Adenylyl Cyclases in the Behavioral Response to Stress

我们实验室的长期目标是阐明参与应激行为和神经内分泌反应的分子途径，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的改变，导致不适应，从而加剧医学和精神疾病。钙刺激的腺苷酸环化酶(Acs)是神经生理调节的关键控制点，参与神经功能的活性依赖性改变。为了确定参与应激反应的分子途径，我们产生了钙刺激的腺酰环化酶III型(AC8)缺陷小鼠(KO)。AC8KO小鼠表现出钙刺激的海马区AC活性受损，海马CA1区长期抑郁(LTD)受损，以及应激后未能激活CA1区CREB。AC8KO小鼠没有表现出应激诱导的学习，这与海马区功能的这些生化和电生理变化相一致。在这项提案中，我们试图确定AC8在应激诱导的信号转导中的作用，该信号对海马区LTD和行为改变至关重要。结合分子遗传学、电生理学和行为学的方法，我们将1)开发一个体内转基因系统，允许AC8在海马区CA1区的调控表达；2)确定在脑发育和应激暴露期间，AC8的激活是何时需要传递应激诱导的学习；3)确定神经元功能和行为的改变是否源于AC8缺乏的CA1神经元对糖皮质激素的影响的抵抗。这些研究中的发现将作为建议调整AC8作用的基础，作为治疗人类精神和慢性应激产生的疾病的一种新方法。

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.