Regulation of Stress-Induced Cortical Monoamine Activity

描述(由申请人提供)：对压力的反应不同可能是精神疾病和社交障碍的基础或加重。在应激期间，大脑杏仁核内的活动似乎改变了内侧前额叶皮质(MPFC)的单胺类神经递质活性，mPFC内的神经传递参与了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的神经传递还不是很清楚。此外，单胺5-羟色胺在应激期间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单胺活动，并检查这种神经活动的行为后果。预计这些知识将提供对调节应激的神经回路的更多了解，并促进旨在设计药物干预以调节精神或社会障碍的应激反应的研究。 这项拟议的研究将首先绘制出杏仁核刺激mPFC中单胺活动的大脑通路，在大鼠模型中使用活体计时电流测量法。这将涉及对麻醉大鼠杏仁核的电刺激，在钠通道阻滞剂利多卡因短暂阻断通路之前和之后，mPFC记录的结果是单胺释放。随后使用类似方法的实验将确定神经激素促肾上腺皮质激素释放因子(CRF)在应激期间CRF增加时是否参与激活这些途径，CRF是杏仁核输出神经元使用的主要神经递质。具体地说，CRF阻滞剂对杏仁核引起的mPFC单胺释放变化的影响将被评估。预计结果将确定靶向CRF在大脑中的释放或传递是否将为药物治疗提供有用和可行的方向。最后的实验将使用微透析在自由活动的大鼠中评估mPFC内5-羟色胺能活动的药理学变化(包括增加和减少)是否改变了对急性应激源的行为反应。这些积极的发现将提供关于5-羟色胺在压力中的作用的基本信息，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.