Thalamic reticular nucleus regulation of behavioral flexibility through modulation of a thalamocortical circuit

项目摘要 行为灵活性，如逆向学习所模拟的那样，对于在面对困难时实现预期结果至关重要。 不断变化的环境，但在许多神经精神疾病中受损。损坏 外侧眶额皮质（LOFC）或内侧背丘脑（MD）产生类似反向学习 这表明这两个区域相互作用，以促进最佳行为。虽然我们不知道 在这些区域之间发生信息交换以支持行为灵活性，其中一个区域可以 调节LOFC和MD之间通讯的是丘脑网状核（TRN）。TRN是主要的 丘脑抑制性输入的来源，在睡眠和感觉选择中起作用，并影响丘脑输出 基于来自皮层的前馈信息和来自丘脑的反馈信息的整合。 虽然TRN与感觉丘脑的解剖和功能相互作用是很好的特征，但它是 未知TRN如何与相关丘脑核团及其皮质靶点相互作用。缺少资料 限制了我们对大脑如何在丘脑和皮层之间处理高阶认知的理解 结构.该项目将1）表征TRN操纵对MD和LOFC活性的影响，2） 鉴定TRN抑制对行为灵活性和细胞类型特异性LOFC活性的影响，以及3） 确定TRN是否将前额叶皮层（PFC）输入整合到MD。光遗传学刺激的影响 TRN对协调MD和LOFC神经活动的影响将在目标1a中使用纤维光度法进行评估。在 此外，TRN的光遗传学抑制对a）LOFC兴奋性神经元和B）LOFC兴奋性神经元中活性的影响 接受MD投射的神经元将使用跨突触双色纤维光度法进行检查 方法（目标1b）。为了评估TRN对行为灵活性和细胞类型特异性LOFC活性的影响， TRN将在逆转学习过程中被光遗传学抑制（Aim 2a），并且细胞类型特异性LOFC活性 (Aim 2b）将使用免疫组织化学方法定量。最后，我将研究 不同的PFC输入到TRN→MD投射神经元，以确定联合投射TRN是否具有 解剖组织允许PFC整合（目标3）。这项研究将揭示新的洞察TRN的 与相关丘脑结构及其皮质靶点的相互作用，以及确定TRN是否是 行为灵活性的必要条件。这一建议的总体结果将确定创新方法， 大脑执行神经元活动的远程协调以支持联想学习。

PROJECT ABSTRACT Behavioral flexibility, as modeled by reversal learning, is critical to achieving desired outcomes in the face of an ever-changing environment, but is impaired across numerous neuropsychiatric conditions. Damage to the lateral orbitofrontal cortex (LOFC) or mediodorsal thalamus (MD) produce similar reversal learning impairments, suggesting the two regions interact to promote optimal behavior. While it is unknown how information exchange occurs between these regions to support behavioral flexibility, one region that may regulate communication between LOFC and MD is the thalamic reticular nucleus (TRN). TRN is the main source of inhibitory input to the thalamus, has roles in sleep and sensory selection, and affects thalamic output based on integration of feedforward information from the cortex and feedback information from the thalamus. While TRN’s anatomical and functional interactions with sensory thalamus are well-characterized, it is unknown how TRN interacts with associative thalamic nuclei and their cortical targets. This lack of information limits our understanding of how the brain processes higher order cognition across thalamic and cortical structures. This project will 1) characterize the effects of TRN manipulation on MD and LOFC activity, 2) identify the effects of TRN inhibition on behavioral flexibility and cell-type specific LOFC activity, and 3) determine whether TRN integrates prefrontal cortex (PFC) inputs to MD. The impact of optogenetic stimulation of TRN on coordinated MD and LOFC neural activity will be assessed in Aim 1a using fiber photometry. In addition, the impact of optogenetic inhibition of TRN on activity in a) LOFC excitatory neurons and b) LOFC neurons receiving projections from MD will be examined using a trans-synaptic, dual-color fiber photometry approach (Aim 1b). To assess the impact of TRN on behavioral flexibility and cell-type specific LOFC activity, TRN will be optogenetically inhibited during reversal learning (Aim 2a), and cell-type specific LOFC activity (Aim 2b) will be quantified using an immunohistochemical approach. Finally, I will examine the overlap of different PFC inputs to TRN→MD projecting neurons to determine whether associative-projecting TRN has the anatomical organization to permit PFC integration (Aim 3). This research will uncover novel insight into TRN’s interactions with associative thalamic structures and their cortical targets, as well as determine whether TRN is necessary for behavioral flexibility. The overall results of this proposal will identify innovative ways in which the brain performs long range coordination of neuronal activity to support associative learning.