Effects of NPY on Hippocampal Circuit Function

 描述（由申请人提供）：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），并且已经提出增加NPY水平作为PTSD和其他焦虑症的潜在疗法。在PTSD患者和啮齿类动物中，使用Predator Scent Stress模型测量了低水平的β-NPY，该模型是压力诱导的焦虑/PTSD模型。然而，捕食者气味应激对海马神经肽Y释放的影响尚未得到证实。焦虑症被认为是一种适应不良的学习形式，海马功能障碍与焦虑症和创伤后应激障碍有关。由于其许多临床意义，重要的是要了解如何内源性释放的神经肽Y的调节。在海马体中，NPY从也释放GABA的抑制性中间神经元的子集释放。尽管神经肽Y的重要性，很少有人知道的生理特性的中间神经元在海马体中释放神经肽Y。本实验将研究海马CA 1区含有NPY的中间神经元的突触诱发的尖峰特性，包括来自CA 3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已被证明可以调节SC突触到CA 1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诱导的对CA 1锥体细胞的前馈抑制。我们将测试外源性（浴应用）NPY的兴奋/抑制比和电路功能在CA 1响应SC和TA刺激的影响。此外，将测试内源性释放的NPY对CA 1锥体细胞的影响。最后，我们将测试在焦虑的小鼠模型中CA 1中内源性NPY释放的改变，测试变化的机制，并研究对CA 1电路功能的影响。这些研究将导致对NPY细胞尖峰的调节和内源性释放的NPY的作用的更好理解，并且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.