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疾病的一个因素，这些疾病都与前额皮质（PFC）失调有关， 以及 PFC 介导的执行功能受损。目前的治疗方法不足，并且残留认知 症状常常持续存在。这可能是因为多个 PFC 电路失调，扰乱了多个 认知过程。如果不同的 PFC 电路影响不同的机制，则有益的治疗方法 对一个人来说可能无效，甚至对另一个人有害。多年来，我们研究了慢性压力引起的 使用不同的压力范式发现内侧 PFC 和眶额皮质 (OFC) 的认知障碍，但是 我们从未直接比较过这些次区域。然而，我们观察到信号传导方面的差异 机制和功能可塑性表明它们对慢性压力的反应可能不同。我们有 还发现慢性不可预测压力（CUS）会导致这两个区域的认知缺陷。因此，我们现在将 在本提案中利用 CUS 进行竞争更新，以直接比较和对比电路级失调 CUS 在 mPFC 和 OFC 中引起潜在的认知障碍。我们将围绕四个具体目标进行研究 通过评估这些区域中与压力相关的不同行为的变化来评估影响的普遍性 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中的功能可塑性，以确定是否观察到变化 压力后的缓解足以缓解压力引起的认知缺陷，如果对抗压力则具有治疗作用。我们会 研究可能是差异背后的信号转导和结构解剖可塑性的差异 CUS 引起 mPFC 和 OFC 功能反应的变化。在目标 1 中，我们将评估以下方面的差异： 通过测量应力引起的电变化，研究 CUS 后 mPFC 和 OFC 的功能可塑性 刺激来自内侧丘脑和腹侧海马的传入输入而引起的反应 mPFC，以及从内侧丘脑和基底外侧杏仁核到 OFC。在目标 2 中，我们将使用光电 遗传学来测试在这些相同回路中直接增强或减弱传入诱发反应的效果 mPFC 和 OFC 介导的行为。我们预测 mPFC 和 增强 OFC 的反应将模仿压力的影响，而在每个区域引起相反的效果 该区域将有助于挽救应激动物中由 CUS 引起的认知缺陷。在目标 3 中，我们将评估 压力后 PFC 锥体细胞树突复杂性和棘密度的变化，并测试新的作用 光遗传学诱导可塑性影响中的脊柱形成。在目标 4 中，我们将测试以下角色的不同作用： mPFC 和 OFC 中与可塑性相关的信号通路。我们预测 CUS 将减弱 PI3K-Akt mPFC 中的信号传导并减弱 OFC 中的 JAK 信号传导。我们预测这些赤字将通过光电来恢复 遗传诱导的可塑性可以挽救 PFC 介导的认知。通过揭示压力如何使 PFC 失调 调节执行功能的回路，这些结果可能会为改善治疗提供新的、有针对性的策略。