Environmental regulation of spinal cord development

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During development, the cells that form the brain need to produce many different kinds of neurons in order to generate the complicated neural circuits found in adults, a process called differentiation. Many different molecules affect the patterning of the embryonic nervous system; these molecules have been used to identify biochemical pathways that are part of the developmental programs cells utilize to acquire their individual neuronal identities. However, the extent to which the environment intervenes in the functioning of this developmental program, is an understudied aspect of neural development. This research project documents ways in which nervous system development is dynamic and sensitive to the environment in which it occurs, challenging the idea of a predetermined, rigid genetic program that completely dictates the fate of neural cells before they are born. A mechanistic explanation for the observed plastic changes (that the environmental plasticity produces neural circuits that better match an individual's performance to the particular environment they develop in) is also tested. The research will assess the influence of temperature on neuronal differentiation in the embryonic frog spinal cord, and chart the mechanisms through which temperature differences change the sensorimotor behavior of developing tadpoles. Understanding these basic mechanisms of nervous system development will benefit society by contributing to knowledge about neurodevelopmental disorders and spinal cord regeneration. In addition, this project will establish an educational program at the K-12 school in Shriners Hospital for Children Northern California. Children are patients, mostly from low-income families; they will be offered a school program when they need to stay long-term at the Hospital, a non-profit organization that cares for the children at no cost. The project will expose these children to hands-on science activities and the scientific method. This investigation hypothesizes that environmental cues modulate embryonic calcium activity in developing neurons, thus regulating spinal neuron differentiation and the establishment of effective locomotor circuitry. Using a multidisciplinary approach, this study will identify the mechanisms by which environmental temperature modulates calcium-mediated spontaneous electrical activity resulting in specification of developing spinal neurons. The study hypothesizes that the cold-sensitive transient receptor potential cation channel M8 (TRPM8) contributes to the higher frequency calcium spike activity observed at cold temperatures. Pharmacological and genetic approaches will be implemented to assess the necessity and sufficiency of TRPM8 in cold temperature-induced changes in calcium activity. Differentiation and patterns of connectivity of sensory and motor neuron populations in animals grown at different temperatures after reaching identical tadpole stages will be examined by immunostaining and luciferase assay reporters. This investigation will determine the mechanisms underlying the changes in sensory and motor neuron differentiation by rescuing the temperature-driven phenotype through imposing counteracting approaches to the changes in calcium spike activity. To determine the consequences of the temperature-driven changes in neuronal differentiation on sensorimotor behavior and to test whether there is interaction between the temperature at which animals are grown and the sensorimotor performance, embryos will be raised at different temperatures until tadpole stages when the flexion reflex and the swimming pattern will be assessed at different temperatures.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.