Behavioral and mechanistic dissection of a cognitive thalamo-cortical network

摘要 皮层和丘脑之间的相互作用对于感觉、行动和认知至关重要。虽然 丘脑在感觉处理中的作用已得到充分研究，但其在认知中的作用才刚刚开始被研究 阐明了。该提案将重点关注丘脑内侧（MD），它是最大的丘脑核之一 哺乳动物大脑，调节前额皮质（PFC）的认知控制和灵活性活动。 MD-PFC 已知精神分裂症中的相互作用受到干扰，但治疗选择有限，因为回路 这些相互作用背后的机制尚不清楚。在这个提案中，我们将测试一个总体模型 MD 通过增强 PFC 连接模式来匹配行为环境 与情境相关的活动模式和抑制与情境无关的活动模式。具体来说，我们的模型假设 MD 神经元通过有选择地加强携带基本信息的 PFC 输入来生成上下文特定信号 这些信号的元素，但不对上下文进行显式编码。两种 MD 细胞类型似乎产生 这些信号，其中一个使用它来增强上下文一致的 PFC 活动，而另一个则抑制 上下文不一致的活动。最后，我们的模型假设这些独特的丘脑效应是由 不同的 PFC 电路基序，分别是兴奋性/去抑制性和抑制性。在目标 I 中，我们将测试 假设 MD 神经元根据来自 PFC 的上下文非特定输入生成上下文特定输出。 在目标 II 中，我们将检验两种 MD 功能细胞类型映射到不同遗传类型的假设。在 目标 III，我们将检验以下假设：PFC 的两种 MD 依赖性效应：增强和抑制 的活动模式，是由不同的局部电路图案实现的。总的来说，我们的工作应该澄清电路 MD 影响 PFC 活动的机制，为检查其普遍性提供了起点 跨越不同的任务切换范式以及与高阶丘脑功能的关系更多 广泛地说。我们的工作还应该与 NIH 的中心使命相关，即理解与 治疗潜力。

Abstract Interactions between the cortex and thalamus are essential for sensation, action and cognition. Although the role of the thalamus in sensory processing is well-studied, its role in cognition is just beginning to be elucidated. This proposal will focus on the mediodorsal thalamus (MD), one of the largest thalamic nuclei of the mammalian brain, in regulating prefrontal cortex (PFC) activity in cognitive control and flexibility. MD-PFC interactions are known to be perturbed in schizophrenia, but therapeutic options are limited because the circuit mechanisms underlying these interactions are unknown. In this proposal, we will test an overarching model that the MD regulates PFC connectivity patterns to match the behavioral context through enhancement of context-relevant activity patterns and suppression of context-irrelevant ones. Specifically, our model posits that MD neurons generate context-specific signals by selectively strengthening PFC inputs that carry the basic elements of these signals but do not encode the context explicitly. Two MD cell types appear to generate such signals, one of which uses it to enhance context-congruent PFC activity while the other suppresses context incongruent activity. Lastly, our model posits that these distinct thalamic effects are mediated by different PFC circuit motifs, an excitatory/disinhibitory and an inhibitory, respectively. In Aim I, we will test the hypothesis that MD neurons generate context-specific output based on context non-specific inputs from PFC. In Aim II, we will test the hypothesis that the two MD functional cell types map onto distinct genetic types. In Aim III, we will test the hypothesis that the two MD-dependent effects on PFC, enhancement and suppression of activity patterns, are implemented by distinct local circuit motifs. Overall, our work should clarify the circuit mechanisms by which the MD influences PFC activity, providing a starting point for examining their generality across different task switching paradigms as well as relationship to higher order thalamus function more broadly. Our work should also be relevant to central mission of the NIH in understanding mechanisms with therapeutic potential.