Associative properties of the perirhinal network

描述（由申请人提供）：周围皮层（PR）是一个背侧导向的皮层，参与识别和联想记忆。先前的单单元研究表明，PR对识别记忆的贡献涉及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左脑皮层突触重量的活动依赖性变化。然而，目前尚不清楚相同的网络如何支持这两种看似相反的可塑性形式。我们认为，这个悖论的解决方案在于外源性新皮层输入与内源性长时间PR连接形成的差异，这些连接是由PR皮层的前馈抑制性中间神经元形成的。事实上，先前的研究表明，在PR神经元中，新皮层输入触发强烈的前馈抑制，而纵向内在通路介导明显纯粹的兴奋性反应。由于新皮质输入可以根据受体PR细胞是超极化还是去极化而经历有限或LTP，因此我们假设，活动依赖性突触可塑性的极性（LTD或LTP）取决于接受新皮质输入的PR细胞是否也接受来自纵向PR连接固有系统的收敛输入。这一假设将在以下具体目标中进行检验。在Aim #1中，我们将使用顺行示踪结合银强化预包埋GABA免疫细胞化学，比较新皮质轴突与纵向PR轴突形成的突触比例。在目标#2中，我们将测试在不同程度上招募纵向PR连接的新皮层刺激模式是否会导致活动依赖性LTP或LTD。为了验证这一点，在动脉灌注的体外全脑中，我们将比较θ波爆发刺激在一个和两个远端新皮质部位的效果。将使用细胞外记录和电压敏感染料的光学成像来监测诱发反应。在Aim #3中，我们将通过结合细胞内记录和药理学操作、场电位记录和光学成像，确定新皮层输入集中激活与分布式激活诱导的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交通的抑制机制，从而为我们提供控制癫痫样活动传播的因素的独特见解。此外，本研究还将分析使周围皮层参与记忆形成的网络特性。由于在神经和精神疾病的早期阶段，鼻皮质主要和/或选择性地受损，因此本文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.