Cortico-limbic Circuits for Learning and Memory

学习和记忆的皮质边缘回路

• 批准号: RGPIN-2016-04364
• 负责人: Phillips, Anthony
• 金额: $ 2.26万
• 依托单位: University of British Columbia
• 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=662085
• 关键词: Cortico; limbic; Circuits; Learning; Memory

This renewal extends a basic research project focused on neural mechanisms of synaptic plasticity required for learning and memory. We have made significant progress in understanding the role of synaptic Long-Term Depression (LTD) in the learning of fear conditioning and other aspects of memory including stress-induced disruption of spatial memories. A better understanding of the role of LTD in cognition will enhance our understanding of the biological bases of learning and memory. ***Success is due to the development of a small artificial peptide (‘3Y-interference peptide'-patent-pending) that disrupts the regulated endocytosis of the AMPA class of ionotropic glutamate receptors the critical final step in the induction of LTD. This allows for the manipulation of LTD at different stages of the learning/memory cascade. Our research strategy also requires sophisticated and reliable behavioral tests to assess specific aspects of learning and memory in rodents. The proposed experiments will utilize : 1) Attentional set-shifting requiring a switch in choice of which lever to press for food reward, based on location of the lever or position of a discriminative light cue; 2) Latent Inhibition (LI) of 2-way active avoidance responding in which repeated pre-exposure to a salient discriminative stimulus causes significant retardation in the acquisition of avoidance responses; 3) Discriminative stimulus learning whereby brief presentation of a specific sensory stimulus such as a tone or light predicts time-limited access to food reward. Related experiments will identify specific brain regions where disruption of LTD causes selective disruption of one or more of the learned behaviors. Direct evidence that the ‘interference peptide' disrupts LTD in specific regions of the brain, will be provided by blocking LTD within specific brain regions by i.v administration of the ‘interference peptide'. ***Previous NSERC-funded research on the functional nature of synaptic plasticity revealed that direct electrical stimulation of glutamatergic afferents to the hippocampus can serve as a discriminative stimulus in the acquisition of a new response for food reward which in turn was enhanced significantly by induction of long-term potentiation (LTP). Our highly selective technique for blocking LTD in brain, coupled with our brain-stimulation signal detection procedure will provide a unique opportunity to resolve a fundamental issue in the study of synaptic plasticity and memory the functional effects of ‘ LTD-induced depotentiation” of LTP. ***In summary, the present proposal builds on our recent success in linking LTD to processes responsible for response flexibility and extinction of previously acquired memory. Collectively this research has significant theoretical importance and should provide new insights into the relationship between synaptic plasticity and information processing in brain.**

这一更新扩展了一个基础研究项目，重点关注学习和记忆所需的突触可塑性的神经机制。我们在理解突触长期抑制 (LTD) 在学习恐惧调节和记忆的其他方面（包括压力引起的空间记忆破坏）中的作用方面取得了重大进展。更好地理解LTD在认知中的作用将增强我们对学习和记忆的生物学基础的理解。 ***成功归功于一种小型人工肽（“3Y-干扰肽”-正在申请专利）的开发，它破坏了 AMPA 类离子型谷氨酸受体的调节内吞作用，这是诱导 LTD 的关键最后一步。 这允许在学习/记忆级联的不同阶段操作 LTD。我们的研究策略还需要复杂且可靠的行为测试来评估啮齿类动物学习和记忆的特定方面。 拟议的实验将利用：1）注意力转移，需要根据杠杆的位置或辨别性光提示的位置，选择按下哪个杠杆来获得食物奖励； 2）双向主动回避反应的潜在抑制（LI），其中重复预先暴露于显着的辨别刺激会导致回避反应的获得显着延迟； 3) 辨别刺激学习，通过简短呈现特定的感官刺激（例如音调或灯光）来预测在有限时间内获得食物奖励。相关实验将识别特定的大脑区域，在这些区域中，LTD 的破坏会导致一种或多种习得行为的选择性破坏。通过静脉内施用“干扰肽”阻断特定大脑区域内的LTD，可以提供“干扰肽”破坏大脑特定区域中的LTD的直接证据。 ***之前 NSERC 资助的关于突触可塑性功能性质的研究表明，对海马体谷氨酸传入神经的直接电刺激可以作为获得食物奖励新反应的辨别刺激，而这种反应又通过诱导长时程增强 (LTP) 而显着增强。我们在大脑中阻断 LTD 的高度选择性技术，加上我们的大脑刺激信号检测程序，将为解决突触可塑性和记忆研究中的基本问题（即 LTP 的“LTD 诱导的去势”）的功能效应提供一个独特的机会。***总而言之，本提案建立在我们最近成功地将 LTD 与负责反应灵活性和先前获得的记忆消退的过程联系起来的基础上。 这项研究具有重要的理论意义，应该为大脑突触可塑性和信息处理之间的关系提供新的见解。 **