Increased activity of DRD1-MSNs in dorsolateral striatum underlies Cry1Δ11 mutation-induced repetitive behaviors.

Abstract

Repetitive behaviors are classically associated with autism spectrum disorder and obsessive compulsive disorder, but also occur prominently in attention-deficit/hyperactivity disorder (ADHD), yet the underlying mechanisms remain poorly understood. Our recent work identified ADHD-like behaviors in Cry1Δ11 mice, in which a mutation in a core circadian gene Cry1 produces a CRY1Δ11 protein that fails to inhibit the Gαs subunit, leading to hyperactive signaling of dopamine D1 receptor (DRD1). Although this dysregulation was initially reported in the ventral striatum, we hypothesized that similar mechanisms might be present in the dorsal striatum, a brain region critically involved in the generation of repetitive behaviors and densely populated by DRD1-expressing medium spiny neurons (MSNs). Here, we demonstrate that Cry1Δ11 mice exhibit robust repetitive behaviors, including excessive self-grooming and stereotyped rearing, which are associated with increased activity of DRD1-MSNs in the dorsolateral striatum. Chemogenetic manipulation further revealed that activation of these neurons induces excessive self-grooming, whereas their inhibition reduces such behavior, indicating bidirectional control over repetitive action. Critically, systemic administration of the DRD1 antagonist SCH23390 fully rescued both neuronal hyperactivity and behavioral abnormalities in mutant mice. Together, our findings establish a direct mechanistic link among a core circadian gene mutation, striatal dopaminergic hyperactivity, and repetitive behaviors, thereby identifying aberrant DRD1 signaling in the dorsolateral striatum as a promising target for therapeutic intervention.