Workshop Report: Neurodevelopment


Background

In fiscal year (FY) 2008, the NIH Neuroscience Blueprint will focus on providing specific tools and resources to advance the field of neurodevelopment.  The NIH Blueprint ICs share an interest in understanding normal neural developmental processes as well as how aberrant developmental trajectories may impact physical and emotional health for a lifetime. In addition to developmental disorders that become apparent during early postnatal life and childhood (e.g. mental retardation, autism, learning disorders), it is becoming increasingly clear that later-emerging neurological and behavioral disorders (e.g. Parkinson’s disease, schizophrenia) also have developmental antecedents. Moreover, each developmental stage or transition may be impacted by genetic and environmental factors that remain to be defined. The study of neural development encompasses many levels of analysis, from molecular to behavioral research, and ranges from animal models to human studies. NIH implementation of timely tools and resources for neural development will be critical for improved comprehension of normal development as well as elucidation of a wide array of nervous system disorders based in aberrant developmental processes.

In preparation for 2008, the NIH utilized a two-pronged approach for polling the scientific community: 1) a broad Request for Information published in the NIH Guide for Grants and Contracts and 2) a focused NIH Neuroscience Blueprint Workshop on Neurodevelopment (November 13-15, 2006).  The research community and workshop participants were asked to address a series of questions, including the following: What fundamental problems in basic and/or clinical research in neurodevelopment require additional tools to facilitate advancement? What roadblocks or systemic challenges need to be addressed in the immediate future to facilitate the rapid advance of knowledge and new discovery? What major technical gaps must be addressed in the immediate future in order to advance current knowledge?

Workshop Summary

In November 2006, the Blueprint Neurodevelopment workshop convened approximately 30 developmental neuroscientists from diverse areas of investigation in order to identify and discuss the major, cross-cutting challenges in neurodevelopment research that can be uniquely addressed by the Blueprint.  As the Neuroscience Blueprint is designed to be a catalyst for NIH-supported neuroscience research, participants were encouraged to think broadly and creatively about areas of neurodevelopment that would benefit from accelerated strategic investments. The overarching goal was to generate ideas for new FY2008 initiatives designed to promote the creation of tools and resources to rapidly advance research in neurodevelopment.

Meeting co-chairs BJ Casey and Pat Levitt identified two themes central to neurodevelopment research: transition (within species) and translation (between species). Characterization of developmental transitions at the cellular, circuitry and behavioral levels within a species is needed to understand typical and atypical developmental trajectories. Translation of developmental findings across species at the cellular, circuitry, and behavioral levels are needed to characterize gene-environment interactions and developmental processes that are involved in human disease.  During the workshop, a series of plenary talks set the stage for detailed discussion of issues at hand. The participants were then divided into four topic-based breakout groups, including 1) Neurogenesis, Differentiation and Cell Fate; 2) Circuit Formation; 3) Developmental Plasticity; and 4) Developmental Disorders and Risk Factors. Each group brought forward a series of 3-5 prioritized recommendations for discussion with the entire group and with the Directors of the NIH Neuroscience Blueprint ICs.

In general, workshop participants requested that the NIH Blueprint direct the creation, expansion and distribution of tools and resources and implement guidelines for advancing model systems of neurodevelopment. For example, the workshop participants identified the increased availability of validated monoclonal antibodies, new markers for measuring circuit function, and advanced genetic reagents as crucial needs. Improved understanding of the biological bases of behavior was at the forefront of discussion; both basic and clinically-oriented researchers supported the improved study of neural development across time periods (transitions) and species (translation).  Finally, those working on developmental disorders stressed the need for the creation of public databases which could be used to combine and to share the wealth of existing and novel genetic, behavioral and imaging resources.

One of the most consistent expectations from the Neurodevelopment workshop was that deliverables provided by the Blueprint must be of broad utility to the community, well-validated, and reasonably priced. Furthermore, coordination of ongoing and nascent NIH efforts was seen as optimal. In general, the recommendations made by workshop participants fall into three general categories:

  1. Creation and validation of new tools and resources
  2. Targeted improvement of existing resources
  3. Database development/enhancement, standardization and access

These general areas of identified need and specific areas for future emphasis are presented below.

