Rhythmic activity as a readout to find genes involved in neurodegeneration.

CAROLINA REZAVAL, SANTIAGO WERBAJH, M. FERNANDA CERIANI

Mérida, México

Workshop; 2005 Meeting of HHMI International Research Scholars.; 2005

HHMI

Our laboratory is interested in unraveling the molecular and cellular basis underlying behavior, and how such processes are modified throughout life.  We focus in the control of rhythmic rest-activity cycles which can be monitored at different stages in adult life.  This behavior greatly depends on the synchronous firing of a discrete group of neurons, among them the ventral lateral neurons (LNvs).  A miss-expression genetic screen is used to identify new elements in pathways involved in neurodegeneration in Drosophila.  The screen is based on the induction of the expression of genes tagged by the insertion of a P-element containing the upstream activating sequence (UAS) specifically recognized by GAL4.  These ‘target’ lines are then  crossed to a source of GAL4, exclusively expressed in the LNvs, so that it transcribes genomic sequences flanking the insertion site.  We hypothesize that altering the levels of genes relevant for neuronal or circuitry function and homeostasis should be translated into defective behavior.  Over 800 novel insertion lines have been generated (and new ones are constantly added to the collection) and have been monitored for defects on rhythmic behavior using an automated locomotor activity setup at two stages in adult life, newly eclosed and 3-4 week old males.  As a secondary screen we express the tagged gene in the eye, whose highly organized structure has been chosen to model neurodegenerative diseases, as well as under panneuronal drivers to look for signs of degeneration in frontal sections of fly brains.  We have identified several loci which distinctively affect locomotor activity in older flies; molecular characterization of several ones is underway.  Given the increasing interest in understanding neurological disorders, progress in this model system is likely to have a broad impact, ultimately assisting the dissection of these relevant pathways in the human brain.