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在压力和弹性中调节 诸如焦虑和抑郁之类的精神障碍是主要的健康问题 不减少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Mal- 在脑电路中出现的适应性。为了获得更有效的治疗，更好的机理 需要了解脑电路整合。通常，有动力的行为和执行职能 需要处理感官触发的兴奋性神经传递和情感环境的分配。这 发生在纹状体中，皮质谷氨酸能和中脑多巴胺能输入融合到大脑 奖励和压力反应等功能。纹状体功能障碍广泛地与许多人的病因有关 精神疾病。例如，压力引起的与奖励相关大脑区域活动的改变，例如 伏隔核（NAC）与抑郁症的病理生理有关。深入了解该机制 在NAC中集成了谷氨酸和多巴胺神经传递可能会揭示某些原因 精神疾病，或暗示新药物靶标和治疗策略。在这里，我们介绍了一个新的信号 我们假设的机制由纹状体谷氨酸能和多巴胺能信号控制 PKA活动的协同调节。具体而言，我们的初步数据表明谷氨酸控制 CDK5的RII-BETA（RIIB）调节亚基的组成型磷酸化，然后直接影响PKA D1型多巴胺受体通过第二个PKA依赖性自身磷酸化机制激活。我们 假设这种独特的机制介导了纹状体可塑性和对压力的行为反应，并且 慢性应激会在这种机制中引起恶性适应，以使谷氨酸和多巴胺信号传导是 未偶联和PKA信号传导失调。我们进一步假设该机制可能针对 提高纹状体可塑性和行为弹性。为了追求这个新颖的前提，我们建议1）研究 调节RIIB/PKA并在体外和体内探索下游效应子； 2）研究RIIB/PKA的作用 腹侧纹状体神经元兴奋性和突触可塑性中的磷酸化，3）研究该调节 急性和慢性应激的机制，并确定其如何促进对压力的行为反应。 这些研究将产生有关整合大脑电路及其如何结合的机制的重要信息 受压力的影响。因此，我们将更好地理解压力可能有助于复杂的一些基础 焦虑和抑郁等精神障碍以及如何更有效地治疗它们。