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，慢性压力通常会导致行为和生理上的改变，导致适应不良，从而加剧医学和精神疾病。钙刺激的腺苷酸环化酶（ACs）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，我们制造了钙刺激腺苷酸环化酶VIII型（AC8）缺乏的小鼠。AC8 KO小鼠表现出钙刺激的海马体AC活性受损，海马CA1长期抑制（LTD）受损，应激后CA1区域CREB无法激活。与这些海马功能的生化和电生理改变一致，AC8 KO小鼠没有表现出应激性学习。在本提案中，我们试图确定AC8在应激诱导信号转导中的作用，这些信号对海马LTD和行为改变很重要。整合分子遗传学，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，允许在海马CA1区域调节AC8的表达；2)确定在大脑发育和应激过程中何时需要AC8激活来传递应激性学习；3)判断神经元功能和行为的改变是否源于缺乏AC8的CA1神经元对糖皮质激素作用的抵抗。这些研究的发现将作为提出调节AC8作用作为人类精神和慢性应激性疾病的新治疗方法的基础。

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.