The discovery that neurons are polarized cells and the deduction that signals travel from dendrites to cell bodies to axons allowed Ramon y Cajal to determine the connectivity between neurons and the direction of flow of information in the brain. Disruptions in neuronal connectivity are characteristic of neurological disease, age- related mental decline, and loss of motor function after injury. This proposal addresses the question: is cell polarity essential for neuronal function? Neuronal polarity will be addressed in Hydra, freshwater relatives of jellyfish. Hydra have a very simple, decentralized nervous system, called a nerve net, yet demonstrate complex behaviors including nodding, sway- ing, somersaulting, and responding to environmental stimuli. Hydra neurons lack obvious morphological polarity and do not show clear evidence of axons and dendrites, suggesting that they are not polarized. On the other hand, there are some clues that Hydra may have neuronal polarity: they have polarized chemical synapses and genetic components of the axon initial segment. Furthermore, Hydra contain a core set of evolutionarily con- served proteins that are associated with cell polarity in neurons of higher organisms. Thus, whether Hydra neu- rons are polarized is an open question. To determine whether or not neurons in Hydra are polarized, a number of cellular and molecular criteria that distinguish axons and dendrites are proposed. These criteria, to be tested in Aim 1, include neurite length, diameter, number of branch points, microtubule polarity, and the organization of actin and intermediate filaments. To assess these criteria, the proposal will take advantage of new molecular tools that are becoming available in Hydra and which allow individual cells to be fluorescently labeled, and their constituent proteins localized.
In Aim 2, the nature of information flow through Hydra nerve nets will be examined. By imaging neuronal activity with calcium sensors following a sensory stimulus, the extent to which signals move directionally through the nerve net will be determined.
In Aim 3, mathematical models will be used to predict how neuronal architecture emerges from neurite branching and growth rules, and the models will tested by studying regeneration. Completion of these aims will assess the extent to which neuronal polarity is an essential component of neuronal function, or whether it evolved as a specialization of centralized nervous systems. These experiments will provide insight into the evolution of nervous systems in higher animals and humans and is a step toward a long-term goal of understanding the role of connections in behavior. Regardless of whether or not polarity and directional signaling are necessary for neuronal function and behavior, the proposed studies are expected to provide insight into the function and dysfunction of the nervous system.
Determining how neurons connect and relay information to each other is essential for understanding neurological function and neurodegenerative diseases. Because of the complexity of the human nervous system, a simple animal, Hydra, which is related to jellyfish, will be used to study how neurons make connections and signal to each other to coordinate behavior. Molecular and cellular principles gleaned from this organism is likely to give important clues for understanding neuronal development and function in higher animals.