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Background <p>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 <i>Bmal1</i> in dopamine neurons, investigating its effects on behavioral outcomes and dopamine signaling.</p> Results <p><i>Bmal1</i> conditional knockout (cKO) mice specific to dopamine neuron were generated by crossing <i>Bmal1</i>-flox strain with the <i>Dat</i>-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 <i>Bmal1</i>-cKO mice. Additionally, electrophysiological recording showed that striatal neurons in <i>Bmal1</i> knockout mice exhibited increased neuronal excitability. Amphetamine and dopamine D1 receptor antagonist SCH23390 treatment attenuated the hyperactivity behavior in cKO mice.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月11日

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  • Yichun Zhang,
  • Xin Li,
  • Yong Liu,
  • Xiangyu Li,
  • Dengfeng Liu,
  • Qingyun Han,
  • Xiran Liu,
  • Xuyi Wang,
  • Jia-Da Li,
  • Suixin Deng

摘要

Background

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.

Results

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.

Conclusions

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.