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Micro-circuitry and output connectivity of the striosomes and matrix network and striosomes contribution to reinforcement driven behaviors

par Torres Nupan, Martha
Président du jury Dewachter, Laurence
Promoteur Schiffmann, Serge N.
Publication Non publié, 2025-01-27

Thèse de doctorat

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Résumé :

The striatum is the main input nucleus of the basal ganglia and is primarily composed of GABAergic medium spiny neurons (MSNs) giving rise to the direct and indirect pathways. An additional compartmentalization of the striatum, consisting of the striosomes and the matrix was described decades ago. The respective network organization and functions of these compartments are much less understood along with the differences in their MSNs intrinsic properties. This thesis aimed to dissect the microcircuitry and output connectivity of the striosomes-matrix network, and evaluate the specific role of striosomes neurons in reinforcement-driven behaviors. The tools and approaches used to achieve this goal included: BAC-Cre transgenic mice, viral constructs, ex vivo slice electrophysiology, optogenetics, and chemogenetics.In the first part of this thesis, we characterized the intrinsic properties of D1- and D2-MSNs in both the striosomes and matrix compartments. Our findings revealed that striosomes MSNs exhibit higher excitability than matrix MSNs, with D1- and D2-MSNs in the striosomes showing higher excitability than their matrix counterparts. These differences in excitability were accompanied by distinct presynaptic dynamics, with short-term depression observed at matrix MSNs-GPe, striosomes MSNs-GPe, and matrix MSNs-SNr synapses, while short-term facilitation took place at striosomes MSNs-SNr and SNc synapses. These results contrast with previous reports that suggested short-term facilitation as the hallmark of striatonigral and striatopallidal synapses while aligning with evidence showing facilitation at striosomes MSNs-SNc synapses. In the third part of this thesis, we investigated the role of striosomes neurons in reward processing and drug-reinforcing behavior using an amphetamine-conditioned place preference (CPP) model. Chemogenetic inhibition of striosomes neurons during conditioning did not alter the magnitude of amphetamine-induced place preference but it did prolong the extinction phase of the CPP protocol.These findings highlight specific intrinsic properties and functional connectivity dynamics of striosomes and matrix neurons that may support the optimal function of the basal ganglia network and in the particular case of striosomes neurons, they suggest a role in dopamine signaling regulation, particularly concerning state value association and reward prediction error.