Opposing Roles of Distinct Output Projections From Prefrontal Cortex

描述（由申请人提供）：前额叶皮层（PFC）功能障碍被认为是许多成瘾性适应不良行为的基础。虽然许多研究已经调查了PFC的子区域如何有助于认知加工和药物寻求，但很少有研究研究单个层的功能贡献。PFC投射神经元通过它们的输出靶点分离，包括投射到背侧核（NAc）核心与头内侧被盖核（RMTg）的前边缘PFC内的分离子层，这两种结构通常对大鼠的行为具有相反的影响，包括与恐惧和药物寻求相关的影响。目前的一组研究的目的是测试新的假设，投射神经元亚层是一个重要的组织特征的PFC，和亚层的传入，传出和功能的差异是至关重要的PFC在一系列的行为反应的不同功能。PFC投射神经元亚层的功能作用在成瘾研究中被忽视，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。本申请的第一个目的是研究投射到NAc与RMTg的PFC投射神经元子层是否对行为具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）和条件性恐惧（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，并且NAc与RMTg中PFC末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。本申请的第二个目的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。这些基础研究将表明，投射神经元亚层在PFC成瘾中具有可分离的作用，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，以前被忽视了。

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.