Neuronal primary cilia and cognitive disorders

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Project Summary Primary cilia are microtubule-based sensory organelles expressed in most mammalian cells including neurons. They regulate numerous physiological functions including sensation, cognition, and energy balance. Malfunctions of neuronal primary cilia cause many neurological disorders such as cognitive impairment, intellectual disability, neurodegeneration, and obesity. The type 3 adenylyl cyclase (AC3) is a key enzyme that mediates the cyclic adenosine monophosphate (cAMP) signaling pathway in neuronal cilia throughout the nervous system. Mechanistically, it remains to be elucidated how neuronal primary cilia and ciliary cAMP modulate neuronal function and contribute to learning and memory formation. Our long-term goals are to determine the role of neuronal primary cilia and ciliary cAMP signaling in regulating neuronal activity and modulating hippocampus-dependent memory formation, understand how defects in neuronal primary cilia cause cognition dysfunction-related disorders, and develop novel intervention strategies to treat cognitive disorders by modulating ciliary signaling. Recently, based on in vivo calcium imaging coupled with trace fear conditioning experiments, we discovered that the overall activity levels of hippocampal principal neurons exhibit a right- skewed lognormal distribution, with a small portion of highly active “primed” hippocampal neurons actively engaged with trace memory formation and retrieval. Intriguingly, the appearance of burst synchronization among primed hippocampal neurons coincides with trace memory formation and retrieval. These findings suggest that both the priming of hippocampal neurons and burst synchronization among the primed neurons are important for forming trace fear memory. Here, we will test the hypothesis that neuronal primary cilia and AC3 regulate the priming of hippocampal neurons by elevating their basal neuronal excitability, affecting the induction of burst synchronization among hippocampal neurons and memory formation. To this end, we will first determine if ablation of neuronal primary cilia or AC3 affects the priming of hippocampal neurons and trace memory formation. Second, we will determine the roles of elongated neuronal primary cilia in regulating basal neuronal activity and memory formation. This work will advance our understanding of the contribution of neuronal primary cilia to modulating memory formation. In addition, this AREA award will enrich the research environment at the University of New Hampshire (UNH) and provide laboratory experience to at least four undergraduate students, who otherwise would not have the opportunity to be exposed to such research training.