Associative properties of the perirhinal network

描述(申请人提供)：大脑周围(PR)皮质是一种与识别和联想记忆有关的、以吻尾为导向的皮质条带。先前的单单位研究表明，PR对再认记忆的贡献涉及PR神经元对熟悉刺激的反应性降低。相反，联想记忆的形成依赖于PR神经元对配对刺激的反应增加。这两种现象都被认为反映了PR皮层内突触重量的活动依赖变化。然而，目前尚不清楚同一网络如何支持这两种看似相反的可塑性形式。我们认为，这一悖论的解决方案在于外源性新皮质输入与内在长程PR连接与PR皮质的前馈抑制中间神经元形成的差异连接。事实上，以前的研究表明，新皮质的输入在PR神经元中触发了强烈的前馈抑制，而纵向内在通路则介导了明显纯粹的兴奋性反应。由于新皮质的输入可以经历LTD或LTP，这取决于受体PR细胞是超极化还是去极化，我们假设PR皮质中活性依赖的突触可塑性的极性(LTD或LTP)取决于接受新皮质输入的PR细胞是否也接受来自PR纵向连接的内在系统的汇聚输入。这一假设将在以下具体目标中得到检验。在目标1中，我们将使用顺行追踪结合银染的包埋前GABA免疫细胞化学方法，比较新皮质轴突和纵向PR轴突与GABA能中间神经元形成的突触的比例。在目标2中，我们将测试不同程度招募纵向PR连接的新皮质刺激模式是否会导致活动依赖型LTP或LTD。为了测试这一点，在体外通过动脉灌流保存的整个大脑中，我们将比较在一个和两个遥远的新皮质部位施加theta Burst刺激的效果。将使用细胞外录音和电压敏感染料的光学成像来监测诱发反应。在目标#3中，我们将结合细胞内记录和药物操作，结合场电位记录和光学成像，确定集中激活和分布式激活新皮质传入所诱导的LTD和LTP的诱导和表达机制。所提出的研究将阐明调节鼻皮质冲动传递的抑制机制，从而使我们对控制癫痫样活动传播的因素有独特的见解。此外，这项拟议的工作将分析允许大脑周围皮质参与记忆形成的网络特性。由于鼻皮质在神经和精神疾病的早期阶段主要和/或选择性地受损，这里提出的基础研究计划可能会提高我们对记忆障碍的理解。

DESCRIPTION (provided by applicant): The perirhinal (PR) cortex is a rostrocaudally-oriented strip of cortex involved in recognition and associative memory. Previous single-unit studies have revealed that PR contributions to recognition memory involve a reduction in the responsiveness of PR neurons to familiar stimuli. In contrast, associative memory formation is dependent on increasing responses of PR neurons to paired stimuli. Both phenomena are thought to reflect activity-dependent changes in synaptic weights within the PR cortex. However, it is currently unclear how the same network could support these two seemingly opposite forms of plasticity. We believe the solution to this paradox resides in the differential connections formed by extrinsic neocortical inputs vs. intrinsic long-range PR connections with feedforward inhibitory interneurons of the PR cortex. Indeed, it was previously shown that neocortical inputs trigger strong feedforward inhibition in PR neurons whereas longitudinal intrinsic pathways mediate apparently pure excitatory responses. Since neocortical inputs can undergo LTD or LTP depending on whether recipient PR cells are hyper- or depolarized, we hypothesize that the polarity (LTD or LTP) of activity-dependent synaptic plasticity in the PR cortex depends on whether PR cells receiving neocortical inputs also receive convergent inputs from the intrinsic system of longitudinal PR connections. This hypothesis will be tested in the following specific aims. In Aim #1, we will compare the proportion of synapses formed by neocortical axons vs. longitudinal PR axons with GABAergic interneurons using anterograde tracing combined with silver intensified pre-embedding GABA immunocytochemistry. In Aim #2, we will test whether neocortical stimulation patterns that recruit longitudinal PR connections to different extents lead to activity-dependent LTP or LTD. To test this, in the whole brain kept in vitro by arterial perfusion, we will compare the effects of theta burst stimulation applied at one vs. two distant neocortical sites. Evoked responses will be monitored using extracellular recordings and optical imaging with a voltage sensitive dye. In Aim #3, we will determine the induction and expression mechanisms of the LTD and LTP induced by focused vs. distributed activation of neocortical inputs using a combination of intracellular recordings and pharmacological manipulations with field potential recordings and optical imaging. The proposed studies will shed light on the inhibitory mechanisms regulating impulse traffic in the rhinal cortices and thus give us unique insights in the factors controlling the propagation of epileptiform activity. Moreover, the proposed work will analyze the network properties that allow the perirhinal cortex to participate in memory formation. Since the rhinal cortices are primarily and/or selectively damaged during early stages of neurological and psychiatric diseases, the basic research program proposed here may improve our understanding of memory disorders.