What are the neurobiological mechanisms mediating operant self-learning?

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In operant learning, two evolutionarily conserved mechanisms are engaged, one where the subject learns about causal relations in the environment (world-learning) and another where the subject learns about the outcomes of their own behavior (self-learning). The neurobiological mechanisms mediating world-learning are well understood: they are evolutionarily conserved and thus nearly identical to those in many other learning experiments such as classical conditioning. However, we know very little about the neurobiology of operant self-learning. Building on the previous funding period’s successful combination of molecular biology and a behavioral experiment that isolates the operant self-learning component, we propose an analogous project to further elucidate the genes and neurons involved in operant self-learning. The previous funding period provided results that suggest that FoxP-dependent plasticity is not required in the brain but in motor neurons in the ventral nerve cord that innervate specific direct wing steering muscles. We also discovered that the gene product of the atypical protein kinase C (aPKC) is required in FoxP-positive neurons. One core research question for this funding period will be to identify more components of the FoxP/aPKC pathway mediating the plasticity in motor neurons that underlies operant self-learning. To this end, we will use two molecular techniques, DamID and TurboID. With DamID we will identify the target genes that FoxP binds to and regulates. With TurboID, we will identify the target proteins that aPKC interacts with. The most promising candidate genes from these two techniques will be manipulated and tested for operant self-learning. In addition to these molecular techniques, we have generated a list of candidate genes from the literature, in order to identify plasticity mechanisms beyond FoxP/aPKC. Finally, in cooperation with Prof. Dr. Li Liu in Beijing, we will also validate the candidates identified in his screen for brain neurons involved in operant activity, the process that leads to self-learning. The Liu laboratory has already discovered neurons in the brain that are required for operant self-learning, irrespective of whether they express FoxP or not. In our collaboration, we will independently replicate the results from this laboratory and the laboratory in Beijing will replicate our most promising candidate line experiments.