Integrative Analysis of Memory in Drosophila

Throughout our lives, we take in information from our surroundings and store this information as memories-what our parents look like, the way that pizza smells, the events of our first day of school, etc.  For many of us,  these memories remain stored in our brains for an indefinite length of time.   Recall of these memories sometimes requires conscious effort; at other times, the recall is more automatic.  In any case, memories can take on increasingly complex forms, and philosophers have even argued that consciousness itself depends upon the existence of memory. This implies that who we are depends upon what we remember, either implicitly or explicitly.  Regardless of whether you believe this statement, it is not something to be taken for granted-when our memories deteriorate (as happens in diseases such as Alzheimer's) the results are nothing less than tragic.

While impressive progress has been made in last fifty years to understand the biological basis of memory, a complete description of the acquisition, storage, and retrieval mechanisms still evades us.  Somewhere encoded in our genes are the instructions for the memory machinery, and when we sense outside stimuli, these instructions are played out in complex genetic networks that echo through a complex neural network to ultimately dictate our behavior and whether we will remember the encountered stimuli.  It is a problem that traverses many scales, from the microscopic to the macroscopic and back again.

Recognizing this complexity, one can choose to study "simple" systems with the hope of uncovering the basic mechanisms for memory.  The fruit fly Drosophila melanogaster is such a system.  Drosophila can be trained to perform a surprising number of different tasks, especially olfactory and visual associative tasks.  While the fly is by no means a simple biological system, the ease with which the fly can be genetically manipulated, coupled with a short life span, has greatly elucidated the gene/brain/behavior interaction.

To complement the behavioral and molecular genetic approaches to identifying the biochemical mechanisms of memory, we are taking an engineering approach to memory formation in Drosophila. This view combines mathematical engineering theories (control theory, communication theory, computation theory, etc.) with the underlying biology to develop a working model for how events are sensed, how this information is processed, stored, and finally, how the behavior is actuated.   In other words, we treat the fly as a complex machine and study how this machine works.  Ultimately, we are looking for a network-level description of memory akin to the descriptions of engineered processes common in systems engineering.

Our research is realized through several parallel methods.  First, we study the behavior of the fly in quite an unnatural environment: the fly is tethered in a flight simulator and presented with visual/olfactory cues.  The setup also allows for electrophysiological recordings of neural activity, which will allow us to study the learning/memory behavior of flies in real time as they are trained and tested.   Secondly, we examine how flies use memory in their interactions with their environment by studying the free-form behavior of a walking fly.  These experiments are intended to drive the development of our models-we do not want to stray too far from the data!  Such a network-level model of memory will assist in prediction of genes and molecular pathways involved in memory and will elucidate the networks of neurons used in the memory process, as well as the role these networks play.  Ultimately, this will allow us to design more efficient systems (both man-made and biological) and can provide insights into therapies for memory disorders.

This project is part of the DART Neurogenomics Alliance and will be carried out in close collaboration with experimental efforts headed by Tim Tully and Josh Dubnau at the genetic, cellular and neural systems levels.

Contributors:

Patha Mitra
Dan Valente