Neurotransmitter modulation of neurogenesis in the adult enteric nervous system

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The enteric nervous system (ENS), embedded within the wall of the gut, contains nerve circuits that can modulate gut function in the absence of any connections to the central nervous system. Enteric neurons have adapted to survive the hostile environment of the gut, where large distending boluses of food and the likelihood of infection and inflammation can impact the ENS. Enteric neurons are capable of impressive plasticity of form and function, including long-lasting changes in synaptic transmission, neuronal morphology and neurochemistry. Importantly, a population of neural precursor cells (NPCs or stem cells) has recently been identified within the adult ENS. These cells are a subset of enteric glia and are capable of generating new enteric neurons and glial cells in vitro. Enteric neurogenesis has also been demonstrated in vivo, although neurogenesis occurs more readily in vitro. Unfortunately, the signaling pathways that modulate the proliferation and differentiation of enteric NPCs are currently unknown. * *During embryonic development, the proliferation, migration and differentiation of enteric NPCs are subject to modulation by enteric neurotransmitters. We hypothesised that the proliferation and differentiation of adult enteric NPCs in vivo are suppressed by enteric neurotransmission, and that removal of this inhibitory influence during in vitro dissociated culture promotes neurogenesis. Our preliminary data strongly support this hypothesis. Therefore, we will study the effects of drugs that manipulate enteric neurotransmission on enteric neurogenesis. We will examine how neurotransmitters modulate two fundamental processes in neurogenesis: i) proliferation of NPCs and ii) their differentiation to mature neurons. Acetylcholine, noradrenaline, ATP, serotonin and substance P will be examined, due to their roles as enteric neurotransmitters and evidence for enteric glial expression of receptors for these neurotransmitters. Using primary cultures of dissociated myenteric neurons and glia, which lack synaptic transmission, and organotypic cultures of intact myenteric plexus, which retain functional synapses, we will address the following aims: * *Aim 1. Identify which neurotransmitters and receptors modulate enteric NPC proliferation. Immunohistochemical experiments and labeling of proliferating cells will be employed to determine the effects of neurotransmission of enteric NPC proliferation. **Aim 2. Determine whether enteric neurotransmitters modify the differentiation of enteric NPCs into mature enteric neurons. We will utilize electrophysiological recordings and quantification of the neurochemical classes of enteric neurons to characterise the effects of enteric neurotransmitters on neuronal differentiation. The proportion of glial cells and neurons formed in vitro will also be compared to the proportions formed during embryonic development. **In addition to providing superb training for highly qualified individuals, these experiments could re-define the roles of neurotransmission in the ENS. These data are also likely to improve our understanding of how enteric neurons have adapted to the relatively hostile environment of the gut. Our findings may ultimately lead to a paradigm shift in how neural stem cells can be manipulated in vivo.