and Heutink discuss linkage, association, candidate genes and issues of phenotype definition in a manner that is accessible to even the genetically unsophisticated audience, and as such this paper is highly recommended reading for those wanting a comprehensive introduction to this topic. They cite a number of advances in the genetics of psychiatric disorders, including work on Disc-1, Disbindin and other genes underlying genetic risk for schizophrenia that support their optimistic assessment of the outlook for the field of human psychiatric genetics. Here, the field has already made the jump successfully from humans to animal models in some cases. One of the neural circuits underlying complex behavior that has been extensively studied over the last two decades involves brain regions mediating fear and anxiety, which consist of highly conserved pathways that are very amenable to modeling in rodents. As Stoppel et al. note in their article ‘Genes and Neurons: Molecular Insight into Anxiety’, anxiety disorders and related conditions such as post-traumatic stress disorder (PTSD), while having a heritable component in humans, are complex genetic conditions likely involving multiple genes interacting with the environment. Stoppel and colleagues appropriately champion the use of animal models, which allow molecular dissection of this circuitry, one gene at a time. They point out that studying these mouse models has allowed molecular dissection of molecules that modulate anxiety in the mouse, which has in turn clearly informed our understanding of human disease. In the case of fear conditioning, the knowledge of the behavior, circuitry and some initial molecular clues allowed for productive exploitation of this system in rodents to understand human anxiety in disease. QTL mapping in mouse has identified several loci that modulate distinct aspects of this process, and these loci can be compared with those identified in human conditions to help identify genes. Similarly, genes that modulate mouse behavior become candidates in studies of humans. This translational work is in its beginning, but the authors make it clear that the genes and systems already identified will be fruitful for understanding human genetic variation, perhaps related to PTSD and other debilitating neuropsychiatric disorders. Furthermore, because anxiety is such a prominent symptom in many human brain disorders, including dementia and developmental conditions such as Fragile X syndrome, better molecular targeting of this symptom domain is of great public health importance. The concept of MR as a phenotype driving genetic studies is controversial from the standpoint of modern cognitive neuroscience, which often emphasizes the study of discrete cognitive processes and the specific neural circuits that are their basis. However, from the standpoint of both public health impact and human genetics, MR syndromes are illustrative of success in multiple domains of the mouse model from gene identification and diagnostic testing to modeling. Dierssen and Ramakers highlight the phenomenon of dendritic pathology as a unifying feature across syndromes and across species. Such a neuropathological endophenotype is optimal for cross-species translation. These authors discuss the common pathology observed in MR as possibly affecting ‘communication systems’ in a global fashion across the brain. In this particular case, it is not clear precisely which anatomical or physiological substrates the authors are referring to by the terminology ‘communication systems.’ Perhaps, they mean to liken MR to a global disconnection syndrome involving higher order association areas, a concept that serves as one of the foundations of modern behavioral neurology (Catani & ffytche 2005; Geschwind 1965a, b). In this context, defects in axon pathfinding, neuronal migration or placement, synaptic plasticity and signaling properties of neurons all could lead to similar phenotypes, in which most primary sensory systems function, but carefully timed interregional communication of second-order and third-order association areas necessitated by most higher cognitive processes would be impeded. The authors discuss data from animal models of Down syndrome and Fragile X syndrome and in afflicted humans using functional imaging modalities that provide support for this disconnection hypothesis. Should such common processes be involved in rare and diverse forms of MR, it would provide potential for common treatment avenues in the future. In contrast to MR, memory function has been one of the topics explored most by modern cognitive neuroscience. Here, a huge literature on memory function in humans and animal models can be brought to bear on molecular genetic approaches. Homologous systems, from molecules, to regions, to specific forms of memory, have been identified across divergent species, including humans. Davis and Laroche review one of the hottest areas in the molecular basis of memory, the role of MapK signaling pathways in coupling synaptic signals to transcriptional changes that modify neuronal excitability at specific synapses. This is a confusing area to those outside the field, filled with a veritable alphabet soup; hence, although most of us wish to know more about MapK's, ras, rafs and Erks phosphorylate CREBs and other four letter words, this material is often hard to access at some basic, yet current level. Here, the authors not only