Neural Circuitry Mechanisms Underlying Maladaptive Reward Memories in Drosophila - PROJECT SUMMARY:
Alcohol addiction constitutes one of the most serious public health problems worldwide. According to the CDC,
the total economic cost of excessive alcohol use is estimated to be $249 billion. Despite its devastating impact,
there are few effective treatments. Neural circuit based approaches to treat addiction provide a powerful
opportunity to develop more specific and effective treatments. However, circuit complexity is a significant
obstacle to a comprehensive understanding of the mechanisms by which memory circuits are altered to create
enduring preferences for alcohol associated cues. The current proposal will take place at Bryant University, a
primarily undergraduate institution, and will capitalize on the genetic tractability of Drosophila melanogaster and
precise neurogenetic tools available to interrogate how identified memory circuits are altered by alcohol and why
alcohol associated memories are so resistant to change. Although only 100,000 neurons comprise the central
nervous system of Drosophila, the neural circuitry underlying reward and addiction is remarkably complex and
similar to mammals. Like mammals, Drosophila show robust preference for cues associated with alcohol
intoxication that persist in the face of aversive consequences. Studies proposed here will capitalize on
established and newly developed neurogenetic tools that allow for the precise manipulation of individual neurons
and visualization of circuit activity. Doing so will enable us to test the hypothesis that alcohol disrupts memory
circuit activity and drives maladaptive reward seeking by engaging significantly more dopamine neurons during
acquisition. Specifically, we will use a combination of optogenetics, thermogenetics, and two-photon microscopy
to capture the precise changes in dopamine neural dynamics while Drosophila learn to associate odor cues with
alcohol intoxication. Additionally, we will determine if alcohol-independent activation of dopamine neurons is
sufficient to induce maladaptive memories for natural rewards. Finally, we will investigate the role of recently
identified downstream regions of the fan-shaped body in modulating alcohol reward memories to understand the
stability and persistence of these memories. We expect that extracellular dopamine levels and number of
recruited dopamine neurons will significantly increase across alcohol exposures and this increase is sufficient to
drive maladaptive reward seeking behavior. Further, we predict that downstream convergent regions play a
critical role in behavioral flexibility and disruption to these functional connections results in memories that lack
flexibility and drive maladaptive reward seeking. Ultimately, understanding general circuitry principles described
first in Drosophila will provide insight to how alcohol co-opts mammalian circuits to create enduring preference
for alcohol and drive maladaptive choice. An AREA grant is essential to continue our efforts in exposing
students to hands-on meritorious research, providing superior research experiences, and strengthening
the research environment at Bryant University, thereby enabling more students to participate.
