Opposing Roles of Distinct Output Projections From Prefrontal Cortex

描述（由申请人提供）：前额皮质（PFC）功能障碍被认为是许多成瘾特征的适应不良行为的基础。尽管许多研究已经研究了PFC的子区域如何影响认知加工和药物寻找，但很少有研究检查了单个层的功能贡献。PFC投射神经元根据它们的输出目标是分离的，包括边缘前PFC内分离的亚层，分别投射到伏隔核（NAc）核心和rostromedial被盖核（RMTg），这两个结构通常对大鼠的行为有相反的影响，包括与恐惧和药物寻求相关的结构。当前的一系列研究旨在验证一个新的假设，即投射神经元亚层是PFC的一个重要组织特征，并且亚层在传入、传出和功能上的差异对PFC在一系列行为反应中的不同功能至关重要。投射神经元亚层在PFC中的功能作用在成瘾研究中被忽视，进一步研究PFC功能障碍在成瘾中的作用需要进一步研究行为功能和解剖连通性。该应用程序的第一个目的是研究PFC投射神经元亚层投射到NAc和RMTg是否对行为有独立和可分离的贡献。这些研究将使用复发和恐惧的啮齿动物模型：在自我给药范式中恢复可卡因寻求（线索诱导的杠杆按压）和条件恐惧（线索诱导的冻结）。逆行标记的PFC神经元中的c-Fos激活模式将用于确定独立功能，NAc和RMTg中PFC终端的光遗传学抑制将用于测试这两个亚层的相反功能贡献。该应用程序的第二个目标将使用跨突触逆行追踪技术来研究投射到NAc或RMTg的PFC子层的传入连接的差异。这些基础研究将证明PFC中的投射神经元亚层在成瘾中具有可解离的作用，并且输出投射亚群的离散分割是PFC组织和功能的关键组成部分，这在以前被忽视。

DESCRIPTION (provided by applicant): Prefrontal cortex (PFC) dysfunction is thought to underlie many of the maladaptive behaviors that characterize addiction. Although many studies have investigated how subregions of PFC contribute to cognitive processing and drug seeking, very few studies have examined the functional contribution of individual layers. PFC projection neurons are segregated by their output targets, including segregated sublayers within prelimbic PFC projecting to nucleus accumbens (NAc) core vs. rostromedial tegmental nucleus (RMTg), two structures that often have opposing influences on behavior in rats, including those associated with fear and drug seeking. The current set of studies is aimed at testing the novel hypothesis that projection neuron sublayers are an important organizational feature of PFC, and that sublayer differences in afferents, efferents, and function are critical to the diverse functionality of PFC across a range of behavioral responses. The functional role played by projection neuron sublayers in PFC has been overlooked in addiction studies, and further studies of both the behavioral function and anatomical connectivity are necessary for understanding the role that PFC dysfunction plays in addiction. The first aim of the application will investigate whether PFC projection neuron sublayers projecting to NAc vs. RMTg have independent and dissociable contributions to behavior. These studies will use rodent models of relapse and fear: reinstatement of cocaine seeking in a self-administration paradigm (cue-induced lever pressing), and conditioned fear (cue-induced freezing). c-Fos activation patterns in retrogradely-labeled PFC neurons will be used to determine independent function, and optogenetic inhibition of PFC terminals in NAc vs. RMTg will be used to test opposing functional contributions of these two sublayers. The second aim of the application will use trans-synaptic retrograde tracing technology to investigate differences in afferent connectivity to PFC sublayers projecting to either NAc or RMTg. These basic research studies will demonstrate that projection neuron sublayers in PFC have dissociable roles in addiction, and that discrete segmentation of output projection subpopulations is a key component of PFC organization and function that has been overlooked previously.