Cortico-limbic Circuits for Learning and Memory

这次更新扩展了一个基础研究项目，重点是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）在学习恐惧条件反射和记忆的其他方面（包括压力诱导的空间记忆中断）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。* 成功是由于开发了一种小的人工肽（“3 Y干扰肽”-正在申请专利），该肽破坏了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纵LTD。我们的研究策略还需要复杂可靠的行为测试来评估啮齿动物学习和记忆的特定方面。 本实验将利用：1）注意定势转换，需要根据杠杆的位置或辨别性光提示的位置来选择按哪个杠杆获得食物奖励; 2）双向主动回避反应的潜伏抑制（LI），其中重复预先暴露于显著辨别性刺激导致回避反应的获得显著延迟; 3）辨别性刺激学习，其中特定感觉刺激（例如音调或光）的短暂呈现预测对食物奖励的时间限制访问。相关实验将确定LTD的破坏会导致一种或多种习得行为选择性破坏的特定大脑区域。“干扰肽”在脑的特定区域中破坏LTD的直接证据将通过静脉内施用“干扰肽”阻断特定脑区域内的LTD来提供。* 以前NSERC资助的关于突触可塑性的功能性质的研究表明，直接电刺激海马体的多巴胺能传入神经可以作为获得食物奖励的新反应的区别性刺激，这反过来又通过诱导长时程增强（LTP）而显着增强。我们的高选择性技术，在大脑中，加上我们的脑刺激信号检测程序，将提供一个独特的机会，以解决突触可塑性和记忆的“LTD诱导的去增强”的LTP的功能效应的研究中的一个基本问题。* 总之，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。总之，本研究具有重要的理论意义，为研究突触可塑性与脑内信息加工之间的关系提供了新的视角。

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.**