Sexually Dimorphic Amygdala Dysfunction in a Mouse Model of Global Cerebral Ischemia

全脑缺血小鼠模型中的性二形性杏仁核功能障碍

• 批准号: 10828626
• 负责人: Jose Jacob Vigil
• 金额: $ 4.03万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10828626
• 关键词: Affective; Amygdaloid structure; Animal Model; Animals; Anxiety; Association Learning; Award; Behavior; Behavioral; Biological Models; Brain; Calcium; Cardiopulmonary Resuscitation; Cerebral Ischemia; Clinical; Cognitive; Communication; Complement; Cues; Dendritic Spines; Development; Distal; Education; Electrophysiology (science); Emotional; Emotional disorder; Excitatory Postsynaptic Potentials; Food; Functional disorder; Future; Goals; Heart Arrest; Hippocampus; Human; Image; Impaired cognition; Impairment; Individual; L-Type Calcium Channels; Learning; Long-Term Potentiation; Measurement; Measures; Mediating; Memory; Mental Depression; Methods; Modeling; Molecular; Molecular Target; Mus; N-Methyl-D-Aspartate Receptors; Nerve Degeneration; Neurosciences; Outcome; Pharmacology; Phase; Population; Post-Traumatic Stress Disorders; Postdoctoral Fellow; Prevalence; Quality of life; Research; Research Personnel; Resuscitation; Science; Site; Slice; Stimulus; Survivors; Synaptic Transmission; System; Techniques; Training; Universities; Vertebral column; behavioral response; career; conditioned fear; emotional experience; emotional functioning; experience; experimental study; hippocampal pyramidal neuron; improved; in vivo; in vivo calcium imaging; male; mouse model; neuropsychiatric disorder; patient population; pre-doctoral; response; saliva secretion; sensory stimulus; sex; sexual dimorphism; two-photon; young adult

Project Summary/Abstract While advances in resuscitation science have improved cardiac arrest survival, we lack therapies to improve cognitive-affective outcomes in this patient population. Our lab has previously identified cognitive dysfunction in a mouse model of global cerebral ischemia (GCI) which has been attributed to hippocampal neurodegeneration and impaired hippocampal plasticity. However, no study has attempted to identify amygdala dysfunction after GCI, despite clinical evidence of emotional dysfunction, such as anxiety and Post-Traumatic Stress Disorder (PTSD). Therefore, it is important to identify the effect that GCI has on the amygdala, the emotional center of the brain. Our lab has a well-developed, translatable mouse model of GCI, the cardiac arrest/cardiopulmonary resuscitation model (CA/CPR), that has been instrumental in assessing amygdala function after GCI. I have utilized the amygdala-dependent delay-fear conditioning (DFC) paradigm to assess associative learning and memory and have performed field excitatory post-synaptic potential (fEPSP) recordings in two circuits within the amygdala, as measures of amygdala function. I have found a sexually dimorphic and circuit specific deficit in amygdala function after GCI and am working toward identifying the mechanism of this dysfunction. I have found that there is a male specific impairment in amygdala-dependent associative learning and a concomitant deficit of long-term potentiation (LTP) in the cortical input to the basolateral amygdala. I have also found no evidence that these deficits of amygdala function can be attributed to neurodegeneration within the amygdala. I have verified that there are differential mechanisms of LTP induction between the two circuits and this difference has led to the development of my hypothesis put forth in this proposal. The difference being, LTP of the cortical input to the BLA requires functional NMDA receptors and L-type calcium channels (LTCCs), whereas the intra amygdala circuit only requires functional NMDA receptors. Thus, I hypothesize that GCI induces dysfunction of LTCC's within the BLA of male mice, thereby contributing to the deficits in amygdala-dependent behavior and LTP. To assess this hypothesis, I have isolated and recorded LTCC mediated currents from BLA pyramidal neurons. This method, while powerful, has yielded no significant difference between CA/CPR and sham animals. However, a caveat of the method is that only somatic and peri somatic LTCCs can be measured. Therefore, to fully evaluate my hypothesis, I have proposed more site-specific experiments that will evaluate the contribution of LTCC's to synaptic transmission at individual distal dendritic spines. I will use two-photon calcium imaging of individual spines in the BLA while electrically inducing LTP of the cortical input to the BLA. I will then use pharmacology to identify the LTCC component of the calcium response and compare between sham and CA/CPR animals.

项目概要/摘要 虽然复苏科学的进步提高了心脏骤停的生存率，但我们缺乏改善心脏骤停的治疗方法 该患者群体的认知情感结果。我们的实验室之前已经发现认知功能障碍 归因于海马神经变性的全脑缺血（GCI）小鼠模型 和海马可塑性受损。然而，没有研究试图确定术后杏仁核功能障碍。 GCI，尽管有临床证据表明存在情绪功能障碍，例如焦虑和创伤后应激障碍 （创伤后应激障碍）。因此，确定 GCI 对杏仁核（大脑的情感中心）的影响非常重要。 脑。我们的实验室有一个成熟的、可翻译的 GCI 小鼠模型，即心脏骤停/心肺 复苏模型 (CA/CPR)，有助于评估 GCI 后的杏仁核功能。我有 利用杏仁核依赖性延迟恐惧调节（DFC）范式来评估联想学习和 记忆并在两个回路中进行了场兴奋性突触后电位（fEPSP）记录 杏仁核，作为杏仁核功能的衡量标准。我发现了性别二态性和电路特异性缺陷 GCI 后杏仁核发挥功能，目前正在努力确定这种功能障碍的机制。我已经找到了 杏仁核依赖的联想学习存在男性特有的损伤以及伴随的缺陷 皮质输入基底外侧杏仁核的长时程增强（LTP）。我也没有找到证据 杏仁核功能的这些缺陷可归因于杏仁核内的神经变性。我有 验证了两个电路之间存在 LTP 感应的差异机制，并且这种差异 导致了我在该提案中提出的假设的发展。区别在于，皮质输入的 LTP BLA 需要功能性 NMDA 受体和 L 型钙通道 (LTCC)，而内部 杏仁核回路只需要有功能的 NMDA 受体。因此，我推测 GCI 会导致 LTCC 位于雄性小鼠的 BLA 内，从而导致杏仁核依赖性行为的缺陷 LTP。为了评估这个假设，我从 BLA 锥体中分离并记录了 LTCC 介导的电流 神经元。这种方法虽然强大，但在 CA/CPR 和假动物之间没有产生显着差异。 然而，该方法的一个警告是只能测量体细胞和体周 LTCC。因此，要 充分评估我的假设，我提出了更多针对特定地点的实验来评估贡献 LTCC 到单个远端树突棘的突触传递。我将使用双光子钙成像 BLA 中的单个棘，同时电诱导 BLA 皮质输入的 LTP。然后我将使用 药理学来识别钙反应的 LTCC 成分并比较假手术和假手术 CA/CPR 动物。