STRESS INDUCED PLASTICITY IN LIMBIC 5HT CIRCUIT

边缘 5HT 回路中的应力诱导可塑性

• 批准号: 6703085
• 负责人: SHERYL G BECK
• 金额: $ 21.25万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6703085
• 关键词: adrenalectomy; behavior test; carbachol; corticosterone; electrophysiology; hippocampus; hormone regulation /control mechanism; laboratory rat; mathematical model; neural plasticity; neurons; neurotransmitters; psychological stressor; pyramidal cells; radioimmunoassay; receptor binding; second messengers; serotonin; serotonin receptor; statistics /biometry; synapses

Chronic stress causes long term changes in neural circuits that may underlie symptoms of depression. The CA3 subfield of the hippocampus is one of these important neural circuits because it is the induction site for the oscillatory neuronal activity seen during many different behavioral states. This neural activity has been correlated with cognitive functions. The neurons that comprise the circuit are regulated by 5HT projections from the median raphe. Recent evidence indicates that 5HT postsynaptic receptor-effector mechanisms are altered by stress. These postsynaptic changes may be responsible for the long-term alterations in CA3 neural activity following stress. The long term goal is to elucidate the cellular substrates for alterations in CA3 hippocampal function induced by stress. The working hypothesis is that one of the cellular mechanisms underlying stress induced changes in the CA3 hippocampal circuit is a change in the 5HT modulatory input. Intracellular recording techniques in hippocampal brain slice preparations will be used to record CA3 neural activity. Specific aim 1: To characterize postsynaptic 5-HT receptor-mediated responses in CA3 pyramidal cells. Hypothesis: 5-HT concentration response curve characteristics and second messenger systems linked to the 5-HT-1A , 5-HT-4 and 5-HT-7 receptors will not be the same. Specific aim 3: To determine the effects of 5-HT and CA3 oscillatory activity as induced by carbachol. Hypothesis: Selective activation of isolated 5-HT receptors will differentially modulated carbachol induced oscillatory activity. Specific aim 3: To determine the effects of stress on postsynaptic 5-HT receptor-mediated responses, carbachol induced oscillatory activity and 5-HT modulation of carbachol induced oscillatory activity. Two different behavioral stress paradigms will be used, i.e., forced swimming and inescapable restraint as well as a treatment group that has endogenous levels of the stress hormone corticosterone controlled. It is expected that the modulatory effects of the three protocols can be discriminated because the nature and duration of the stressors are vastly different. Together these studies will systematically examine multiple mechanisms for stress induced changes in the neural circuitry of the CA3 subfield. These mechanisms may underlay many of the debilitating symptoms and cognitive deficits seen in depression and stress related disorders. Understanding these mechanisms may also provide important information for the development of new treatments for depression and stress related disorders.

慢性压力会导致神经回路的长期变化，这可能是基础的 抑郁症状。海马的CA3子场就是其中之一 重要的神经回路是因为它是振荡的感应位点 在许多不同行为状态下看到的神经元活性。这个神经 活动与认知功能有关。神经元 该电路由中位raphe的5HT预测调节。 最近的证据表明5HT突触后受体效应器机制 被压力改变。这些突触后的变化可能是 压力后CA3神经活动的长期改变。长期 目标是阐明CA3海马的改变的细胞底物 压力引起的功能。工作假设是细胞之一 应力引起的机制在CA3海马电路中发生变化为 5HT调节输入的变化。细胞内记录技术 海马脑切片制剂将用于记录CA3神经 活动。特定目标1：表征突触后5-HT受体介导的 CA3锥体细胞的反应。假设：5-HT浓度响应曲线 与5-HT-1A，5-HT-4和 5-HT-7受体不会相同。特定目标3：确定效果 卡尔巴乔诱导的5-HT和CA3振荡活性的。假设： 隔离的5-HT受体的选择性激活将差异调制 卡尔巴乔诱导的振荡活性。特定目标3：确定 压力对突触后5-HT受体介导的反应Carbachol的影响 诱导的振荡活性和5-HT诱导的5-HT调节 振荡活动。将使用两个不同的行为应力范例， 即强制游泳和不可避免的限制和治疗组 它具有内源水平的应力激素皮质酮控制。它 可以预期这三个方案的调节效应可以是 歧视是因为压力源的性质和持续时间非常 不同的。这些研究将共同​​研究多个 压力引起的机制导致CA3神经回路的变化 子场。这些机制可能会使许多令人衰弱的症状和 在抑郁症和压力相关疾病中看到的认知缺陷。 了解这些机制也可能为 开发针对抑郁症和压力相关疾病的新疗法。