Role of dopamine in the maturation of prefrontal cortex and associated behaviors.

多巴胺在前额皮质成熟和相关行为中的作用。

• 批准号: RGPIN-2015-04761
• 负责人: Srivastava, Lalit
• 金额: $ 2.4万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=665768
• 关键词: Role; dopamine; maturation; prefrontal; cortex

The refinement of mature cognitive, motivational and social behaviors typically takes place during adolescence, and is linked to the protracted development of the prefrontal cortex (PFC). Among neural inputs to the PFC, the mesofrontal dopamine (DA) system is interesting as DAergic afferents peak when key organizational events are taking place in the PFC. DAergic signaling, besides its acute effects on cortical excitatory and inhibitory neuron excitability, also mediates synaptic remodeling and long-term plasticity. While a large body of literature exists on the role of adult DA system, very little is known of the long-term consequences of early dysregulated DA homeostasis on the development of prefrontal networks and associated behaviors.****To study the effects of disruption in DA homeostasis, we are using the cre-inducible DREADD (designer receptors activated by designer drugs) pharmacogenetic system in mice to remotely silence or stimulate the mid-brain DA neurons up to several hours, reversibly and at defined developmental periods. The method involves adeno-associated virus (AAV)-mediated expression of genetically engineered hM3Dq (for neuronal activation) or hM4Di (for inhibition) in DA transporter (DAT)-cre mice. The receptors are stimulated by a synthetic (and otherwise physiologically inert) drug clozapine-N-oxide (CNO). Our preliminary data using the viral vector with hM3Dq shows that mid-adolescence sub-chronic activation of ventral tegmental area (VTA) neurons led to a marked increase in novelty-induced locomotor activity and deficits in a task of temporal order memory that is linked to the activity of PFC circuits.****In the proposed research programme, we want to systematically examine post-adolescent developmental trajectory of PFC-linked behaviors such as locomotion, PPI, anxiety, social interaction, and social and working memories in mice with sub-chronic adolescent stimulation of VTA DA neurons using the pharmacogenetic system. We have previous experience with the assessment of behaviors in rats and mice of different ages and required equipment is available in our laboratory or the Douglas Neurophenotyping Centre. We will also longitudinally assess cortical gray matter development and synaptic pruning in the PFC using structural magnetic resonance imaging (MRI) and histological techniques. Possible mechanisms that may mediate the effects of DA stimulation will be studied, e.g., the role of different DA receptors and intracellular signaling pathways. Future studies will similarly examine the effects of adolescent DA inhibition on brain and behavior, as well as the effects of early adolescent and neonatal DA manipulations. We believe that these studies will contribute significantly to our understanding of regulatory mechanisms that participate in the transition from adolescent to adult behavior.****

成熟的认知，动机和社会行为的完善通常发生在青春期，并与前额叶皮层（PFC）的长期发展有关。 在PFC的神经输入中，中额叶多巴胺（DA）系统是有趣的，当PFC中发生关键组织事件时，DA能传入达到峰值。DA能信号除了对皮层兴奋性和抑制性神经元兴奋性产生急性影响外，还介导突触重塑和长期可塑性。 虽然存在大量关于成年DA系统作用的文献，但对于早期DA稳态失调对前额叶网络和相关行为发展的长期后果知之甚少。为了研究破坏DA稳态的影响，我们正在小鼠中使用Cre-inducible DREADD（由设计药物激活的设计受体）药物遗传学系统来远程沉默或刺激中脑DA神经元长达数小时，可逆地并在定义的发育期。 该方法涉及在DA转运蛋白（DAT）-cre小鼠中腺相关病毒（AAV）介导的基因工程hM 3Dq（用于神经元激活）或hM 4Di（用于抑制）的表达。 受体被合成的（或者生理惰性的）药物氯氮平-N-氧化物（CNO）刺激。 我们使用带有hM 3Dq的病毒载体的初步数据显示，青春期中期腹侧被盖区（VTA）神经元的亚慢性激活导致新奇感诱导的运动活动显著增加，并且与PFC回路活动相关的时间顺序记忆任务出现缺陷。在拟议的研究计划中，我们希望系统地研究PFC相关行为的青春期后发展轨迹，如运动，PPI，焦虑，社交互动，以及使用药物遗传学系统对VTA DA神经元进行亚慢性青春期刺激的小鼠的社交和工作记忆。 我们之前有评估不同年龄大鼠和小鼠行为的经验，我们的实验室或道格拉斯神经表型中心提供所需设备。 我们还将纵向评估皮质灰质的发展和突触修剪PFC使用结构磁共振成像（MRI）和组织学技术。 将研究可能介导DA刺激效应的可能机制，例如，不同DA受体和细胞内信号通路的作用。 未来的研究将类似地检查青少年DA抑制对大脑和行为的影响，以及青少年早期和新生儿DA操作的影响。我们相信，这些研究将大大有助于我们理解参与从青少年到成人行为转变的调节机制。