Adenylyl Cyclases in the Behavioral Response to Stress

我们实验室的长期目标是阐明参与行为和神经内分泌应激反应的分子途径，并确定这些机制如何影响发育和衰老过程中的认知变化。重要的是，慢性压力往往会导致行为和生理上的改变，这些改变是适应不良的，会加剧医学和精神疾病。 钙离子刺激的腺苷酸环化酶（AC）为神经元生理调节提供了一个关键的控制点，并与神经功能的活动依赖性改变有关。 为了确定参与应激反应的分子途径，我们产生了钙刺激腺苷酸环化酶VIII型（AC 8）缺陷（KO）小鼠。 AC 8 KO小鼠表现出海马中钙刺激的AC活性受损，海马CA 1长期抑郁症（LTD）受损，以及应激后CA 1区CREB激活失败。 与海马功能中的这些生物化学和电生理学改变一致，AC 8 KO小鼠未表现出应激诱导的学习。 在这个提议中，我们试图确定AC 8在海马LTD和行为改变的重要应激诱导信号转导中的作用。 结合分子遗传学、电生理学和行为学方法，我们将1）开发一种体内转基因系统，该系统允许AC 8在海马CA 1区内的调节表达; 2）确定在脑发育和暴露于应激期间何时需要AC 8活化来赋予应激诱导的学习; 3）确定神经元功能和行为的改变是否由AC 8缺陷的CA 1神经元对糖皮质激素作用的抗性引起。 这些研究的发现将作为提出调节AC 8作用的基础，作为人类精神和慢性应激产生的疾病的新治疗方法。

The long-term goals of our laboratory are to elucidate the molecular pathways involved in the behavioral and neuroendocrine responses to stress, and to determine how these mechanisms affect cognitive changes during development and aging. Importantly, chronic stress often results in alterations in behavior and physiology that are maladaptive, exacerbating both medical and psychiatric diseases. The calcium-stimulated adenylyl cyclases (ACs) provide a critical control point for the regulation of neuronal physiology, and have been implicated in activity-dependent alterations in neural function. To define the molecular pathways involved in the response to stress, we generated mice deficient (KO) in calcium-stimulated adenylyl cyclase type VIII (AC8). AC8 KO mice demonstrate compromise in calcium-stimulated AC activity in the hippocampus, impaired hippocampal CA1 long-term depression (LTD), and failure to activate CREB in the CA1 region after stress. Consistent with these biochemical and electrophysiological alterations in hippocampal function, AC8 KO mice do not demonstrate stress- induced learning. In this proposal, we seek to define the role of AC8 in transduction of stress-induced signals important for hippocampal LTD and alterations in behavior. Integrating molecular genetic, electrophysiological, and behavioral approaches, we will 1) develop an in vivo transgenic system that allows regulated expression of AC8 within the CA1 region of the hippocampus; 2) determine when during brain development and exposure to stress AC8 activation is required to impart stress- induced learning; 3) determine whether the alterations in neuronal function and behavior arise from resistance of CA1 neurons deficient in AC8 to the effects of glucocorticoids. The findings in these studies will serve as the basis for proposing modulation of AC8 action as a novel therapeutic approach to human psychiatric and chronic stress-generated disorders.