Timed and Targeted Differential Regulation of Nitric Oxide Synthase (NOS) and Anti-NOS Genes by Reward Conditioning Leading to Long-Term Memory Formation

Open Access
Publisher Website
Google Scholar
Abstract
In a number of neuronal models of learning, signaling by the neurotransmitter nitric oxide (NO), synthesized by the enzyme neuronal NO synthase (nNOS), is essential for the formation of long-term memory (LTM). Using the molluscan model systemLymnaea, we investigate here whether LTM formation is associated with specific changes in the activity of members of the NOS gene family:Lym-nNOS1,Lym-nNOS2, and the antisense RNA-producing pseudogene (anti-NOS). We show that expression of theLym-nNOS1gene is transiently upregulated in cerebral ganglia after conditioning. The activation of the gene is precisely timed and occurs at the end of a critical period during which NO is required for memory consolidation. Moreover, we demonstrate that this induction of theLym-nNOS1gene is targeted to an identified modulatory neuron called the cerebral giant cell (CGC). This neuron gates the conditioned feeding response and is an essential part of the neural network involved in LTM formation. We also show that the expression of theanti-NOSgene, which functions as a negative regulator of nNOS expression, is downregulated in the CGC by training at 4 h after conditioning, during the critical period of NO requirement. This appears to be the first report of the timed and targeted differential regulation of the activity of a group of related genes involved in the production of a neurotransmitter that is necessary for learning, measured in an identified neuron of known function. We also provide the first example of the behavioral regulation of a pseudogene.