Prefrontal cortex and stress reactivity

前额皮质和应激反应

• 批准号: 9986185
• 负责人: David A Morilak
• 金额: $ 37.67万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9986185
• 关键词: Address; Affect; Afferent Pathways; Amygdaloid structure; Anatomy; Animals; Attenuated; Behavior; Behavioral; Behavioral inhibition; Brain-Derived Neurotrophic Factor; Cellular Morphology; Chronic; Chronic stress; Ciliary Neurotrophic Factor; Cognition; Cognitive; Cognitive deficits; Data; Evoked Potentials; Executive Dysfunction; FRAP1 gene; Hippocampus (Brain); Impaired cognition; Impairment; Impulsivity; Label; Lead; Ligands; Link; Measures; Medial; Mediating; Mental disorders; Neurobehavioral Manifestations; Pathology; Pathway interactions; Performance; Phosphorylation; Predisposing Factor; Prefrontal Cortex; Process; Pyramidal Cells; Rattus; Reaction Time; Residual state; Reversal Learning; Risk Factors; Role; Short-Term Memory; Signal Pathway; Signal Transduction; Signaling Protein; Stress; Stress Tests; Structure; Symptoms; Synapses; Testing; Thalamic structure; Therapeutic; Vertebral column; behavioral impairment; behavioral plasticity; cognitive process; density; effective therapy; executive function; functional plasticity; improved; inhibitor/antagonist; neurobiological mechanism; neuropsychiatry; novel; optogenetics; prevent; response; stress reactivity; stressor

Chronic stress is a factor in many psychiatric illnesses that share dysregulation of the prefrontal cortex (PFC), and impaired executive function mediated in the PFC. Current therapies are inadequate, and residual cognitive symptoms often persist. This may be because multiple PFC circuits are dysregulated, disrupting multiple cognitive processes. If different mechanisms are affected in different PFC circuits, treatments that are beneficial to one may be ineffective or even detrimental to another. Over the years, we have studied chronic stress-induced cognitive impairment in the medial PFC and the orbitofrontal cortex (OFC) using different stress paradigms, but we have never compared these sub-regions directly. We have, however, observed differences in signaling mechanisms and functional plasticity suggesting that they may respond differently to chronic stress. We have also seen that chronic unpredictable stress (CUS) induces cognitive deficits in both regions. Thus, we will now utilize CUS in this proposal for competing renewal to directly compare and contrast the circuit-level dysregulation underlying cognitive impairment induced by CUS in the mPFC and OFC. In four specific aims, we will investigate the generality of effects by assessing changes in different behaviors mediated in these regions relevant to stress- related psychiatric disorders. We will study differential changes in afferent-evoked responses in mPFC and OFC, then use optogenetics to directly manipulate functional plasticity in those pathways to determine if changes seen after stress are sufficient for stress-induced cognitive deficits, and if opposing them is therapeutic. And we will study differences in signal transduction and structural anatomical plasticity that may underlie the differential changes in functional response induced by CUS in the mPFC and OFC. In Aim 1, we will assess differences in functional plasticity in the mPFC and OFC after CUS by measuring stress-induced changes in electrical responses elicited by stimulation of afferent input from the mediodorsal thalamus and ventral hippocampus to the mPFC, and from mediodorsal thalamus and basolateral amygdala to the OFC. In Aim 2, we will use opto- genetics to test the effects of directly potentiating or attenuating afferent-evoked responses in these same circuits on behaviors mediated in the mPFC and OFC. We predict that attenuating responses in the mPFC and potentiating responses in the OFC will mimic the effects of stress, whereas eliciting the opposite effect in each region will be beneficial in rescuing CUS-induced cognitive deficits in stressed animals. In Aim 3, we will assess changes in dendritic complexity and spine density on PFC pyramidal cells after stress, and test the role of new spine formation in the effects of optogenetically-induced plasticity. In Aim 4, we will test the differential roles of plasticity-related signaling pathways in the mPFC and OFC. We predict that CUS will attenuate PI3K-Akt signaling in mPFC and attenuate JAK signaling in OFC. And we predict these deficits will be restored by opto- genetically-induced plasticity that rescues PFC-mediated cognition. By revealing how stress dysregulates PFC circuits mediating executive function, these results may inform new, targeted strategies to improve treatment.

慢性压力是许多精神病疾病的因素，它们具有前额叶皮层（PFC）的失调， PFC中介导的执行功能受损。当前的疗法不足和残留的认知 症状通常持续存在。这可能是因为多个PFC电路失调，破坏了多个 认知过程。如果在不同的PFC电路中影响不同的机制，则有益的治疗方法 一个人可能无效甚至不利于另一个。多年来，我们研究了慢性应激诱导的 内侧PFC和轨道额皮质（OFC）的认知障碍使用不同的应力范式，但 我们从未直接比较这些子区域。但是，我们观察到信号传导的差异 机制和功能可塑性表明它们对慢性应激的反应可能有所不同。我们有 还可以看出，慢性不可预测的压力（CUS）在两个区域都会引起认知缺陷。因此，我们现在将 在此提案中利用CUS进行竞争续约直接比较和对比电路级失调 MPFC和OFC中CU引起的潜在认知障碍。在四个特定目标中，我们将调查 通过评估与压力相关的这些区域中介导的不同行为的变化来通过评估效应的普遍性 相关的精神疾病。我们将研究MPFC和OFC传入诱发反应的差异变化， 然后使用光遗传学直接操纵这些途径的功能可塑性，以确定是否看到了变化 在压力之后，应有压力引起的认知缺陷，如果相反，则具有治疗性。我们会的 研究信号转导和结构解剖可塑性的研究差异，这些差异可能是差异的基础 MPFC和OFC中CU引起的功能响应的变化。在AIM 1中，我们将评估 通过测量应力诱导的电气变化，MPFC和OFC的功能可塑性 通过刺激中腹丘脑和腹海马的传入输入引起的反应 MPFC，从中型丘脑和基底外侧杏仁核到OFC。在AIM 2中，我们将使用Opto- 在这些相同电路中直接增强或衰减传入的诱发反应的遗传学 关于MPFC和OFC中介导的行为。我们预测，MPFC和 OFC中的增强反应将模仿压力的影响，而在每个方面都会引起相反的效果 区域将有益于挽救压力动物的CUS引起的认知缺陷。在AIM 3中，我们将评估 压力后PFC锥体细胞上树突状复杂性和脊柱密度的变化，并测试新的 脊柱形成在光遗传学诱导的可塑性的作用中。在AIM 4中，我们将测试 MPFC和OFC中与塑性相关的信号通路。我们预测CUS会衰减PI3K-AKT MPFC中的信号传导并减轻OFC中的JAK信号传导。我们预测这些缺陷将通过光电恢复 遗传诱导的可塑性营救了PFC介导的认知。通过揭示应力失调PFC的失调 电路介导执行功能，这些结果可能会为改善治疗的新的针对性的策略提供信息。