Actions of CRF on 5-HT Pathways in Mood Regulation

描述(申请人提供)：应激途径失调是神经精神疾病中最普遍的症状。精神分裂症和自闭症患者在应激经历中表现出高度的应激敏感性和加重的症状。长期以来，人们一直认为，过度活跃的应激系统将应激失调与神经精神疾病联系在一起，这促进了药物对治疗靶点的追求，包括CRF受体-1(CRFR1)的拮抗剂，从而削弱这种反应。利用CRF受体-2(CRFR2)缺陷小鼠，在应激过程中，正常应激神经回路的破坏阻止了体内平衡机制的招募和促进，我们已经证明，无法适应应激具有严重的后果，包括产生5-羟色胺的中缝核团内的细胞死亡，适应不良的生理和行为应激反应，以及增加持之以恒的行为。CRFR2基因缺陷的小鼠表现出促炎症细胞因子及其下游效应因子的增加，包括促凋亡的caspase，小胶质细胞浸润的标志物增加，CRF结合蛋白(CRF-BP)水平增加20倍。这些改变可能导致这些小鼠的细胞死亡和应激敏感表型增加。因此，我们假设，细胞因子诱导的CRF-BP增加阻止CRF激活突触后CRFR1，在中缝产生反直觉的低活性反应，并抑制正常应激诱导的5-羟色胺能神经传递，这是促进觉醒和应对行为所必需的。

DESCRIPTION (provided by applicant): Stress pathway dysregulation is the most pervasive symptom in neuropsychiatric disease. Patients with schizophrenia and autism show heightened stress sensitivity and exacerbated symptoms during stress experience. It has long been postulated that a hyperactive stress system links stress dysregulation to neuropsychiatric disease, which has promoted the pharmaceutical pursuit of therapeutic targets including antagonists of the CRF receptor-1 (CRFR1) that would blunt this response. Utilizing CRF receptor-2 (CRFR2) deficient mice in which disruption of normal stress neurocircuitry prevents the recruitment and promotion of homeostatic mechanisms during stress, we have demonstrated that an inability to adapt to stress has severe consequences, including cell death within the 5-HT producing raphe nucleus, maladaptive physiological and behavioral stress responses, and increased perseverative behaviors. CRFR2-deficient mice showed elevated proinflammatory cytokines and their downstream effectors including proapoptotic caspases, increased markers of microglia infiltration, and a 20-fold increased level of the CRF binding protein (CRF-BP). These alterations likely contribute to the increased cell death and stress-sensitivity phenotype in these mice. Therefore, we hypothesize that cytokine-induced increases in CRF-BP prevent CRF from activating postsynaptic CRFR1, producing a counterintuitive hypoactive response in the raphe and an inhibition of the normal stress-induced 5-HTergic neurotransmission necessary to promote arousal and coping behaviors.