Excitatory and Metabotopic Regulation of PKA in Stress and Resilience

PKA 在压力和恢复力中的兴奋性和代谢调节

• 批准号: 10397651
• 负责人: James A Bibb
• 金额: $ 6.28万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-06 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10397651
• 关键词: Address; Adenylate Cyclase; Affect; Anxiety; Behavior; Behavioral; Brain; Brain region; Catecholamine Receptors; Cells; Chronic stress; Complex; Corpus striatum structure; Coupled; Cyclic AMP; Cyclic AMP Receptors; Cyclic AMP-Dependent Protein Kinases; DNA Primase; Data; Decision Making; Detection; Disease; Dopamine; Dopamine Receptor; Emotional; Etiology; Functional disorder; GTP-Binding Proteins; Glutamates; Goals; Health; Holoenzymes; In Vitro; Light; Link; Major Depressive Disorder; Mediating; Mental Depression; Mental disorders; Midbrain structure; Molecular; Moods; Morbidity - disease rate; Motivation; Motor; Neurobiology; Neuronal Plasticity; Neurons; Nucleus Accumbens; Peptides; Perception; Pharmacotherapy; Phosphorylation; Physiological; Process; Property; Regulation; Research; Rewards; Role; Sensory; Signal Transduction; Stimulus; Stress; Symptoms; Synaptic plasticity; Techniques; Testing; Ventral Striatum; acute stress; behavioral response; biological adaptation to stress; brain circuitry; cell type; cost; effective therapy; executive function; experience; improved; in vivo; insight; mortality; motivated behavior; neuronal excitability; neurophysiology; neuropsychiatric disorder; neurotransmission; new therapeutic target; novel; resilience; response; stress resilience; synaptic function; treatment strategy

STRIATAL EXCITATORY AND METABOTROPIC PKA REGULATION IN STRESS AND RESILIENCE Mental disorders such as anxiety and depression are major health concerns that contribute unabated to a large portion of all morbidity and mortality. These complex disorders may be viewed as mal- adaptations that arise in brain circuitry. In order to achieve more effective treatments, better mechanistic understanding of brain circuitry integration is needed. Normally, motivated behaviors and executive functions require processing of sensory-triggered excitatory neurotransmission and assignment of emotional context. This occurs in the striatum where cortical glutamatergic and midbrain dopaminergic inputs converge to mediate brain functions such as reward and stress responses. Striatal dysfunction is broadly implicated in the etiology of many mental illnesses. For example, stress-induced alterations in the activity of reward-related brain regions, such as the nucleus accumbens (NAc), are linked to the pathophysiology of depression. Insight into the mechanisms by which glutamate and dopamine neurotransmission are integrated within the NAc may shed light on some causes of mental illness, or implicate new drug targets and treatment strategies. Here, we introduce a new signaling mechanism which we hypothesize is controlled by striatal glutamatergic and dopaminergic signaling to allow concerted regulation of PKA activity. Specifically, our preliminary data indicates that glutamate controls constitutive phosphorylation of the RII-beta (RIIb) regulatory subunit by Cdk5, which then directly affects PKA activation by D1-type dopamine receptors via a second PKA-dependent auto-phosphorylation mechanism. We hypothesize that this unique mechanism mediates striatal plasticity and behavioral responses to stress and that chronic stress can cause mal-adaptations in this mechanism so that glutamate and dopamine signaling are uncoupled and PKA signaling is dysregulated. We further hypothesize that this mechanism may be targeted to improve striatal plasticity and behavioral resilience. To pursue this novel premise, we propose to 1) study the regulation of RIIb/PKA and explore downstream effectors in vitro and in vivo; 2) study the role of RIIb/PKA phosphorylation in ventral striatal neuronal excitability and synaptic plasticity and 3) study the regulation of this mechanism by acute and chronic stress, and determine how it contributes to behavioral responses to stress. These studies will yield important information on the mechanisms that integrate brain circuitry and how they are affected by stress. Thus, we will better understand some of the basis by which stress may contribute to complex mental disorders such as anxiety and depression and how they may be more effectively treated.

纹状体兴奋性和代谢性PKA在应激和回弹中的调节 焦虑和抑郁等精神障碍是导致 有增无减，占所有发病率和死亡率的很大一部分。这些复杂的疾病可能被视为精神错乱。 在大脑回路中出现的适应。为了实现更有效的治疗，更好的机械化 我们需要了解大脑回路的整合。正常情况下，动机行为和执行功能 需要处理感官触发的兴奋性神经传递和分配情绪背景。这 发生在纹状体，皮质谷氨酸能和中脑多巴胺能输入汇聚到中枢脑 奖励和压力反应等功能。纹状体功能障碍广泛地与许多 精神疾病。例如，压力导致与奖励相关的大脑区域的活动发生变化，如 伏隔核(NAC)与抑郁症的病理生理学有关。对机制的洞察 NAC中谷氨酸和多巴胺神经传递的整合可能有助于解释某些原因 或牵涉到新的药物靶点和治疗策略。在这里，我们介绍一种新的信令 我们假设的机制是由纹状体谷氨酸和多巴胺能信号控制的 对PKA活动的协同调控。具体地说，我们的初步数据表明，谷氨酸控制 CDK5对RII-β(RIIb)调节亚基的组成性磷酸化，进而直接影响PKA D1型多巴胺受体通过第二个依赖PKA的自动磷酸化机制激活。我们 假设这种独特的机制调节纹状体可塑性和对应激的行为反应，并且 慢性应激可导致这种机制的不良适应，因此谷氨酸和多巴胺信号转导 解偶联，PKA信号转导失调。我们进一步假设，该机制的目标可能是 提高纹状体的可塑性和行为弹性。为了追求这一新的前提，我们建议1)研究 RIIb/PKA的调控及其在体内外的下游效应2)RIIb/PKA的作用研究 腹侧纹状体神经元兴奋性和突触可塑性的磷酸化及其调控研究 通过急性和慢性应激的机制，并确定它如何对应激的行为反应作出贡献。 这些研究将提供关于整合大脑回路的机制以及它们是如何形成的重要信息 受到压力的影响。因此，我们将更好地理解压力可能导致复杂性的一些基础 焦虑和抑郁等精神障碍以及如何更有效地治疗它们。