STRESS INDUCED PLASTICITY IN LIMBIC 5HT CIRCUIT

边缘 5HT 回路中的应力诱导可塑性

• 批准号: 6285786
• 负责人: SHERYL G BECK
• 金额: $ 24.94万
• 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/6285786
• 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发生长期变化，这可能是潜在的原因 抑郁症的症状。海马体的 CA3 子区就是其中之一 重要的神经回路，因为它是振荡的感应部位 在许多不同的行为状态下观察到的神经元活动。这个神经 活动与认知功能相关。神经元 该电路由中缝的 5HT 投影调节。 最近的证据表明 5HT 突触后受体效应机制 因压力而改变。这些突触后变化可能是造成 压力后 CA3 神经活动的长期变化。长期来看 目标是阐明海马 CA3 改变的细胞底物 应激引起的功能。工作假设是细胞之一 压力诱发 CA3 海马回路变化的机制是 5HT 调制输入的变化。细胞内记录技术 海马脑切片制剂将用于记录 CA3 神经 活动。具体目标 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 相关的特征和第二信使系统 5-HT-7受体不会相同。具体目标 3：确定效果 由卡巴胆碱诱导的 5-HT 和 CA3 振荡活性。假设： 分离的 5-HT 受体的选择性激活将受到差异调节 卡巴胆碱诱导振荡活动。具体目标 3：确定 压力对突触后 5-HT 受体介导的反应（卡巴胆碱）的影响 诱导的振荡活性和卡巴胆碱诱导的 5-HT 调节 振荡活动。将使用两种不同的行为压力范式， 即强迫游泳和不可避免的束缚以及治疗组 其内源性应激激素皮质酮水平受到控制。它 预计这三种协议的调节作用可以 由于压力源的性质和持续时间差异很大 不同的。这些研究将共同​​系统地检验多个 压力引起 CA3 神经回路变化的机制 子字段。这些机制可能是许多衰弱症状和 抑郁症和压力相关疾病中出现的认知缺陷。 了解这些机制也可能为以下方面提供重要信息： 开发治疗抑郁症和压力相关疾病的新疗法。