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Abstract
Neural circuits continuously undergo structural and physiological modifications to regulate their function in response to everchanging environments and new experiences. Recently, complete mapping of the Drosophila melanogaster brain connectome has provided opportunities for investigating the neural circuits regulating the extensive repertoire of Drosophila behaviors in more detail than ever before. Based on this mapping as well as physiological findings from the field, I first propose a new model explaining how the unique anatomy and circuitry of the Drosophila memory center, the mushroom body, enables the various memory behaviors reported in fruit flies, and predicts the fly’s ability to perform more complex memory behaviors that have only been shown in mammals. I next develop the first ex vivo model of the mushroom body associative memory circuit that accurately recapitulates previous findings from in vivo imaging and behavioral studies. I go on to use this model to investigate the cellular and circuit mechanisms of short-term aversive memory formation and identify a plasticity caused by temporal association of the olfactory and punishment pathway activations; I term this as pairing-dependent plasticity (PDP). This plasticity localizes in the mushroom body α’3 compartment due to the lower threshold of α’β’ cells to olfactory signals. PDP requires the 3’ untranslated region of CaMKII mRNA (a region required for the local translation of CaMKII in synaptic regions) and is blocked by nighttime sleep deprivation. These findings suggest that this ex vivo model is useful for investigations of circuit mechanisms and that PDP can be influenced by experiences prior to brain dissection. Then, I shift my focus to the Drosophila central complex sleep circuit to investigate a molecular mechanism for sleep regulation. Previous work showed that inhibition of the microRNA190 (miR190) decreases and fragments sleep and disinhibits the translation of cholinergic proteins in glutamatergic cells (GluACh cells). I follow up on this work to confirm that the inhibition of miR190 disinhibits acetylcholine co-release from GluACh cells and provide evidence that these cells are most likely dorsal fan-shaped body (dFSB) neurons. Further, I find that the inhibition of miR190 also blocks hyperpolarization-activated currents by regulating HCN channels in the dFSB neurons, and that the downregulation of HCN channels in the dFSB recapitulates the decreased and fragmented sleep phenotype produced by miR190 inhibition. These experiments suggest that the dFSB neurons are the sleep neurons where miR190 suppresses cholinergic co-transmission and permits the function of HCN channels. In sum, my thesis work elucidates molecular and circuit mechanisms governing the mushroom body memory circuit and the central complex sleep circuit, and provides testable predictions on how both circuits cross-communicate to influence each other.
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