STRIATAL NEUROTRANSMISSION AS A DRIVER OF COMPULSIVE BEHAVIOR DEVELOPMENT

Striatal cholinergic interneurons (ChIs) co-express the vesicular transporters VAChT and VGLUT3, enabling dual neurotransmitter release. VGLUT3 enhances vesicular acetylcholine (ACh) loading through vesicular synergy, thereby increasing cholinergic transmission. This ACh/glutamate co-transmission plays a key role in the regulation of dopamine (DA) release: ACh facilitates DA release, whereas glutamate exerts an inhibitory effect. A missense mutation in Slc17a8 (p.T8I), identified in patients with substance use disorders (SUDs) and eating disorders (EDs), disrupts vesicular synergy, leading to reduced cholinergic transmission without affecting glutamate transport. This alteration results in decreased cholinergic signaling in the dorsomedial striatum (DMS), but not in the dorsolateral striatum (DLS), potentially promoting compulsive behaviors. We hypothesize that this striatal cholinergic imbalance induces asymmetric DA signaling between DMS and DLS, thereby favoring habit formation and compulsivity. To test this hypothesis, we investigated compulsivity-related behaviors in T8I mutant mice. In the splash test, T8I mice displayed a progressive increase in grooming duration, which was normalized by donepezil, an acetylcholinesterase inhibitor, supporting the involvement of cholinergic dysfunction.
To further explore the underlying neurochemical mechanisms, ACh and DA release will be measured using fiber photometry in the DMS and DLS. In addition, chemogenetic approaches (DREADDs) will be used to selectively modulate DA signaling in the DMS in order to assess its causal role in compulsive behaviors.
Overall, this study provides new insights into the role of striatal cholinergic dysfunction in compulsive disorders and highlights cholinergic transmission as a potential therapeutic target.