Compartmentalization of Cyclic Nucleotide Signaling in the Ventral Hippocampus

社会缺陷是一些神经精神疾病的关键特征，如自闭症、精神分裂症和创伤后应激障碍，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、从社会中获取资源和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会行为时，他经常会被排斥。社会孤立使身心健康恶化，并增加死亡率，特别是老年人和精神病患者的死亡率。更糟糕的是，社会孤立进一步损害了随后的社会行为，从而形成了恶性循环。尽管适当的社会行为对于在一个人的环境中茁壮成长至关重要，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知之甚少。这阻碍了社会缺陷有效治疗方法的发展。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的老鼠不能正确地参与社会互动，也不能形成涉及社会线索的长期记忆。PDE11A几乎只在大脑的一个小区域腹侧海马中表达，但在背侧海马中也有低水平的表达。基于这种分布，我们假设PDE11A4主要通过控制腹侧海马体中的环核苷酸来调节社会行为。在这三个目标中，我们采取了一种综合的实验方法，将体内遗传操作与体内行为测试以及体外分子和生化终点相结合。在具体目标1中，我们将确定PDE11A调节社会行为的位置（VHIPP与背侧HIPP）和时间（成年期与青春期）。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Specific Aim 3中，我们将定义控制PDE11A亚细胞定位的信号。这些创新的研究将为复杂社会行为的基本机制以及PDE11A在大脑中的功能和调节提供急需的见解。靶向PDE11A可能是一种选择性地恢复调节社会行为的特定大脑区域的环核苷酸信号的方法，而不会影响其他地方的信号。这可能会减轻社会赤字，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.