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

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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.