Introduction: Aplysia as an Emerging Model in the Biology of Aging

Frontiers in Aging Neuroscience www.frontiersin.org May 2010 | Volume 2 | Article 6 | 1 age-related mechanisms also take into account a high level of conservation among many epigenetic processes known to be lost in nematodes and fl ies which have extremely short lifecycles and particularly derived genomes (Figure 1). Most importantly, Aplysia posses the largest nerve cells (ranging from 30 to 1,100 μm, see Figure 2) in the entire animal kingdom with only eggs being larger (Kandel, 1976) and truly gigantic growth cones (up to 630 μm, Lovell and Moroz, 2006). These cells can be uniquely identifi ed and mapped in terms of their well-defi ned interactions with other neurons, and have a limited number of recognized synaptic connections forming relatively simpler neural circuits underlying several stereotypic and learned behaviors (Kandel, 1976, 1979). As indicated in numerous studies dealing with memory mechanisms, synaptogenesis (Kandel, 2001; Hawkins et al., 2006) and initial genomic characterization (Moroz et al., 2006) Aplysia has many parallels and similarities with learning and aging in mammalian models and humans including the presence of NMDA receptors (Moroz et al., 1993; Ha et al., 2006) and nitric oxide signaling pathways (Katzoff et al., 2002, 2006; Bodnarova et al., 2005; Moroz, 2006; Antonov et al., 2007). The phenomenology of aging dynamics in Aplysia has been studied in suffi cient detail both in nature and under controlled aquaculture environments (Stommes et al., 2005; Gerdes and Fieber, 2006). Aplysia has a moderately short lifespan with a well INTRODUCTION: APLYSIA AS AN EMERGING MODEL IN THE BIOLOGY OF AGING The complexity of events associated with age-related changes in nervous systems cannot be overestimated. The problem is further complicated by the enormous diversity of neurons in the central nervous system (CNS) and even in synapses of one neuron within a neural circuit. Large scale single-neuron analysis is not only challenging but mostly impractical for any model currently used in the neurobiological analysis of aging or age-related memory loss. We simply do not know: Do all neurons and synapses age differently or are some neurons (or synapses) more resistant to aging than others? What is happening in any given neuron while it undergoes “normal” aging? What are the genomic changes that make aging apparently irreversible? What would be the balance between neuron-specifi c vs. global genome-wide changes in aging? In this paper we begin to address these questions by developing a new model to study the entire scope of genomic and epigenomic regulation in aging at the resolution of single functionally characterized cells and even cell compartments. Biology has often advanced by making use of relatively simple model systems. We selected Aplysia californica as the foremost experimental organism for the goals of the program. The sea slug, Aplysia is a representative of the largest superclade of bilaterian animals (Lophotrochozoa) which include annelids, fl at worms and about ten less known phyla. The proposed long-term regulatory Do different neurons age differently? Direct genome-wide analysis of aging in single identifi ed cholinergic neurons