# Knockout of Bmal1 in dopaminergic neurons induces ADHD-like symptoms via hyperactive dopamine signaling in male mice

## TL;DR

Deleting the Bmal1 gene in dopamine neurons of male mice causes ADHD-like behaviors due to increased dopamine activity.

## Contribution

Discovers a new role for Bmal1 in regulating dopamine signaling and ADHD-like symptoms in mice.

## Key findings

- Bmal1 knockout in dopamine neurons leads to ADHD-like symptoms in male mice.
- Increased dopamine release and neuronal excitability were observed in Bmal1-cKO mice.
- Hyperactivity in knockout mice was reduced by amphetamine and a dopamine receptor antagonist.

## Abstract

The central circadian clock coordinates daily oscillations in physiology, metabolism and behavior. Disruptions to core circadian clock genes not only perturb sleep-wake rhythms but also contribute to psychiatric disorders. While dopaminergic dysfunction is strongly associated with mental illnesses, the mechanistic connection between circadian clock genes and dopamine signaling remains elusive. In the current study, we directly examine the role of the core circadian gene Bmal1 in dopamine neurons, investigating its effects on behavioral outcomes and dopamine signaling.

Bmal1 conditional knockout (cKO) mice specific to dopamine neuron were generated by crossing Bmal1-flox strain with the Dat-Cre strain, with knockout efficiency validated through immunofluorescence. BMAL1 deficiency in dopaminergic neurons induces attention-deficit hyperactivity disorder (ADHD)-like phenotypes, including hyperactivity, impairments in attention and working memory. Dopamine sensor detection revealed increased dopamine release in Bmal1-cKO mice. Additionally, electrophysiological recording showed that striatal neurons in Bmal1 knockout mice exhibited increased neuronal excitability. Amphetamine and dopamine D1 receptor antagonist SCH23390 treatment attenuated the hyperactivity behavior in cKO mice.

This study finds that BMAL1 ablation in dopaminergic neurons induces ADHD-like phenotypes in male mice, identifying hyperactive dopamine signaling as a potential mediator of these phenotypes. It unveils a novel role for BMAL1 in regulating dopamine signaling and provide insights into circadian gene-driven psychiatric pathophysiology.

The online version contains supplementary material available at 10.1186/s12993-025-00287-w.