Regulation of Stress-Induced Cortical Monoamine Activity

描述（由申请人提供）：压力反应的变化可能导致或加剧精神疾病和社会障碍。在应激过程中，大脑杏仁核内的活动似乎会改变内侧前额叶皮层（mPFC）中的单胺神经递质活性，mPFC内的神经传递有助于与应对应激情况相关的认知和内分泌过程。目前，杏仁核如何改变mPFC中的神经传递尚不清楚。此外，在应激过程中，单胺5-羟色胺在mPFC中的具体作用尚不清楚。该项目旨在确定杏仁核的神经输出如何整合到其他大脑区域以改变mPFC单胺活性，并检查这种神经活动的行为后果。预计这些知识将提供更好的理解的神经回路认为调解压力，并推进研究，旨在设计药物干预，以调节精神或社会障碍的压力反应。 拟议的研究最初将在大鼠模型中使用体内计时电流法绘制杏仁核刺激mPFC中单胺活性的大脑通路。这将涉及对麻醉大鼠杏仁核的电刺激，在用钠通道阻滞剂利多卡因短暂阻断通路之前和之后记录mPFC产生的单胺释放。随后的实验，使用类似的方法将确定参与的神经激素促肾上腺皮质激素释放因子（CRF）在激活这些途径的CRF增加在压力，是一个主要的神经递质所使用的杏仁核的输出神经元。具体而言，将评估CRF阻滞剂对杏仁核引起的mPFC单胺释放变化的影响。预期结果将确定靶向CRF在脑中的释放或传递是否将为药物治疗提供有用且可行的方向。最后的实验将评估是否药理学改变（增加和减少）的mPFC内的胆碱能活性改变行为反应对急性应激源，使用微透析在自由活动的大鼠。这里的积极发现将提供有关血清素在压力中的作用的重要信息，并为药物治疗的“微调”提供选择，以限制压力反应和帮助康复。

DESCRIPTION (provided by applicant): Variation in responses to stress can underlie or exacerbate psychiatric illness and social disorders. During stress, activity within the amygdala of the brain appears to alter monoamine neurotransmitter activity in the medial prefrontal cortex (mPFC), and neurotransmission within the mPFC contributes to the cognitive and endocrine processes associated with coping in stressful situations. Currently, how the amygdala alters neurotransmission in the mPFC is not well understood. Also, the specific role of the monoamine serotonin in the mPFC during stress is unclear. This project aims to determine how the neural output from the amygdala is integrated in other brain regions to alter mPFC monoamine activity, and also examine the behavioral consequences of this neural activity. It is anticipated that such knowledge will provide greater understanding of the neural circuitry thought to mediate stress, and advance research directed at designing pharmacological interventions to modulate stress responsiveness in psychiatric or social disorders. The proposed studies will initially map out brain pathways by which the amygdala stimulates monoamine activity in the mPFC, using in vivo chronoamperometry within a rat model. This will involve electrical stimulation of the amygdala in anaesthetized rats, with resultant monoamine release recorded from the mPFC before and after transient blockade of pathways with the sodium channel blocker lidocaine. Subsequent experiments using a similar methodology will determine the involvement of the neurohormone corticotrophin releasing factor (CRF) in activating these pathways as CRF increases during stress, and is a major neurotransmitter used by the output neurons of the amygdala. Specifically, the effects of a CRF blocker on amygdala-elicited changes in mPFC monoamine release will be assessed. It is expected that results will determine whether targeting CRF release or transmission in the brain will provide a useful and feasible direction for pharmaceutical therapeutics. The final experiments will assess whether pharmacological alterations (both increases and decreases) in serotoninergic activity within the mPFC change behavioral responsiveness towards an acute stressor, using microdialysis in freely moving rats. Positive findings here will provide essential information as to the role of serotonin in stress, and offer options for the 'fine-tuning' of pharmacological therapeutics to limit stress responsiveness and aid rehabilitation.