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

摘要 丘脑室旁核(PVT)调节包括诱发行为在内的动机行为 通过压力暴露。PVT接受来自蓝斑(LC)的广泛投射，蓝斑是一个重要的 应激反应系统的组成部分，调节应激反应的唤醒和认知方面 也是大脑中去甲肾上腺素(NE)的主要来源。因此，PVT和LC都很重要 在应激过程中的唤醒和注意力的作用，从而导致正负价态，RDoC 在多种精神病理学中很重要的结构。然而，LC投影对PVT的作用 调解对压力的反应很少或根本没有受到关注。我们先前在大鼠PVT方面的工作 结果表明，PVT后部(PPVT)优先调节对重复应激的反应。 此外，初步数据表明，pPVT中的神经元活性在易患PPVT的动物中更高 与适应力强和控制能力强的动物相比，反复的社会失败。对失败的敏感性与 对LC细胞更大的刺激性输入。这些数据表明LC投射到pPVT的活性是 在容易受到反复社会失败影响的个人中得到增强。基于初步的和 根据已公布的数据，这一探索性/发展性建议的中心假设是 LC/NE投射到pPVT的活性导致对社会失败的易感性。雄鼠和雌鼠都有 将会被研究。实验将使用GRABNE传感器通过纤维光度法评估NE在 PPVT在反复的社会失败中，将使用化学遗传学来抑制pPVT投射的LC细胞在 DBH-cre小鼠。我们预计pPVT中NE的释放将在失败后在小鼠中达到最高水平 社交回避/易感以及在社交失败期间抑制pPVT投射LC-NE细胞 减少社交回避，从而降低失败的敏感性。我们还预计会有更多的NE释放和 与雄鼠相比，LC-pPVT抑制对雌鼠的影响较小。这些研究的完成 将提供有关LC-NE输入到PVT如何调节应激反应的第一信息 首先是关于这些输入功能的性别差异的信息。阐明去甲肾上腺素释放对血管内皮细胞的影响 投射pPVT的LC细胞中pPVT和OF的活性将为个体提供新的机制洞察 对压力的反应不同。

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.