SUMMARY Uncovering fundamental mechanisms of neuronal connectivity that enable associative brain centers to learn is an important goal of neuroscience. In the Drosophila melanogaster mushroom body, the constituent Kenyon cells receive input from olfactory projection neurons. Each projection neuron connects to one of the 50 glomeruli in the antennal lobe, the primary olfactory processing center. Our previous work has shown that these connections are random in that there are no sets of glomeruli converging preferentially onto a given Kenyon cell. However, the glomeruli are not represented with equal frequency among Kenyon cell inputs. Certain glomeruli are significantly overrepresented or underrepresented, even though a uniform distribution would be optimal for learning performance. We are proposing to test the idea that this non-uniform distribution, which we termed ‘biased randomness’, serves an important function, namely to predispose the learning ability of an associative brain center towards certain ethologically pertinent stimuli. To test this idea, first, the representation of individual glomeruli will be compared in three different Drosophila species and investigated for correlations to differences in chemosensory ecology (Specific Aim 1). Second, molecular regulators of glomerular representation will be identified in D. melanogaster to manipulate the representation of individual glomeruli and test for effects on olfactory representation in the mushroom body and learning (Specific Aim 2). The research in this proposal has the potential to reveal a fundamental mechanism by which neuronal connectivity is fine-tuned to predispose learning towards particularly pertinent stimuli, thus possibly accounting for cognitive biases. 1