Forgetting is a dynamic and intrinsic cognitive process that allows humans and animals to make rapid and flexible
behavioral choices. Imbalances in memory stability/retrieval vs forgetting may result in detrimental pathologies
common in many neurological and psychiatric disorders. The neuroscience of active forgetting is underexplored;
historically, experimental psychology studies have frequently posited forgetting as passive. Yet, recent findings
in Drosophila challenge this notion and illustrate that forgetting is also active. One form of active forgetting,
termed intrinsic forgetting, engages a small group of protocerebral posterior lateral 1 dopamine neurons (PPL1
DAn). The PPL1 DAn slowly and chronically erase labile olfactory memories after learning, but potently remove
them when the neurons are stimulated. Two critical questions that remain unexplored is whether the forgetting
signal from these DAns also impair the expression of consolidated protein-synthesis dependent long-term
memories (PSD-LTM), and whether the impairment is due to memory erasure or a transient block in retrieval.
My preliminary studies indicate that stimulating a single PPL1 DAn transiently inhibits the retrieval of PSD-LTM.
Currently, knowledge about the neurobiological mechanisms that lead to transient forgetting does not exist.
Thus, my initial observations offer the first entrée, to our knowledge, of potential mechanisms that underly
transient forgetting. This proposal is aimed to address these knowledge gaps. The overarching hypothesis is
that transient forgetting is intrinsic to the fly’s memory management system and that factors extrinsic to the fly,
such as interfering stimuli, can trigger the forgetting network to modulate the retrieval of PSD-LTM.
To support my hypothesis, I will incorporate detailed behavioral and in vivo functional imaging assays, combined
with multiple sophisticated genetic manipulations and novel paradigm designs. From Aim 1, I will confirm and
extend my preliminary data indicating that only a single DAn in each brain hemisphere is responsible for transient
forgetting. The data will reveal the minimal DAn components that are required for transient forgetting, which is
essential for deeper experiments and to provide complete experimenter control over transient forgetting. From
Aim 2, I will obtain data that will uncover the key DA receptor mediating the DAn-forgetting signal. Excitingly, I
will identify the widely unchartered LTM cellular traces 3 days after spaced training and assay how these profiles
change upon activating the DAn-forgetting pathway. These data may provide the molecular- and cellular-circuit
based mechanisms that underscore transient forgetting. Lastly, from Aim 3, I will identify and characterize the
extrinsic factors essential to induce top-down memory suppression to trigger transient memory loss. In sum, the
outcomes of my proposed experiments will be the first to characterize the underlying extrinsic and intrinsic
mechanisms that mobilize the DAn-forgetting pathway to cause transient memory loss.