Neurotrophic Mechanisms in the Adult Nervous System: A Novel Molecular Pathway Regulating Reward and Addiction

The molecular mechanisms underlying the structural and functional adaptations in neuronal circuits involved in reward and drug addiction are incompletely understood.

The main goal of this proposal is to bridge that knowledge gap building upon recent breakthroughs from our laboratory and applying cutting-edge technologies in genetics and single cell genomics.

We have recently discovered a novel mechanism necessary for behavioral sensitization to cocaine in which the dopamine D1 receptor synergizes with the activin/ALK4/Smad3 pathway to potentiate the generation of ∆FosB mRNA in medium spiny neurons (MSNs) of the NAc via activation of the RNA-binding protein PCBP1, a regulator of mRNA splicing.

Based on these findings, the specific objectives of this proposal are: (1) Establish the importance of activin/ALK4 signaling for cocaine addiction using a self-administration paradigm (proof-of-principle for pharmacological interventions); (2) Elucidate the role of PCBP1 in cocaine sensitization and addiction; (3) Elucidate the role of microglia-derived activin A in cocaine sensitization and addiction; (4) Investigate cellular and molecular changes in NAc of Alk4, Pcbp1 and Inhba mutant mice before and after cocaine sensitization using single-nucleus RNA sequencing.

All 4 aims are expected to run in parallel.

This knowledge is crucial for the development of therapeutic approaches to such conditions as well as programs to mitigate their associated costs to society.