Compartmentalization of Cyclic Nucleotide Signaling in the Ventral Hippocampus

腹侧海马环核苷酸信号传导的区室化

基本信息

批准号：
9270603
负责人：
Michy Patrice Kelly
金额：
$ 33.38万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-08 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9270603
关键词：
Acute Adolescence Adolescent Adult Adverse effects Affect Anterior Area Autistic Disorder Automobile Driving Binding Proteins Biochemical Brain Brain region Chronic Complex Controlled Study Coupling Cues Cyclic AMP Cyclic GMP Cyclic Nucleotides Development Diffuse Dorsal Elderly Environment Enzymes Exhibits Goals Hippocampal Formation Hippocampus (Brain)Homodimerization Impairment In Vitro Individual Inflammatory Interleukin-6 Knock-out Knockout Mice Label Length Longevity Mediating Medicine Mental Health Mentally Ill Persons Molecular Molecular Profiling Mus Mutation Nature Odors Outcome Outcome Study Partner in relationship Phosphorylation Pilot Projects Post-Translational Protein Processing Post-Traumatic Stress Disorders Primates Protein Isoforms Proteins Psyche structure Regulation Resources Schizophrenia Secure Signal Pathway Signal Transduction Social Behavior Social Controls Social Interaction Social isolation Societies Subfamily lentivirinae Symptoms System Therapeutic Tissues Transgenic Organisms Treatment Efficacy base behavior test cytokine drug discovery effective therapy experience genetic manipulation in vivo innovation insight long term memory memory recognition mortality neuropsychiatric disorder new therapeutic target phosphodiesterase 11a physical conditioning prevent public health relevance social social engagement symptom treatment trafficking

Acute Adolescence Adolescent Adult Adverse effects Affect Anterior Area Autistic Disorder Automobile Driving Binding Proteins Biochemical Brain Brain region Chronic Complex Controlled Study Coupling Cues Cyclic AMP Cyclic GMP Cyclic Nucleotides Development Diffuse Dorsal Elderly Environment Enzymes Exhibits Goals Hippocampal Formation Hippocampus (Brain)Homodimerization Impairment In Vitro Individual Inflammatory Interleukin-6 Knock-out Knockout Mice Label Length Longevity Mediating Medicine Mental Health Mentally Ill Persons Molecular Molecular Profiling Mus Mutation Nature Odors Outcome Outcome Study Partner in relationship Phosphorylation Pilot Projects Post-Translational Protein Processing Post-Traumatic Stress Disorders Primates Protein Isoforms Proteins Psyche structure Regulation Resources Schizophrenia Secure Signal Pathway Signal Transduction Social Behavior Social Controls Social Interaction Social isolation Societies Subfamily lentivirinae Symptoms System Therapeutic Tissues Transgenic Organisms Treatment Efficacy base behavior test cytokine drug discovery effective therapy experience genetic manipulation in vivo innovation insight long term memory memory recognition mortality neuropsychiatric disorder new therapeutic target phosphodiesterase 11a physical conditioning prevent public health relevance social social engagement symptom treatment trafficking

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项目摘要

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.

描述（申请人提供）：腹侧海马社会缺陷中环状核苷酸信号传导的隔室化是几种神经精神疾病的关键特征，例如自闭症，精神分裂症和PTSD，但没有药物可用于补救这些症状。没有可接受的社会行为，我们吸引伴侣，从社会那里获得资源并建立安全/安全的环境的能力受到严重损害。当一个人缺乏适当的社会行为时，经常被排斥。社会隔离会恶化精神和身体健康，并增加死亡率，尤其是在老年人和精神病患者中。更糟糕的是，社会隔离进一步损害了随后的社会行为，因此创造了一个恶性循环。尽管适当的社会行为对于在一个人的环境中蓬勃发展至关重要，但对控制社会行为的分子机制或社会经验如何改变这些信号传导途径的分子机制几乎没有理解。这阻碍了为社会缺陷的有效治疗学的发展。要开发有效的治疗方法，我们需要更好地了解社会缺陷构成的分子机制。磷酸二酯酶11A（PDE11A）是一种分解营地和CGMP的酶，PDE11A可能是调节社会行为的重要分子机制。我们已经表明，缺乏PDE11A的小鼠没有适当地参与社交互动，也没有形成涉及社会提示的长期记忆。 PDE11a几乎仅在称为腹侧海马的一小部分大脑区域中表达，但背侧海马也有低表达。基于此分布，我们假设PDE11A4主要通过控制腹侧海马中的环状核苷酸来调节社会行为。在这3个目标中，我们通过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耦合，采用一种综合实验方法。在特定的目标1中，我们将确定（Vhipp vs.背hipp）以及（成年与青春期）pde11a的何时何处调节社会行为。在特定的目标2中，我们将确定社会隔离如何改变PDE11A隔间化，从而损害随后的社会行为。在特定的目标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的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可能是一种选择性地恢复调节社会行为的特定大脑区域中循环核苷酸信号传导的方法，而不会影响其他地方的信号传导。这可能会减轻社会缺陷而不会造成不必要的副作用。