Elucidation of the mediodorsal thalamic regulation of prefrontal function

阐明丘脑内侧对前额叶功能的调节

• 批准号: 9340034
• 负责人: Brielle Ferguson
• 金额: $ 2.02万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-23 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9340034
• 关键词: Address; Adult; Affect; Animals; Anterior; Attention; Autistic Disorder; Bathing; Behavior; Behavioral; Clinical; Clozapine; Cognition; Cognitive; Cognitive deficits; Disease; Down-Regulation; Drug Targeting; Electrophysiology (science); Equilibrium; Glutamates; Impaired cognition; Impairment; Interneurons; Lead; Lesion; Ligands; Link; Medial; Mediating; Membrane; Methodology; Neurons; Operative Surgical Procedures; Output; Oxides; Parvalbumins; Performance; Pharmacogenetics; Physiological; Play; Population; Prefrontal Cortex; Property; Pyramidal Cells; Rattus; Regulation; Role; Schizophrenia; Sensory; Short-Term Memory; Slice; Structure; Synaptic Transmission; Techniques; Thalamic structure; Time; Whole-Cell Recordings; base; behavior influence; cingulate cortex; designer receptors exclusively activated by designer drugs; executive function; flexibility; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; induced pluripotent stem cell; inhibitory neuron; nerve supply; neurotransmission; novel; positive allosteric modulator; receptor; therapeutic development; tool

PROJECT SUMMARY/ABSTRACT The mediodorsal thalamus (MD) is suggested to play a critical role in cognition through its extensive glutamatergic innervation of the medial prefrontal cortex (mPFC). These MD terminals provide AMPA-mediated excitation to both excitatory pyramidal neurons and gamma-aminobutyric (GABA)-ergic inhibitory interneurons. GABAergic interneurons, particularly the parvalbumin (PV)-expressing fast-spiking subtype, are fundamental in regulating the output of their neighboring pyramidal neurons, maintaining the excitation/inhibition (E/I) balance, and coordinating synchronous activity in populations of neurons. Interestingly, this neuronal subtype receives MD inputs, and their activity has been linked to working memory, attention, and executive functions associated with the PFC. However, how inhibitory interneurons are modulated by MD thalamocortical input remains unknown. We hypothesize that MD afferents drive mPFC inhibitory activity, aiding in the regulation of local circuit activity and thus optimizing performance on mPFC dependent tasks. This is based on feedforward inhibition observed not only in primary thalamic relays, but also recent evidence of this phenomenon in the anterior cingulate cortex. Given this, we propose that downregulation of MD activity will impair GABAergic activity in the prelimbic mPFC, causing dysregulation of local circuit activity, and cognitive deficits. To explore this possibility, we utilize Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) that allow us to selectively target glutamatergic MD neurons, and transiently inhibit their activity in adult rats by expression of the inhibitory hM4D receptor. Using pharmacogenetics, we can evaluate the consequences of MD inhibition by two primary methodologies. With the designer ligand, Clozapine-N-Oxide (CNO), we will treat animals systemically and explore the effects of MD inhibition on mPFC-dependent behaviors using a working memory and cognitive flexibility task. We will also take slices containing the mPFC and MD afferents, bath apply CNO, and determine resultant changes in the circuitry using whole cell-recordings. Thus far, we have successfully demonstrated that MD inhibition resulted in a significant decrease of GABAAR-mediated IPSCs in PFC pyramidal neurons. This loss in IPSCs appears to be greater at α1- GABAARs. Further, these decreases of GABA activity in the PFC are associated with cognitive dysfunction in our MD-inhibited animals. Using a T- maze delayed-alternation task, we have shown that MD inhibition impairs working memory performance, which can be rescued by treatment with the GABAergic α1-positive allosteric modulator, indiplon. These findings raise intriguing questions of how MD inhibition mechanistically influences mPFC local circuitry, and whether the MD regulates the mPFC through PV interneurons to impact cognition. We will further address these questions using a combination of surgical, electrophysiological, behavioral, and pharmacogenetic techniques.

项目摘要/摘要 建议通过其广泛的认知中介绍丘脑（MD）在认知中发挥关键作用 培养基前额叶皮层（MPFC）的谷氨酸能神经。这些MD终端提供AMPA介导的 激发兴奋性金字塔神经元和γ-氨基丁基（GABA） - 抗抑制性中间神经元的激发。 GABA能中间神经元，尤其是表达快速刺激性亚型的Parvalbumin（PV），在 调节其相邻金字塔神经元的输出，维持兴奋/抑制（E/I）平衡， 以及神经元种群中的同步活动。有趣的是，这种神经元亚型接收 MD输入及其活动与工作记忆，注意力和执行功能有关 与PFC。但是，如何通过MD丘脑皮质输入调节抑制性中间神经元 未知。我们假设MD传入驱动MPFC抑制活性，有助于局部调节 电路活动，从而在MPFC依赖任务上优化性能。这是基于饲料 不仅在原发性丘脑继电器中观察到的抑制作用，而且在最新的证据中也观察到这种现象 前扣带回皮质。鉴于此，我们建议MD活动的下调会损害GABA能 前BIMBIC MPFC的活性，导致局部电路活性失调和认知缺陷。探索 这种可能性，我们利用设计器受体专门由设计师药物（Dreadds）激活，这些受体允许 我们有选择地靶向谷氨酸能MD神经元，并通过 抑制性HM4D受体的表达。使用药物遗传学，我们可以评估 通过两种主要方法抑制MD。使用设计师配体，氯氮平-N-氧化物（CNO），我们将处理 动物有系统地探索MD抑制对MPFC依赖性行为的影响 记忆和认知灵活性任务。我们还将拿包含MPFC和MD传入的切片，洗澡 应用CNO，并使用全细胞录制确定电路的结果变化。那远，我们有 成功证明MD抑制作用导致GABAAR介导的IPSC的显着降低 PFC锥体神经元。 IPSC中的这种损失在α1-GABAARS上似乎更大。此外，这些下降 PFC中的GABA活性与我们的MD抑制动物中的认知功能障碍有关。使用t- 迷宫延迟抗议任务，我们表明MD抑制会损害工作记忆表现，这 可以通过使用GABA能α1阳性变构调节剂Indiplon处理来挽救。这些发现 提出有关MD抑制如何机械影响MPFC局部电路的有趣问题，以及是否是否 MD通过PV中间神经元调节MPFC以影响认知。我们将进一步解决这些问题 结合手术，电生理，行为和药物遗传学技术。