Cocaine-induced neuroplasticity: a new role for TGF beta signaling

描述(申请人提供)：拟议的研究调查激活素受体信号级联在调节大脑奖赏回路的长期变化中的作用，这些变化导致复杂的行为异常，包括成瘾状态。到目前为止，对可卡因等兴奋剂成瘾还没有有效的药物治疗，这突显了进一步了解这种滥用药物如何重新连接大脑的迫切需要。神经元可塑性被认为是长期成瘾状态的神经底物，但缺乏探索可卡因诱导结构可塑性的分子机制的机制证据。在令人兴奋的初步数据的指导下，在自我给予可卡因的动物的伏核(NAC)中，激活素受体的表达和信号转导增加，这一应用将检验以下假设：(目的I)可卡因自我给予调节激活素受体-Smad途径。因此，在可卡因给药后，激活素-Smad通路调节(A)肌动蛋白动力学和(B)Smad基因靶点；(Aim II)激活素-Smad通路是可卡因诱导NAC神经元树突棘可塑性的关键分子机制；(目的III)激活素受体和Smad信号通路直接介导可卡因寻求和渴求，通过恢复行为来衡量。这项应用提供了一个机会，通过检测可卡因诱导的细胞(即结构)和行为水平(即恢复)的可塑性，首次确定TGFbeta/激活素-Smad信号级联在促进药物寻找行为中的因果作用。这项应用工作的发现将阐明慢性可卡因暴露诱导NAc神经元可塑性长期变化的机制，并为开发新的可卡因成瘾治疗方法提供新的方向。

DESCRIPTION (provided by applicant): The proposed studies investigate the role of activin receptor signaling cascades in mediating the long-lasting changes in the brain's reward circuits, which contribute to the complex behavioral abnormalities that comprise an addicted state. To date there is no effective pharmacotherapy for addiction to stimulants, such as cocaine, highlighting the dire need for further understanding of how such drugs of abuse "re-wire" the brain. Neuronal plasticity is considered a neural substrate of the long-term addicted state, but there is a scarcity of mechanistic evidence that explores the molecular mechanism of cocaine-induced structural plasticity. Guided by exciting preliminary data demonstrating that in the Nucleus Accumbens (NAc) of animals of self-administering cocaine, activin receptor expression and signaling is increased, this application will test the following hypotheses: (Aim I) cocaine self-administration regulates the activin receptor-Smad pathway. Consequently, following cocaine self-administration the activin-smad pathway regulates both (a) actin dynamics and (b) Smad gene targets; (Aim II) Activin-Smad pathways are key molecular mechanisms underlying cocaine-induced dendritic spine plasticity of NAc neurons following cocaine self-administration; (Aim III) Activin receptor and Smad signaling pathways directly mediate cocaine seeking and craving as measured by reinstatement behaviors. This application presents an opportunity to determine, for the first time, the causal role for TGFBeta/activin-smad signaling cascades in facilitating drug seeking behaviors by examining cocaine-induced plasticity on cellular (i.e. structural) and behavioral levels (i.e. reinstatement). The findings from the work in this application will elucidate mechanisms by which chronic cocaine exposure induces long-term changes in plasticity of NAc neurons, and provides new directions for the development of novel therapies for cocaine addiction.