explain what is known about this cascade in clear detail but also relate it to a wide variety of learning paradigms in model systems, from fear conditioning to object memory. Although the distinction between short-term and long-term memory has been clear at the psychological and anatomical level in primates and mice, the molecular basis of this distinction should be of particular interest for those outside of this rapidly moving field. One of the most interesting and highly conserved systems regulating complex human behavior is the circadian system, in which variation affects most of the other systems covered in this supplement, including memory, anxiety and social behavior. Henrik Oster reviews work in animal systems, including Drosophila, that have informed the study of human circadian behaviors at a molecular level. Oster contrasts the concepts of central vs. peripheral pacemakers, describing how both can be orchestrated in a hierarchical manner. Here, microarray studies have proven valuable, showing that nearly 10% of genes show circadian variability in expression. It is also important to note in the context of translation between animal models and humans that there is emerging data showing that this work has clearly informed human genetics and the molecular basis of sleep and circadian rythms in humans (Lowrey & Takahashi 2004; Xu et al. 2005). Two final papers address mechanisms of disease at the ends of the developmental spectrum, during early childhood and aging. Santos and Maciel review the role of the epigenetic regulation of gene expression in brain function and development. At a molecular level, epigenetic changes involve reversible but often heritable modifications that alter DNA function without changing actual DNA sequence. The role of epigenetics in neurodevelopmental disorders is emphasized by the role of imprinting in Prader–Willi/Angelman syndrome and dysregulation of a canonical form of epigenetic modulation, DNA methylation, in Rett Syndrome. In Rett syndrome, loss-of-function mutations in the global transcriptional regulator, MECP2, cause a striking, regressive and degenerative MR syndrome. Santos and Maciel critically analyze some of the unexpected results of classic microarray experiments performed on MECP2-null animals and provide a clear synthesis of the data on MECP2 targets that is moving to unravel the mystery of Rett pathophysiology. Furthermore, they review several studies that support their view that chromatin structure alterations are likely to play a role in a variety of cognitive and behavioral phenotypes in humans and provide a mechanism whereby environmental factors can have lasting effects on an individual genome and the genetic control of behavior. In the final paper of this supplement, Grazina et al. discuss their hypothesis-driven approach to unravel the genetics of a disease that has been challenging to model in rodents, Alzheimers Disease (AD). They provide an extensive summary of current literature on AD pathophysiology to highlight 12 potential biological pathways. In their synthesis, they elegantly couple an emerging literature on oxidative stress and the function of known Mendelian mutations to findings of energetic deficits in post-mortem AD brains, lending support to the hypothesis that mtDNA mutations may contribute to AD susceptibility. They describe a number of findings in case–control studies identifying potential pathophysiologically relevant changes in mtDNA, including one in the related disorder frontotemporal dementia. The data presented strongly support the biological plausibility of the mitochondrial hypothesis, and the authors provide one of the most scholarly analyses of all of the methodological and technical factors that may confound the results that I have seen. However, as they suggest, the absence of clear maternal inheritance, the non-replication of many findings, in what are mostly small case–control association studies, weakens the genetic support for this otherwise worthy hypothesis. In their critical assessment, the authors provide an ample roadmap for future research in this challenging but important area. The major unstated question looming over animal models of complex cognitive and behavioral human phenotypes is how much can we translate between these species that diverge at every level, from the complexity of cortical regions to single nucleotide polymorphisms. It is clear that even mouse and rat are quite distinct in many aspects of their behavior and brain organization. Yet, little has been done to directly address the relevance of mouse work to human cognition and behavior, presumably because of the complexity of such analyses. This is not to diminish the importance of models but to emphasize the necessity of analyzing data in the appropriate comparative and evolutionary context, so as to enable real progress in our understanding of brain dysfunction in neuropsychiatric disease. Such approaches necessitate development of new tools, and the application of systems biology approaches to permit a true synthetic view of human disease. The review articles included in this supplement were written by invited speakers from the course ”Genes and Neurons”, sponsored by the European Science Foundation, Functional Genomics Programme.
Source: Genes Brain & Behavior
Author: D. Geschwind
Institution: University of California, Los Angeles
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W1835633981