Scaffolding of forgetting signalosome
Mechanisms for memory formation and consolidation have been intensely studied for decades. Surprisingly, the process of forgetting, presumably of equal importance, has been virtually ignored. It is thought that forgetting enhances memory flexibility, by reducing the influence of obsolete information. In addition, forgetting may remove specific details of previous experiences, thereby promoting generalization. Thus, forgetting allows intelligent decision-making in a highly dynamic and noisy environment.
Molecular, cellular and systems neuroscience studies using Drosophila have uncovered several major tenets that reveal the logic by which olfactory memories are formed, consolidated and retrieved. Most recently, studies have started to shed some light on the antagonist process to memory acquisition and consolidation, i.e., memory forgetting. Recent molecular genetic studies have identified a role for the small G protein Rac1 in forgetting of olfactory memories. In addition, the dopamine receptor Damb, mediates the process of forgetting and this dopaminergic activity is modulated with the behavioral state of the animal. This project seeks to build on our current understanding of memory loss by exploring a relatively new role for multidomain scaffolding protein, Scribble. We recently found that Scribble scaffolds the molecular machinery involved in the regulation of forgetting, including proteins of the Rac signaling pathway. The long-term goal is to define the molecular and functional nature of this scaffolding protein and its interacting proteins.
Reciprocal synapses in the Mushroom Bodies
Current thought envisions dopamine neurons conveying the reinforcing effect of the unconditioned stimulus during associative learning to the axons of Drosophila mushroom body Kenyon cells for normal olfactory learning. We recently showed using functional GFP reconstitution experiments that Kenyon cells and dopamine neurons form axoaxonic reciprocal synapses. The dopamine neurons receive cholinergic input via nicotinic acetylcholine receptors from the Kenyon cells; knocking down these receptors impairs olfactory learning revealing the importance of these receptors at the synapse. Our results reveal a new and critical role for positive feedback onto dopamine neurons through reciprocal connections with Kenyon cells for normal olfactory learning.
This project seek to understand the role of these puzzling reciprocal connections in the logic and flow of information in the circuit involved in learning, memory, and forgetting.
In humans and other animals, the instructive value of naturally occurring reinforcing experiences is acquired rather than innately instructive and does not dependent on mere contiguity. For example, the value of money and its capacity to function as a reinforcer is learned rather than innate. The association between seemingly neutral stimuli increases the gamut of possibilities to create meaningful associations and the predictive power of moment-by-moment experiences. Several different types of higher-order conditioning are examples of these types of associations. In higher-order conditioning procedures, neutral stimuli acquire the property to elicit conditional responses even though they have never been in contiguity with a reinforcer. Sensory preconditioning is one example of higher-order conditioning. In sensory preconditioning, two initially neutral stimuli (S1 and S2) are repeatedly presented in contiguity or in sequence (preconditioning phase); later, one of the stimuli (S1) is paired with a reinforcer (conditioning phase). After this, S2 will elicit a conditioned response even though it was never paired with the reinforcer, indicating that the preconditioning phase created an association between S1 and S2. Our lab is using Drosophila to understand the molecular and circuit basis of olfactory unimodal sensory preconditioning.