Cortico-limbic Circuits for Learning and Memory

这项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其他记忆方面的作用方面取得了重大进展，包括压力引起的空间记忆破坏。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（“3y干扰肽”-正在申请专利），该肽破坏了AMPA类嗜离子谷氨酸受体的受调节内吞作用，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对LTD进行操作。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。所提出的实验将利用：1)注意集合转移，需要一个开关来选择按哪个杠杆来获得食物奖励，基于杠杆的位置或区别性光线索的位置；2)双向主动回避反应的潜在抑制作用（Latent Inhibition， LI），即反复预暴露显著的区别性刺激导致回避反应习得的显著延迟；3)判别刺激学习，通过特定感官刺激（如音调或光线）的简短呈现来预测获得食物奖励的时间限制。相关实验将确定特定的大脑区域，在这些区域中，LTD的中断会导致一种或多种习得行为的选择性中断。“干扰肽”破坏大脑特定区域的LTD的直接证据，将通过静脉注射“干扰肽”阻断特定大脑区域内的LTD提供。***先前nserc资助的关于突触可塑性功能本质的研究表明，直接电刺激海马的谷氨酸能传入可以作为对食物奖励获得新反应的鉴别刺激，而这一反应又通过诱导长期增强（LTP）而显著增强。我们的高选择性阻断大脑中LTP的技术，加上我们的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一个基本问题提供一个独特的机会，即LTP的“LTD诱导去增强”的功能影响。***总之，目前的建议建立在我们最近成功地将LTD与负责响应灵活性和先前获得的记忆的消除的过程联系起来的基础上。总的来说，这项研究具有重要的理论意义，并将为突触可塑性与大脑信息加工之间的关系提供新的见解

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.**