The general body plan of most animals follows a bilateral symmetry. Some organs such as the heart and liver break this gross anatomical symmetry, while other structures such as the brain display a superficial bilaterally symmetric anatomy. Nonetheless, it has been known for a long time that the two hemispheres of the human brain serve distinct functions, and many classical examples in neuroscience and psychology have shown the importance of asymmetry in brain function. For example, higher order cognitive abilities such as language, spatial orientation, attention, and visual processing exhibit left-right (L-R) functional asymmetries in humans. Importantly, a number of neuropsychiatric conditions such as schizophrenia or autism spectrum disorders have been shown to display defects in brain laterality. Other animals such as birds, rodents and fish also display both lateralized functions and brain anatomy. Zebrafish have asymmetrically developed dorsal habenular nuclei, which are part of the epithalamus. These nuclei are characterized by different sizes, development, connectivity, and function. However, in these examples, asymmetric connectivity and function is mirrored in asymmetric anatomical structures. Whether asymmetric connectivity exists in anatomically symmetric structures, and what its function may be, remains largely unknown. We have identified an asymmetric synaptic connection between two pairs of sensory neurons that displays experience-dependent plasticity in the nematode Caenorhabditis elegans. The goal of this proposal is to investigate the developmental, plastic and functional aspects of this connection using Caenorhabditis elegans as a model system.
In Specific Aim 1, we will determine whether the asymmetric connection forms during embryonic development, or is initially established as a symmetric connection and pruned during larval development. Further, we will test (1) whether the pre- or postsynaptic cells are important for establishment of the observed synaptic asymmetry, (2) whether genes important for cell fate specification and function of the involved sensory neurons are important, and (3) whether neuronal activity is required for the observed synaptic asymmetry.
In Specific Aim 2, we will determine the dynamics of the plasticity of this connection, which we have found to be dependent on different environmental conditions. In a third and last Specific Aim we will test a potential function of the asymmetric synaptic connection. Specifically, we will quantify the behavioral responses both in populations as well as of individual animals using a worm-tracker and directly correlate these results with a fluorescent label specific to the synaptic connection in individual animals. In sum, this exploratory research program aims to establish basic aspects of a plastic asymmetric synaptic connection. It is expected that this work will lay the foundation towards a fundamental understanding of asymmetric connectivity and function.
The functional asymmetry of human brains has long been known, but it was found only recently that laterality of neuronal function is perturbed in neuropsychiatric disorders such as autism as well as other mental disorders. We have discovered an asymmetric neuronal connection in the small nematode Caenorhabditis elegans. We propose to study this asymmetric neuronal connectivity using a combination of genetic, behavioral, and imaging studies using the model system C. elegans to explore the developmental mechanisms and functional significance of asymmetric neuronal connectivity.
