Contributions of neuropeptide Y to hippocampal-lateral septal-hypothalamic regulation of behavioural defense

恐惧也许是我们最原始的情感。适当程度的恐惧会产生适应性的防御反应，从而促进生存。太多或太少的恐惧或对恐惧的不适当反应都是不适应的。我的研究关注的是负责调节恐惧的神经回路，这是一种有用的适应，但它将帮助我们理解这种回路的改变是如何导致适应不良反应的。根据一种理论，海马体、侧隔及其下丘脑输出结构共同调节对威胁的行为反应。这些结构富含神经肽Y （NPY）。然而，这些位点的NPY是否与恐惧表达有关尚不清楚。我们最近发现，向外侧隔膜微注射NPY可以减少大鼠的恐惧相关防御行为。现在我打算研究NPY是否在侧隔的主要输入（海马体）和输出（下丘脑）结构中起着类似的作用。NPY作用于Y1， Y2和Y5受体。通过将NPY与特定受体阻滞剂共同注射，我计划确定这些部位的不同NPY受体参与恐惧表达。通过结合行为测试和免疫组织化学，我计划确定暴露于威胁是否会激活NPY细胞并增加大脑威胁敏感区域的NPY释放。最后的一系列实验使用免疫组织化学技术来检查表现出高水平恐惧的大鼠在感兴趣的大脑区域是否有较低水平的NPY。在过去的研究中，我们发现在青春期早期（而不是青春期中期）将老鼠暴露在逆境中会增加它们成年后的恐惧相关行为。我们现在的计划是复制这些效应，并确定它们是否部分由大脑中NPY可用性的变化所介导。这些实验结果将进一步深入了解NPY在侧隔及其主要输入和输出结构中在行为防御调节中的功能作用。更广泛地说，这项工作将为理解大脑中的一些变化提供一个总体框架，这些变化可能是人类病理性恐惧和焦虑障碍的基础。

Fear is perhaps our most primal emotion. Appropriate levels of fear yield adaptive defensive responses that promote survival. Too much or too little fear or inappropriate responses to fear are maladaptive. My research is concerned with the neural circuits responsible for mediating fear as a useful adaptation but will help us to understand how alterations in this circuitry could lead to maladaptive responses. According to one theory, the hippocampus, lateral septum and its hypothalamic output structures work together to regulate behavioral responses to threat. These structures are heavily enriched with neuropeptide Y (NPY). However, it is not clear whether NPY at these sites contributes to fear expression. We recently found that micro-injecting NPY into the lateral septum reduced rats' fear-related defensive behaviours. Now I propose to examine whether NPY serves a similar role in the primary input (hippocampus) and output (hypothalamic) structures of the lateral septum. NPY acts at Y1, Y2 and Y5 receptors. By co-injecting NPY with a specific receptor blocker, I plan to determine the involvement of the different NPY receptors at these sites in fear expression. By combining behavioral testing with immunohistochemistry, I plan to determine whether exposure to threat activates NPY cells and increases NPY release in threat sensitive regions of the brain. A final series of experiments uses techniques from immunohistochemistry to examine whether rats that display high levels of fear have lower levels of NPY in the brain regions of interest. In past studies, we found that exposing rats to adversity during early (but not mid-) adolescence increased their fear-related behaviours in adulthood. Our plan now is to replicate these effects and determine whether they are mediated, in part, by changes in NPY availability in the brain. The results of these experiments will further advance basic knowledge about the functional role of NPY in the lateral septum, and its primary input and output structures, in behavioral defense regulation. More broadly, this work will provide a general framework for understanding some of the changes in the brain that might underlie pathological fears and anxiety disorders in humans.