1. Creation and Validation of New Tools and Resources

Participants targeted several areas for the development of new tools and resources that would advance the field. Areas of emphasis included: improved monoclonal antibodies for a prioritized set of developmental markers, methods to detect circuit development, reagents for developmental studies in the non-human primate, and a behavioral “toolkit� for the assessment of behavioral changes across species. For instance, access to well-characterized antibodies that recognize molecules of importance to nervous system development will have a unifying effect for many lines of study across developmental neuroscience, and will provide a valuable resource for investigators supported by all NIH Neuroscience Blueprint Institutes.

Possible strategies might include:

A. Improved analysis of developing cells and circuits

  • Novel tools and markers for cell-type specificity, including a neural development monoclonal antibody resource
  • Innovative approaches to visualize and/or manipulate specific populations of neurons within developing neural circuits
  • New technologies for temporal control of gene expression in mouse

B. Genetic resources

  • Targeted genetic analysis of gene families during development

To test the role of specific gene families (e.g. protein kinases, transcription factors) during development using gain- and loss-of-function (GOF, LOF) assays. GOF assays would focus on the utilization of a standardized toolbox of viral vectors, whereas LOF studies would be shRNA and siRNA-based.

  • RNAi technology/resources for developing neurons and glia

To produce LOF libraries for whole genome analysis, with emphasis on characterizing both neuronal and glial populations in the developing brain

  • Genetic tools for developmental analyses in the non-human primate (e.g., application of viral vectors to manipulate gene expression)

C. Cross-species standardization of assays for behavioral development

A new resource designed to identify existing gaps, build consensus on standardization of terminology and assays, and provide a central database on experimental design for developmentally appropriate behavioral measures across species.

2. Targeted Improvement of Existing Resources

Within the NIH, a number of efforts are underway to guide new research directions, and numerous ongoing administrative efforts focus on delivering reagents to the public. To that end, the group consistently proposed that the NIH Blueprint is uniquely poised to effectively coordinate these activities for the field of neurodevelopment. Participants stated explicitly that improved access to available resources would have a catalytic effect on the field. Similarly, the neurodevelopment group emphasized that several existing reagents or resources were often inadequate for their needs: for example, many ongoing developmental studies do not include adolescent time points, which limits knowledge of this key transitional period.

Possible improvements could include:

  • Addition of adolescent time points to existing and future gene/protein expression resources (e.g., GENSAT)
  • Four-dimensional quantitative imaging: development of a versatile and scalable imagingacquisition and analysis software that could allow real-time, automated, high-throughput, quantitative imaging.  This program would be public domain and open source software compatible with MatLab
  • Increased access to chromatin-based arrays for studying neural development, possibly via centers such as the NIH Neuroscience Microarray Consortium.

3. Database Development/Enhancement, Standardization and Access

Participants agreed that a wealth of information and data is available to the neurodevelopment community. However, due to the disparate nature and location of these resources, significant time is spent searching for relevant information. Specific examples cited included the needfor additional informatics-based knowledge as well as the consolidation of existing information into readily accessible and searchable formats. It was suggested that NIH could take an active role in the standardization of practices and databases across large areas of neurodevelopment.

Possible strategies might include:

  • Developing human/non-human primate gene expression project - A new, centralized expression database in which gene expression would be correlated with digital anatomic MRI in the developing brain.
  • Centralized clinical neurodevelopment database -A central repository for multidisciplinary data (genetic, neuroimaging, cognitive/behavioral) from human clinical studies that is associated with DNA/genetic information.
  • Taxonomy for clinical neuroscience (risk-factor based) - A “bottom-up,â€� multi-level database of genetic and environmental risk factors that contribute to the etiologies of developmental disorders.  This database would take advantage of knowledge from model systems with initial focus on well-characterized genetic and environmental risk factors contributing to defined syndromes and disorders.
  • Gene expression profiles for well-identified and isolated neural populations in developing mouse brain - To construct gene expression profiles for neural precursors, neurons and glia in developing mouse brain, in order to understand the developmental bases of neural diversity and function, to map changes in developmental disorders and to identify vulnerable cells and circuits in developmental disorders and diseases.

Conclusion

The priorities put forward by workshop participants have recently been reviewed by the NIH Neuroscience Blueprint IC Directors; a subset will be released as funding initiatives in the late summer/early autumn of 2007. Consistent with the idea of a catalytic endeavor aimed to rapidly advance the field of neural development, most Blueprint investments will be funded by the NIH over a defined period of time beginning in FY2008. In addition, ideas requiring medium or long-term focus may be revitalized for consideration in coming years.