Department of Neuroscience, Medical University of South Carolina, Charleston, SC 29425.
Department of Neuroscience, Medical University of South Carolina, Charleston, SC 29425
eNeuro. 2023 Sep 19;10(9). doi: 10.1523/ENEURO.0037-23.2023. Print 2023 Sep.
The cerebellum communicates with brain areas critically involved in control of goal-directed behaviors including the prefrontal and orbitofrontal cortices and midbrain and basal ganglia structures. In particular, the posterior cerebellum is important for cognitive flexibility and has been implicated in alcohol and drug-related memory. We hypothesized that the cerebellum, through its multiple connections to reward-related brain circuitry, regulates alcohol consumption. To test this, we expressed inhibitory designer receptors exclusively activated by designer drugs (DREADDs) in molecular layer interneurons (MLIs) in anterior (IV-V) or posterior (VI-VIII) cerebellar lobules of male and female mice and activated them during alcohol drinking sessions. In a home-cage drinking paradigm, alcohol consumption was significantly decreased by clozapine-N-oxide (CNO) or deschloroclozapine (DCZ) administration in male mice expressing DREADDs in posterior but not anterior lobules. CNO/DCZ injections did not affect drinking in DREADD expressing female mice or in male mice expressing the control vector. Activation of DREADDs expressed in anterior or posterior lobules had no effect on sucrose or quinine consumption in male or female mice. During operant self-administration sessions, DCZ decreased the number of licks and bouts in male but not female mice expressing DREADDs in posterior lobules with no effect in control vector mice. Performance on an accelerated rotarod was unaffected by chemogenetic manipulation while distance traveled in the open field was decreased by DREADD activation in anterior but not posterior lobules. These results indicate that neuronal activity within the posterior cerebellar cortex plays an important role in the control of alcohol consumption in male mice.
小脑与大脑区域进行交流，这些区域在控制目标导向行为方面起着至关重要的作用，包括前额叶和眶额皮质以及中脑和基底神经节结构。特别是，小脑后叶对于认知灵活性很重要，并且与酒精和药物相关的记忆有关。我们假设小脑通过与奖励相关的大脑回路的多种连接来调节酒精的消耗。为了验证这一点，我们在雄性和雌性小鼠的前（IV-V）或后（VI-VIII）小脑叶的分子层中间神经元（MLIs）中表达了专门被设计药物激活的抑制性设计受体（DREADDs），并在酒精摄入期间激活它们。在家庭笼中饮酒范式中，在表达 DREADDs 的雄性小鼠的后叶而不是前叶中用氯氮平-N-氧化物（CNO）或去氯氯氮平（DCZ）给药，可显著降低酒精消耗。CNO/DCZ 注射不会影响在表达 DREADD 的雌性小鼠或在表达对照载体的雄性小鼠中的饮酒。在前叶或后叶中表达的 DREADDs 的激活对雄性或雌性小鼠的蔗糖或奎宁消耗没有影响。在操作性自我给药期间，DCZ 减少了表达 DREADDs 的雄性小鼠后叶中舔舐和发作的次数，但对对照载体小鼠没有影响。化学遗传操作对加速转棒试验的性能没有影响，而在前叶而非后叶中激活 DREADD 会减少开放场中的行进距离。这些结果表明，小脑后叶皮质内的神经元活动在雄性小鼠的酒精消耗控制中起着重要作用。
