Mechanisms underlying the effects of retinoic acid on neurite outgrowth and network plasticity

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The main aim of my research program is to study the effects of the essential Vitamin A metabolite, retinoic acid, on nervous system function. Retinoic acid is important for nervous system development and regeneration, as well as for learning and memory in the adult brain. We study these aspects of retinoid signaling using the central nervous system (CNS) of the mollusc, Lymnaea stagnalis. Unlike most vertebrate species, molluscan adult CNS neurons can regenerate. Growth cones, which are located at the tips of growing nerve fibres (neurites) play an important role in axon guidance during development and regeneration. In Lymnaea, growth cones of cultured regenerating CNS neurons are large and robust and we have shown that they respond to and turn toward a focal source of retinoic acid, which we hypothesize is acting as an important guidance molecule during development and regeneration. It is known that many guidance molecules are well conserved across vertebrate and invertebrate species, so Lymnaea neurons are ideal for investigating the cellular and molecular mechanisms underlying retinoic acid-induced growth cone turning, which are currently largely unknown. Over the next grant cycle, we will  investigate the role of retinoid receptors and potential downstream second messengers in the growth cone turning response to retinoic acid. ***Recently, we have also discovered an extremely novel "floating growth cone" phenomenon, where regenerating neurites from the cut nerves of a dissected Lymnaea CNS, grow along the air-water interface. As substrate-adhesion is normally required for neurite outgrowth and regeneration, this is a novel regenerating event which will be used to provide novel insights into growth cone behaviour that can not easily be addressed in cell culture or in the intact animal.****Another advantage of using Lymnaea is that many neurons located on the surface of its CNS are individually identifiable, with known transmitters, synaptic partners and functions. We can culture and/or electrically record from single identifiable neurons involved in a specific behavior, such as feeding or respiration. Furthermore, these behaviours can be modified by training, and animals demonstrate both learning and memory.  We have shown that inhibiting retinoic acid signaling in Lymnaea prevents long-term memory formation, and we are now studying the cellular and network properties affected by this essential signaling molecule. To this end, we can study single identified neurons or synapses in cell culture, but also study these same identified neurons embedded in their neuronal networks in the intact isolated CNS, or a behaving "semi-intact" preparation, in which we can simultaneously monitor behavior and neuronal activity. These studies provide us with a unique opportunity to investigate retinoid functioning in memory formation and the underlying network changes, using a relatively simple nervous system.********