Prefrontal microcircuitry and cognition in schizophrenia

关键的认知能力部分取决于伽马振荡，伽马振荡是由大脑皮层的活动同步产生的。 兴奋性锥体神经元（PN）的抑制从小清蛋白（PV）含有篮细胞（PVBC）， 在背外侧前额叶皮层（PFC）的第3层（L3）中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L3 PN的改变， PVBCs的代偿性变化。在L3 PN中，这些异常包括1）基因表达改变 调节支持细胞形态的肌动蛋白动力学，2）较小的体大小和较少的树突棘 (the主要部位的兴奋性输入的PN），3）下调的活动依赖性标记和4）减少标记 能源生产。这些发现提出了一些关键问题，只有通过在 单个L3 PN的水平。首先，改变肌动蛋白调节，较小的染色体大小，和较低的标记物， 活动和能源生产共同本地化内和相关的L3 PNs在深圳（目的1）？共 一些L3 PN的局部改变将支持个别L3 PN的单一测量的少数研究， 表明SZ中仅L3 PN的一个子集受到影响。神经元之间的相关改变将支持 一种L3 PN固有的致病途径，其中改变的肌动蛋白调节产生形态异常 这导致对受影响的L3 PN的兴奋性输入减少，从而降低其活动和能量需求 生产第二，受影响的L3 PN是否表现出抑制性突触的代偿性下调， 其PVBC输入的强度（目标2）？一个肯定的答案将支持这样的观点，即干扰的内在 L3 PN的活性是PVBC改变的上游，因为较低的L3 PN活性被认为会诱导PVBC的减少。 通过突触内稳态机制抑制。第三，L3 PN活性的降低是否诱导较低的 抑制性突触强度在成年猴PFC的L3 PN-PVBC微回路（目的3）？这种突触 内稳态发生在未成熟啮齿动物的感觉皮层中，但尚未在成年灵长类PFC中进行研究， 其具有多种独特的突触和连接特性。这种自我平衡的实验证据 成熟灵长类PFC中的机制支持PVBCs显示代偿反应的观点 L3 PN活性较低。第四，受影响的PFC L3 PNs的变化幅度是否预示着 不同诊断的认知指数（目标4）？一个肯定的答案将支持L3 PN- PVBC微电路改变有助于SZ认知缺陷的神经基质。拟议的研究 我将回答这些问题，1）定量，单电池分析的PFC L3 PN-PVBC微电路的水平 的分辨率，是唯一的死后人类研究，2）概念验证实验测试的关键 猴子的微电路功能特性，以及3）微电路和认知测量的直接比较 在相同的科目。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.