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

项目摘要 以反向学习为模型的行为灵活性对于在面临挑战时实现预期结果至关重要 环境不断变化，但在许多神经精神疾病中受损。损坏的地方 外侧眶前叶皮质(LOFC)或丘脑内侧背核(MD)产生类似的反转学习 损伤，表明这两个区域相互作用，促进最佳行为。虽然还不清楚是如何做到的 在这些区域之间进行信息交换以支持行为灵活性，其中一个区域可能 调节LOFC和MD之间的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，并影响丘脑的输出 基于来自皮质的前馈信息和来自丘脑的反馈信息的整合。 虽然TRN与感觉丘脑在解剖和功能上的相互作用有很好的特点，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。这种信息的缺乏 限制我们对大脑如何处理丘脑和大脑皮层的高级认知的理解 结构。该项目将1)表征TRN操纵对MD和LOFC活性的影响，2) 确定TRN抑制对行为灵活性和细胞类型特定LOFC活性的影响，以及3) 确定TRN是否将前额叶皮质(PFC)的输入整合到MD。光遗传刺激的影响 TRN对协调MD和LOFC神经活性的影响将在目标1a中使用纤维光度法进行评估。在……里面 此外，TRN的光发生抑制对a)LOFC兴奋性神经元和b)LOFC活动的影响 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 接近(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， 在反转学习过程中，TRN将受到光遗传抑制(目标2a)，并具有细胞类型特异性LOFC活性 (目标2b)将使用免疫组织化学方法进行量化。最后，我将研究一下 向TRN-→-MD投射神经元的不同PFC输入以确定联合投射的TRN是否具有 允许PFC整合的解剖组织(目标3)。这项研究将揭示对TRN的新见解 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 对于行为灵活性来说是必要的。这项提案的总体结果将确定创新的方式， 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.