Opposing Roles of Distinct Output Projections From Prefrontal Cortex

描述(由申请人提供)：前额叶皮质(PFC)功能障碍被认为是许多以成瘾为特征的适应不良行为的基础。虽然许多研究已经研究了PFC的亚区如何对认知加工和药物寻找做出贡献，但很少有研究考察各个层的功能贡献。PFC投射神经元通过它们的输出靶点被分离，包括投射到伏核(NAC)核心和被盖嘴侧核(RMTg)的初级PFC内的隔离亚层，这两个结构经常对大鼠的行为产生相反的影响，包括与恐惧和药物寻找相关的结构。目前的一系列研究旨在验证这一新的假设，即投射神经元亚层是PFC的重要组织特征，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。在成瘾研究中，投射神经元亚层在PFC中的功能作用一直被忽视，进一步研究PFC的行为功能和解剖连接对于理解PFC功能障碍在成瘾中的作用是必要的。该应用程序的第一个目标将调查投射到NAC和RMTg的PFC投射神经元亚层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：在自我管理范式中恢复寻求可卡因(线索诱导杠杆按压)，以及条件性恐惧(线索诱导冻结)。逆行标记的PFC神经元的c-Fos激活模式将被用来确定独立的功能，而NAC和RMTg中的PFC终末的光遗传抑制将被用来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亚层的传入连接的差异。这些基础研究将证明PFC内的投射神经元亚层在成瘾中具有不可分离的作用，而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，这一点以前被忽视。

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.