The goal of this project is to understand how newly born neurons integrate into existing neural circuits and change sensorimotor responses from juvenile to adult. Throughout development, the nervous system undergoes drastic changes in neuron number, neural connectivity, and neurotransmitter properties. From sensory periphery to neuromuscular junctions, circuits expand as new cellular components, differentiated from progenitors, update sensorimotor responses and adapt to changing body plans at each new life stage. A full understanding of the interplay between anatomical, functional, and behavioral changes across development, requires dynamic and structural models of complete neural circuits at different stages. To construct these models, we need to identify and perform physiological analysis of all circuit components. Because circuit function is flexible and heavily modulated by sensory feedback, we need to perform these studies in vivo in behaving animals where key sensorimotor feedback loops are intact. The nematode C. elegans is a particularly suitable model to unravel the interplay between the developing sensorimotor circuits, and the altering behavioral patterns. The genetic accessibility, known adult neural connectivity, and optical transparency of C. elegans provides an exceptional opportunity to fully dissect relationships between overall animal behaviors and the reshaping of neural circuits by the integration and rewiring of new neurons and synapses. Some C. elegans mechanosensory neurons and many motor neurons are born postembryonically, and incorporated the existing circuit during the larval development to the adult sensorimotor circuit. The adult escape response mediated by touch is one of the few behaviors where we know the complete descending pathway, from sensory input to motor output. We found that the C. elegans escape response changes during development. We hypothesize that changes in neural connectivity and integration of sub-motor circuits are required for the compound motor sequence that comprises the adult escape response. To test this hypothesis, we will use: 1) high-throughput serial-section electron microscopy and computer-aided image analysis to precisely map the C. elegans wiring diagram for escape response at each developmental stage, from juvenile larvae to adulthood; 2) quantitative behavioral analysis and optical neurophysiology, to determine the functional contribution of each circuit component to the escape response across development; and 3) optogenetic and genetic perturbation in freely behaving animals, to pinpoint the causative neural connectivities that underlie the execution, transition and developmental changes of the escape motor sequence. Our studies will unravel how neurons integrate into existing circuits with unparalleled resolution, and how new connections shape behavior throughout development. This studies not only are central to our understanding of neural circuit development, and but also has potential biomedical relevance. Cell replacement is viewed as a promising strategy for brain repair, but transplanted neurons often fail to properly integrate into pre-existing circuits. Understanding on how a complete and functioning circuit continuously integrates new components to generate adaptive behavior is critical for advancing an area of basic biology with great translational significance.
From birth to adulthood, the nervous system undergoes drastic changes to adapt to changing body plans and to execute different behavioral patterns appropriate to each life stage. In this project, we will reconstruct the complete neural connectivity of a developing nervous system of an invertebrate model system to understand how the integration of newborn neurons into existing neural circuits lead to the maturation of sensorimotor behavior. These studies will provide fundamental understanding into brain development, and inform cell replacement therapeutic strategies for brain repair.
| Fang, Tao; Lu, Xiaotang; Berger, Daniel et al. (2018) Nanobody immunostaining for correlated light and electron microscopy with preservation of ultrastructure. Nat Methods 15:1029-1032 |
| Lim, Maria A; Chitturi, Jyothsna; Laskova, Valeriya et al. (2016) Neuroendocrine modulation sustains the C. elegans forward motor state. Elife 5: |
| Venkatachalam, Vivek; Ji, Ni; Wang, Xian et al. (2016) Pan-neuronal imaging in roaming Caenorhabditis elegans. Proc Natl Acad Sci U S A 113:E1082-8 |
