Effects of NPY on Hippocampal Circuit Function

NPY 对海马回路功能的影响

• 批准号: 9134219
• 负责人: LYNN E DOBRUNZ
• 金额: $ 36.75万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9134219
• 关键词: Affect; Amygdaloid structure; Animal Model; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Bathing; Biological Assay; Cells; Clinical; Dense Core Vesicle; Equilibrium; Frequencies; Fright; Functional disorder; Glutamates; Health; Hippocampus (Brain); Human; Injection of therapeutic agent; Interneurons; Lead; Learning; Measures; Modeling; Mus; Neurons; Neuropeptides; Pathway interactions; Patients; Pattern; Physiological; Post-Traumatic Stress Disorders; Property; Pyramidal Cells; Regulation; Rodent; Role; Sensory; Severities; Signal Transduction; Stress; Synapses; Testing; Time; Tissues; anxiety symptoms; base; entorhinal cortex; feeding; gamma-Aminobutyric Acid; mouse model; nervous system disorder; neural circuit; neuropeptide Y; neuropsychiatric disorder; new therapeutic target; novel; novel therapeutic intervention; preclinical study; prevent; research study; response; stress resilience; therapeutic target; transmission process

 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.

 描述（由适用提供）：神经肽Y（NPY）是具有耐心焦虑特性的内源性神经肽。 NPY已在多种抗焦虑症中实施，包括创伤后应激障碍（PTSD），并提出了NPY水平的增强，作为PTSD和其他抗焦虑症的潜在疗法。低水平的PTSD患者以及使用捕食者气味压力模型的啮齿动物中的低水平，这是压力引起的焦虑/PTSD的模型。但是，尚未证明捕食者气味应激对海马中NPY释放的影响。尚未证明焦虑症是一种焦虑症的焦虑症。由于其许多临床意义，重要的是了解NPY的内源性释放是在海马中释放的。海马的CA1区域中含有NPY的中间神经元，包括来自Schaffer Colternal（SC）突触的短期可塑性，来自CA3和颞院（TA）突触的突触。已显示外源性NPY可调节SC突触处的谷氨酸释放到CA1锥体细胞上，并降低SC刺激中的前馈抑制强度。尚不清楚NPY是否会调节TA突触或TA诱导的前馈抑制在CA1锥体细胞上。我们将测试响应于SC和TA刺激的CA1兴奋/抑制比和电路功能的外源性（浴）NPY的影响。此外，将测试对内源性释放NPY的CA1锥体细胞的影响。最后，我们将测试在动画的小鼠模型中，在CA1中释放内源性NPY的变化，测试更改的基础机制，并研究对CA1电路函数的影响。这些研究将使人们对NPY细胞峰值的调节和内源性释放的NPY的影响有更深入的了解，并可能导致潜在的治疗靶标，以增加NPY细胞尖峰并从而提高内源性NPY水平。