Effects of NPY on Hippocampal Circuit Function

 描述(申请人提供)：神经肽Y(NPY)是一种内源性神经肽，具有强大的抗焦虑特性。NPY与多种焦虑症有关，包括创伤后应激障碍(PTSD)，提高NPY水平被认为是治疗创伤后应激障碍和其他焦虑症的一种潜在方法。在PTSD患者和啮齿类动物中，使用捕食者气味应激模型测量了低水平的(NPY)，这是一种应激诱导焦虑/PTSD的模型。然而，捕食者气味应激对海马神经肽Y释放的影响尚未被证实。焦虑症被认为是一种不适应的学习形式，海马区功能障碍与焦虑症和创伤后应激障碍有关。由于它的许多临床意义，了解内源性NPY的释放是如何调节的很重要。在海马区，NPY是由抑制性中间神经元的子集释放的，这些中间神经元也释放GABA。尽管NPY很重要，但人们对海马区释放NPY的中间神经元的生理特性知之甚少。这项实验将研究海马区CA1区含NPY的中间神经元突触诱发的放电特性，包括来自CA3的Schaffer侧支(SC)突触和来自内嗅皮层的颞氨(TA)突触的兴奋性输入的短期可塑性。外源性NPY可调节SC突触对CA1锥体细胞的谷氨酸释放，并降低SC刺激的前馈抑制强度。目前尚不清楚NPY是否调节TA突触或TA对CA1锥体细胞的前馈抑制。我们将测试外源性NPY对SC和TA刺激所引起的CA1兴奋/抑制比和电路功能的影响。此外，还将测试内源性释放的NPY对CA1锥体细胞的影响。最后，我们将在焦虑的小鼠模型中检测CA1内源性NPY释放的变化，测试潜在的变化机制，并调查其对CA1回路功能的影响。这些研究将有助于更好地了解NPY细胞尖峰的调节和内源性释放的NPY的作用，并可能导致潜在的治疗靶点，以增加NPY细胞尖峰，从而提高内源性NPY水平。

 DESCRIPTION (provided by applicant): Neuropeptide Y (NPY) is an endogenous neuropeptide with robust anxiolytic properties. NPY has been implicated in a wide variety of anxiety disorders, including posttraumatic stress disorder (PTSD), and enhancement of NPY levels has been proposed as a potential therapy for PTSD and other anxiety disorders. Low levels of (NPY have been measured in patients with PTSD, and in rodents using the Predator Scent Stress model, which is a model of stress-induced anxiety/PTSD. However, the effect of Predator Scent Stress on NPY release in hippocampus has not yet been demonstrated. Anxiety disorders are considered a maladaptive form of learning, and hippocampal dysfunction has been implicated in anxiety disorders and PTSD. Because of its many clinical implications, it is important to understand how the endogenous release of NPY is regulated. In hippocampus, NPY is released from a subset of inhibitory interneurons that also release GABA. Despite the importance of NPY, very little is known about the physiological properties of the interneurons in hippocampus that release NPY. Experiments in this proposal will investigate the synaptically-evoked spiking properties of NPY-containing interneurons in the CA1 region of hippocampus, including the short-term plasticity of their excitatory inputs from Schaffer collateral (SC) synapses from CA3 and temporoammonic (TA) synapses from entorhinal cortex. Exogenous NPY has been shown to modulate glutamate release at SC synapses onto CA1 pyramidal cells and to decrease the strength of feed-forward inhibition from SC stimulation. It is not known if NPY modulates TA synapses or TA-induced feed-forward inhibition onto CA1 pyramidal cells. We will test the effect of exogenous (bath applied) NPY on the excitation/inhibition ratio and circuit function in CA1 in response to SC and TA stimulation. In addition, the effects on CA1 pyramidal cells of endogenously released NPY will be tested. Finally, we will test for alterations in the release of endogenous NPY in CA1 in a mouse model of anxiety, test for mechanisms underlying the changes, and investigate the effects on CA1 circuit function. These studies will lead to a greater understanding of the regulation of NPY cell spiking and the effects of endogenously released NPY, and may lead to potential therapeutic targets to increase NPY cell spiking and thus raise endogenous levels of NPY.