ADRENALCORTICOID EFFECTS ON HIPPOCAMPAL NEURAL ACTIVITY

肾上腺皮质激素对海马神经活动的影响

• 批准号: 3415049
• 负责人: SHERYL G BECK
• 金额: $ 15.97万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-01-01 至 1994-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3415049
• 关键词: action potentials; adrenalectomy; aldosterone; calcium channel; cell membrane; chloride channels; corticosteroid receptors; corticosterone; dexamethasone; electrical potential; electrophysiology; hippocampus; hormone regulation /control mechanism; hypothalamic pituitary axis; inhibitor /antagonist; laboratory rat; microelectrodes; neuroendocrine system; neurons; physiologic stressor; pituitary adrenal axis; potassium channel; pyramidal cells; receptor expression; receptor sensitivity; resting potentials; serotonin receptor; sodium channel; sodium potassium exchanging ATPase; stimulant /agonist; synapses; voltage gated channel; action potentials; adrenalectomy; aldosterone; calcium channel; cell membrane; chloride channels; corticosteroid receptors; corticosterone; dexamethasone; electrical potential; electrophysiology; hippocampus; hormone regulation /control mechanism; hypothalamic pituitary axis; inhibitor /antagonist; laboratory rat; microelectrodes; neuroendocrine system; neurons; physiologic stressor; pituitary adrenal axis; potassium channel; pyramidal cells; receptor expression; receptor sensitivity; resting potentials; serotonin receptor; sodium channel; sodium potassium exchanging ATPase; stimulant /agonist; synapses; voltage gated channel

LONG TERM GOAL: To characterize the receptors and underlying mechanism of action of adrenalcortical steroids on hippocampal pyramidal cell activity. Adrenalcortical receptors in the hippocampus adjust corticosterone (CT) levels by regulating the hypothalamic-pituitary-adrenal axis (HPA). Homeostasis is maintained by basal activation of the hippocampal-HPA. In response to stress, CT secretion is increased. CT activation of receptors in the hippocampus leads to feedback inhibition of the HPA. Excessive CT secretion is neurotoxic to hippocampal pyramidal cells. The mechanism of the hippocampal regulation of the HPA is unknown. A step towards understanding this mechanism is to determine how CT alters pyramidal cell excitability. The hippocampal slice preparation in vitro will be used for intracellular recordings. CT concentrations will be controlled by adrenalectomy (ADX) and steroid replacement. SPECIFIC AIM #1: To determine the contribution of chronic CT receptor activation to pyramidal cell excitability. HYPOTHESES: Persistent Type 1 receptor activation, the non-stressed condition, will result in pyramidal cell depolarization and increased cell excitability as compared to cells from ADX rats. Chronic Type 1 and Type 2 receptor activation, the chronically stressed state, will decrease cell excitability to prolonged synaptic input by increasing the amplitude of an evoked slow hyperpolarization (sAHP). SPECIFIC AIM #2: To characterize the receptors mediating changes in hippocampal pyramidal cell physiology induced by acute CT administration. HYPOTHESES: Type 1 receptor activation will increase a cationic conductance and synaptic activation. Type 2 receptor activation will reduce prolonged synaptic excitability by increasing the sAHP amplitude. Activation of a plasma membrane receptor will hyperpolarize cells. The ionic mechanisms underlying these responses and genomic mediation will be determined SPECIFIC AIM #3: To determine the effect of chronic CT treatment on responses mediated by 5-hydroxytryptamine (5-HT) receptors. 5-HT exerts profound effects on pyramidal cells, and CT modulates 5-HT synthesis and receptor number. HYPOTHESES: CT will increase the sensitivity of the 5-HT(1A) hyperpolarization and decrease the sensitivity of the 5-HT receptor that decreases the amplitude of the sAHP. These results will provide important information on the control of pyramidal cell activity by CT and will help elucidate the mechanism of hippocampal regulation of the HPA.

长期目标：表征受体和基础机制 肾上腺皮质类固醇对海马锥体细胞活性的作用。 海马调节皮质酮（CT）中的肾上腺皮质受体 通过调节下丘脑 - 垂体 - 肾上腺轴（HPA）的水平。 稳态是通过海马HPA的基础激活来维持的。在 对压力的反应，CT分泌增加。受体的CT激活 在海马中，导致对HPA的反馈抑制。过多的CT 分泌是对海马锥体细胞的神经毒性。机制 HPA的海马调节尚不清楚。迈出一步 了解这种机制是确定CT如何改变锥体细胞 兴奋性。体外的海马切片制剂将用于 细胞内记录。 CT浓度将由 肾上腺切除术（ADX）和类固醇替代。特定目的＃1：确定 慢性CT受体激活对锥体细胞的贡献 兴奋性。假设：持续的1型受体激活， 无压力的条件将导致锥体细胞去极化和 与ADX大鼠的细胞相比，细胞兴奋性增加。慢性的 类型1和2型受体激活，长期应力的状态将 通过增加延长突触输入的细胞兴奋性 诱发的缓慢超极化（SAHP）的振幅。特定目标＃2： 表征介导海马锥体细胞变化的受体 急性CT给药引起的生理学。假设：1型受体 激活将增加阳离子电导和突触激活。 2型受体激活将减少长时间的突触兴奋性 增加SAHP振幅。质膜受体的激活 将超极化细胞。这些反应的基础的离子机制 和基因组中介将确定特定的目的＃3：确定 慢性CT治疗对5-羟基丙胺介导的反应的影响 （5-HT）受体。 5-HT对锥体细胞和CT产生深远影响 调节5-HT合成和受体数。假设：CT将增加 5-HT（1A）超极化的灵敏度并降低 5-HT受体的灵敏度降低了SAHP的振幅。 这些结果将提供有关控制的重要信息 CT通过CT锥体细胞活性，将有助于阐明 HPA的海马调节。