Inhibitory neuron circuit organization and function in prefrontal cortex.

 描述(申请人提供)：抑制性神经元是皮层操作的关键调节器。它们的功能障碍被认为是许多大脑疾病的主要因素。虽然最近的研究表明，特定类型的抑制性神经元之间存在生理和功能上的差异，但导致认知和执行功能皮质区存在这些差异的神经回路机制尚不清楚。我们重点研究了内侧前额叶皮质(MPFC)前部的抑制性神经元回路组织和功能。这个区域与精神分裂症、自闭症、注意力缺陷障碍和其他疾病高度相关。这一提议的指导假设是，每种类型的抑制性神经元的不同连接性在计算上不同地控制着mPFC中不同的神经信号转换，并且这些细胞类型之间的电路连接性差异可以被映射以确定它们在调节皮质网络动力学和行为输出中的特定角色。我们建议的实验将集中在三种主要的、不重叠的抑制细胞类型或组(表达小白蛋白、表达生长抑素和表达血管活性肠肽的中间神经元)。一种新的依赖于Cre的、基于狂犬病基因的追踪系统将被用来将完整大脑中的单突触全球电路连接映射到这些选定的抑制性神经元。为了补充解剖的狂犬病追踪，生理输入特征将通过激光扫描光刺激和通道视紫红质(ChR2)辅助的电路标测来完成。这些研究将允许将局部和远程功能输入映射到脑切片准备中每个目标细胞组中已识别的亚型。在评估输入连接的基础上，我们将绘制这些主要抑制性神经元组的局部功能输出图。对特定抑制性神经元类型的输入和输出电路连接的计算和行为分析将用于了解它们如何在体内调节mPFC网络振荡，以及它们如何有助于mPFC控制的动物学习。这将通过与细胞类型特定基因失活的行为表现测量平行进行的电生理记录来实现。总之，这项拟议的研究将产生内侧前额叶皮质抑制神经元回路连接的新图谱，并将广泛阐明抑制神经元回路如何调节与神经精神和神经疾病有关的正常和不适应行为。

 DESCRIPTION (provided by applicant): Inhibitory neurons are key regulators of cortical operations. Their dysfunction has been implicated as a major factor in many brain disorders. While recent studies indicate physiological and functional differences between specific types of inhibitory neurons, neural circuit mechanisms that give rise to these differences in cortical regions underlying cognition and executive function are not well understood. We focus our studies of inhibitory neuron circuit organization and function in the prelimbic area of medial prefrontal cortex (mPFC). This region is highly relevant to schizophrenia, autism, attention deficit disorders and others. The guiding hypothesis for this proposal is that the distinct connectivity of each type of inhibitory neurons differentially governs computationally distinct neural signal transformations in the mPFC, and that circuit connectivity differences between these cell types can be mapped to determine their specific roles in regulation of cortical network dynamics and behavioral output. Our proposed experiments will focus on the three major, non- overlapping inhibitory cell types or groups (parvalbumin-expressing, somatostatin-expressing and vasoactive intestinal peptide-expressing interneurons). A new Cre-dependent, genetically modified rabies-based tracing system will be used to map monosynaptic global circuit connections in the intact brain to these selected inhibitory neurons. To complement the anatomical rabies tracing, physiological input characterization will be accomplished by laser scanning photostimulation and channelrhodopsin (ChR2)-assisted circuit mapping. These studies will allow mapping of both local and long-range functional inputs to identified subtypes within each targeted cell group in brain slice preparations. Building on assessing input connections, we will map local functional outputs of these major inhibitory neuronal groups. Computational and behavioral analysis of the input and output circuit connections of specific inhibitory neuron types will be applied to understand how they regulate mPFC network oscillations in vivo and how they contribute to mPFC-controlled animal learning. This will be achieved by electrophysiological recordings made in parallel with behavioral performance measures with cell-type specific genetic inactivation. Together, the proposed research will generate new maps of inhibitory neuronal circuit wiring in medial prefrontal cortex, and it will broadly illuminate how inhibitory neuronal circuits regulate normal and maladaptive behaviors linked to neuropsychiatric and neurological diseases.