Role of locus coeruleus-paraventricular thalamic projections in social threat processing

总结 丘脑室旁核（PVT）调节动机性行为，包括诱导性行为 通过压力暴露。PVT接受来自蓝斑（LC）的广泛投射，这是一个重要的 应激反应系统中调节应激反应的唤醒和认知方面的成分 也是大脑中去甲肾上腺素（NE）的主要来源。因此，PVT和LC都起重要作用 在压力下的唤醒和注意力中的作用，从而有助于积极和消极的效价状态，RDoC 在多种精神病理学中很重要的结构。然而，LC投射到PVT的作用， 调节对压力的反应很少或根本没有受到关注。我们以前在大鼠PVT方面的工作 显示PVT的后分裂（pPVT）优先调节对重复应激的反应。 此外，初步数据表明，pPVT中的神经元活动在易受影响的动物中更高。 与有弹性和对照动物相比，重复的社会失败。失败的敏感性与 更大的刺激输入到LC细胞。这些数据表明，LC投射到pPVT的活性是 在易受反复社会失败影响的个体中增强。根据初步和 根据已发表的数据，这一探索性/发展性建议的中心假设是， LC/NE对pPVT的投射活动导致对社会失败的易感性。雄性和雌性小鼠 将被研究。实验将使用GRABNE传感器通过纤维光度法评估NE释放， pPVT在反复的社会失败，并将使用化学遗传学抑制pPVT投射LC细胞， DBH-cre小鼠。我们预计，在pPVT中的NE释放将在小鼠失败后最高， 社交回避型/易感型和在社交失败期间抑制pPVT投射LC-NE细胞将 减少社交回避，从而减少失败的可能性。我们进一步预计更大的NE释放， 与雄性小鼠相比，雌性小鼠中LC-pPVT抑制的影响较小。这些研究的完成 将提供关于LC-NE输入到PVT如何调节应激反应的第一个信息， 关于这些输入功能的性别差异的第一份资料。阐明NE释放对 pPVT和pPVT投射LC细胞中活性将提供对个体 对压力反应的差异。

SUMMARY The paraventricular nucleus of the thalamus (PVT) regulates motivated behaviors including behaviors induced by stress exposure. The PVT receives extensive projections from the locus coeruleus (LC), an important component of the stress response system that mediates arousal and cognitive aspects of the stress response and the primary source of norepinephrine (NE) in the brain. Thus, both the PVT and the LC play important roles in arousal and attention during stress, thus contributing to positive and negative valence states, RDoC constructs important in multiple psychopathologies. However, the role of LC projections to the PVT in mediating responses to stress has received little to no attention. Our previous work on the PVT in rats showed that the posterior division of the PVT (pPVT) preferentially regulates responses to repeated stress. Further, preliminary data suggest that neuronal activity in the pPVT is higher in animals susceptible to repeated social defeat compared to resilient and control animals. Susceptibility to defeat is associated with greater stimulatory inputs to LC cells. These data suggest that activity of LC projections to pPVT are enhanced in individuals susceptible to the effects of repeated social defeat. Based on preliminary and published data, the central hypothesis of this exploratory/developmental proposal is that elevations in activity of LC/NE projections to pPVT lead to susceptibility to social defeat. Both male and female mice will be studied. Experiments will use the GRABNE sensor to assess NE release through fiber photometry in the pPVT during repeated social defeat and will use chemogenetics to inhibit pPVT-projecting LC cells in DBH-cre mice. We expect that NE release in the pPVT will be highest after defeat in mice that go on to be socially avoidant/susceptible and that inhibition of pPVT-projecting LC-NE cells during social defeat will reduce social avoidance thereby reducing susceptibility to defeat. We further expect greater NE release and less of an impact of LC-pPVT inhibition in female compared to male mice. The completion of these studies will provide the first information on how LC-NE inputs to the PVT regulate stress responses and the first information on sex differences in functions of these inputs. Elucidating the impact of NE release in the pPVT and of activity in pPVT-projecting LC cells will provide new mechanistic insights into individual differences in the response to stress.