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Biology subjects

Faust, T.

Publications and source records attributed to Faust, T..

2 recordsLinked to original sources

Reward expectation selectively boosts the firing of accumbens D1+ neurons during motivated approach.

The nucleus accumbens (NAc) helps govern motivation to pursue rewards. Two distinct sets of NAc projection neurons-expressing dopamine D1 versus D2 receptors-are thought to promote and suppress motivated behaviors respectively. However, support for this conceptual framework is limited: in particular the spiking patterns of these distinct cell types during motivated behavior have been largely unknown. We monitored identified D1+ and D2+ neurons in the NAc Core, as unrestrained rats performed an operant task in which motivation to initiate work tracks recent reward rate. D1+ neurons preferentially increased firing as rats initiated trials, and fired more when reward expectation was higher. By contrast, D2+ cells preferentially increased firing later in the trial especially in response to reward delivery - a finding not anticipated from current theoretical models. Our results provide new evidence for the specific contribution of NAc D1+ cells to self-initiated approach behavior, and will spur updated models of how we learn from rewards.

neuroscience↗

Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15

The investigational drugs E7820, indisulam and tasisulam (aryl-sulfonamides) promote the degradation of the splicing factor RBM39 in a proteasome-dependent mechanism. While the activity critically depends on the Cullin RING ligase substrate receptor DCAF15, the molecular details remain elusive. Here we present the cryo-EM structure of the DDB1-DCAF15-DDA1 core ligase complex bound to RBM39 and E7820 at 4.4 [A] resolution, together with crystal structures of engineered subcomplexes. We show that DCAF15 adopts a novel fold stabilized by DDA1, and that extensive protein-protein contacts between the ligase and substrate mitigate low affinity interactions between aryl-sulfonamides and DCAF15. Our data demonstrates how aryl-sulfonamides neo-functionalize a shallow, non-conserved pocket on DCAF15 to selectively bind and degrade RBM39 and the closely related splicing factor RBM23 without the requirement for a high affinity ligand, which has broad implications for the de novo discovery of molecular glue degraders.

biochemistry↗