Compartmentalization of Cyclic Nucleotide Signaling in the Ventral Hippocampus

描述（由申请人提供）：腹侧海马中环核苷酸信号传导的区室化社交缺陷是多种神经精神疾病的关键特征，例如自闭症、精神分裂症和创伤后应激障碍（PTSD），但目前还没有药物可以治疗这些症状。如果没有可接受的社会行为，我们吸引配偶、从社会获取资源以及建立安全环境的能力就会受到严重损害。当一个人缺乏适当的社交行为时，他常常会受到排斥。社会孤立会恶化身心健康并增加死亡率，尤其是老年人和精神病患者。更糟糕的是，社会孤立进一步损害了后续的社会行为——从而形成恶性循环。尽管适当的社会行为对于一个人在环境中的繁荣至关重要，但人们对控制社会行为的分子机制或社会经历如何改变这些信号通路了解甚少。这阻碍了针对社交缺陷的有效疗法的开发。为了开发有效的治疗方法，我们需要更好地了解社会缺陷背后的分子机制。 磷酸二酯酶11A（PDE11A）是一种分解cAMP和cGMP的酶，PDE11A可能是调节社会行为的重要分子机制。我们已经证明，缺乏 PDE11A 的小鼠无法正确参与社交互动，也无法形成涉及社交线索的长期记忆。 PDE11A 几乎只在大脑中称为腹侧海马的小区域中表达，但在背侧海马中也有少量表达。基于这种分布，我们假设 PDE11A4 主要通过控制腹侧海马中的环核苷酸来调节社会行为。在这三个目标中，我们采用综合实验方法，将体内遗传操作与体内行为测试以及离体分子和生化终点相结合。在具体目标 1 中，我们将确定 PDE11A 在何处（VHIPP 与背侧 HIPP）以及何时（成年期与青春期）调节社会行为。在具体目标 2 中，我们将确定社会隔离如何改变 PDE11A 区隔，从而损害随后的社会行为。在具体目标 3 中，我们将定义控制 PDE11A 亚细胞定位的信号。这些创新研究将为复杂社会行为的基本机制以及大脑中 PDE11A 的功能和调节提供急需的见解。靶向 PDE11A 可能是一种选择性恢复特定大脑区域中调节社会行为的环核苷酸信号传导的方法，而不影响其他地方的信号传导。这可以缓解社会缺陷，而不会造成不必要的副作用。

DESCRIPTION (provided by applicant): Compartmentalization of Cyclic Nucleotide Signaling in the Ventral Hippocampus Social deficits are key features of several neuropsychiatric disorders, such as autism, schizophrenia, and PTSD, yet no medicines are available to remedy these symptoms. Without acceptable social behaviors, our ability to attract a mate, acquire resources from society, and establish a safe/secure environment is severely compromised. When an individual lacks proper social behaviors, one is often ostracized. Social isolation worsens mental and physical health and increases mortality, particularly among the elderly and mentally ill. To make matters worse, social isolation further impairs subsequent social behaviors-thus, creating a vicious cycle. Despite the fact that appropriate social behaviors are vital to thriving in one's environment, little is understood of the molecular mechanisms that control social behaviors or how social experiences modify these signaling pathways. This hampers the development of effective therapeutics for social deficits. To develop effective treatments, we need to better understand the molecular mechanisms that underlie social deficits. Phosphodiesterase 11A (PDE11A) is an enzyme that breaks down cAMP and cGMP, and PDE11A may be an important molecular mechanism for regulating social behavior. We have shown that mice that lack PDE11A do not properly engage in social interactions and fail to form long-term memories involving social cues. PDE11A is almost exclusively expressed in a small area of the brain called the ventral hippocampus, but there is also a low level of expression in the dorsal hippocampus. Based on this distribution, we hypothesize that PDE11A4 regulates social behavior primarily by controlling cyclic nucleotides in the ventral hippocampus. Across the 3 aims, we take an integrative experimental approach by coupling in vivo genetic manipulations with in vivo behavioral tests as well as ex vivo molecular and biochemical endpoints. In Specific Aim 1, we will determine where (VHIPP vs. dorsal HIPP) and when (adulthood vs. adolescence) PDE11A modulates social behaviors. In Specific Aim 2, we will identify how social isolation modifies PDE11A compartmentalization and, thus, impairs subsequent social behaviors. In Specific Aim 3, we will define the signals that control the subcellular localization of PDE11A. These innovative studies will provide much needed insight into the fundamental mechanisms of complex social behavior as well as the function and regulation of PDE11A in the brain. Targeting PDE11A may be a way to selectively restore cyclic nucleotide signaling in a specific brain region that regulates social behaviors, without affecting signaling elsewhere. This may relieve social deficits without causing unwanted side effects.