Prefrontal microcircuitry and cognition in schizophrenia

关键的认知能力在一定程度上取决于大脑活动同步所产生的伽马振荡。 通过抑制含有小白蛋白(PV)的篮子细胞(PVBC)而兴奋锥体神经元(PNS 在背外侧前额叶皮质(PFC)的第三层(L3)的微电路中相互连接。因此，核心 精神分裂症(SZ)的认知障碍被认为反映了L3PN的变化，这种变化导致 PVBC的代偿性变化。在L3PN中，这些异常包括1)基因表达的改变 调节支持细胞形态的肌动蛋白动态，2)较小的胞体大小和较少的树突棘 (PNS兴奋性输入的主要部位)，3)下调的活性依赖标记物和4)减少的标记物 对能源生产的影响。这些发现提出了一些关键问题，只有通过在 单个L3PN的级别。首先，肌动蛋白调节改变，胞体更小，标志更低 活动和能源生产在深圳L3PN内共同定位并在L3PN之间相互关联(目标1)？共同-- 一些L3PN中的局部性改变将支持对个别L3PN中的单一措施的少数研究，这些研究 建议只有一部分L3PN在深圳受到影响。不同神经元之间的相关改变将支持 L3PN固有的一条因果通路，其中肌动蛋白调节改变会导致形态异常 这导致受影响的L3PN的兴奋性输入更少，从而减少了它们的活动和对能量的需求 制作。第二，受影响的L3PN是否显示抑制性突触的代偿性下调 在他们的PVBC输入端的力量(目标2)？一个肯定的答案将支持这样一种观点，即骚乱是内在的 L3PN是PVBC改变的上游，因为较低的L3PN活性被认为会导致 通过突触内稳态机制进行抑制。第三，L3PN活性的降低是否会导致较低的 成年猴PFC L3PN-PVBC微环路抑制性突触强度(目标3)？这样的突触 动态平衡发生在未成熟啮齿动物的感觉皮质中，但尚未在成年灵长类动物PFC中进行研究， 它具有多种不同的突触和连接特性。这种动态平衡的实验证据 成熟灵长类PFC的机制支持PVBC显示代偿反应的观点 L3PN活性较低的下游。第四，受影响的PFC L3PN的变化幅度是否可以预测 跨诊断的认知指标(目标4)？肯定的答案将支持L3PN- PVBC微回路改变是SZ认知功能障碍的神经基础。建议进行的研究 我将通过1)PFC L3 PN-PVBC微电路水平的定量、单细胞分析来回答这些问题 在身体人体研究中是独一无二的分辨率，2)关键的概念验证实验测试 猴子的微回路功能特性，以及3)微回路和认知测量的直接比较 在相同的科目中。这一结果将为认知的神经基础提供新的见解。 SZ的功能障碍，并成为创新治疗干预的潜在目标。

Key cognitive abilities depend, in part, on gamma oscillations generated by the synchronization of the activity of excitatory pyramidal neurons (PNs) by inhibition from parvalbumin (PV)-containing basket cells (PVBCs) that are reciprocally-connected in a microcircuit in layer 3 (L3) of the dorsolateral prefrontal cortex (PFC). Thus, core cognitive impairments in schizophrenia (SZ) are thought to reflect alterations in L3PNs that produce compensatory changes in PVBCs. In L3PNs, these abnormalities include 1) altered expression of genes regulating the actin dynamics that supports cell morphology, 2) smaller somal size and fewer dendritic spines (the main site of excitatory inputs to PNs), 3) downregulated activity-dependent markers and 4) reduced markers of energy production. These findings raise key questions that can only be answered by conducting studies at the level of single L3PNs. First, are altered actin regulation, smaller somal size, and lower markers of activity and energy production co-localized within and correlated across L3PNs in SZ (Aim 1)? Co- localized alterations in some L3PNs would support the few studies of single measures in individual L3PNs which suggest that only a subset of L3PNs are affected in SZ. Correlated alterations across neurons would support a causal pathway intrinsic to L3PNs in which altered actin regulation produces morphological abnormalities that result in fewer excitatory inputs to the affected L3PNs, reducing their activity and the requirement for energy production. Second, do the affected L3PNs display compensatory downregulation of inhibitory synaptic strength at their PVBC inputs (Aim 2)? An affirmative answer would support the idea that disturbances intrinsic to L3PNs are upstream of alterations in PVBCs given that lower L3PN activity is thought to induce reductions in inhibition via synaptic homeostasis mechanisms. Third, do reductions in L3PN activity induce lower inhibitory synaptic strength in the L3PN-PVBC microcircuit of adult monkey PFC (Aim 3)? Such synaptic homeostasis occurs in sensory cortices of immature rodents, but has not been studied in the adult primate PFC, which has multiple distinctive synaptic and connectivity properties. Experimental evidence of this homeostatic mechanism in the mature primate PFC would support the idea that PVBCs display compensatory responses downstream of lower L3PN activity. Fourth, does the magnitude of alterations in affected PFC L3PNs predict indices of cognition across diagnoses (Aim 4)? An affirmative answer would support the idea that L3PN- PVBC microcircuit alterations contribute to the neural substrate for cognitive deficits in SZ. The proposed studies will answer these questions by 1) quantitative, single cell analyses of the PFC L3 PN-PVBC microcircuit at levels of resolution that are unique in postmortem human studies, 2) proof-of-concept experimental tests of key microcircuit functional properties in monkeys, and 3) a direct comparison of microcircuit and cognitive measures in the same subjects. The results will provide novel insights into the neural substrate of cognitive dysfunction in SZ and into potential targets for innovative therapeutic interventions.