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: 10172980
• 负责人: James A Bibb
• 金额: $ 37.13万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10172980
• 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.

应激和恢复过程中的内源性兴奋和代谢PKA调节 焦虑和抑郁等精神障碍是导致肥胖的主要健康问题， 在所有发病率和死亡率中占很大比例。这些复杂的疾病可能被视为恶性疾病- 大脑回路中出现的适应。为了实现更有效的治疗，更好的机制 需要了解大脑回路的整合。通常，动机行为和执行功能 需要处理感觉触发的兴奋性神经传递和分配情绪背景。这 发生在纹状体，在那里皮质多巴胺能和中脑多巴胺能输入会聚以介导脑 例如奖励和压力反应。纹状体功能障碍与许多疾病的病因广泛相关 精神疾病例如，压力引起的与奖励相关的大脑区域活动的改变，如 脑桥核（NAc）与抑郁症的病理生理学有关。深入了解机制， 谷氨酸和多巴胺神经传递整合在NAc中， 或涉及新的药物靶点和治疗策略。在这里，我们引入一种新的信令， 我们假设这种机制是由纹状体多巴胺能和多巴胺能信号控制的， PKA活性的协同调节。具体来说，我们的初步数据表明，谷氨酸盐控制 RII-β（RIIb）调节亚基被Cdk 5组成性磷酸化，然后直接影响PKA D1型多巴胺受体通过第二PKA依赖性自磷酸化机制激活。我们 假设这种独特的机制介导纹状体可塑性和对压力的行为反应， 慢性压力会导致这一机制的适应不良，因此谷氨酸和多巴胺信号传导被抑制。 解偶联和PKA信号传导失调。我们进一步假设，这种机制可能是针对 改善纹状体可塑性和行为恢复力。为了追求这个新的前提，我们建议1）研究 研究RIIb/PKA的调控机制，探索RIIb/PKA的体内外下游效应子; 2）研究RIIb/PKA在RIIb/PKA中的作用 腹侧纹状体神经元兴奋性和突触可塑性的磷酸化和3）研究这种调节 机制的急性和慢性压力，并确定它如何有助于行为反应的压力。 这些研究将产生重要的信息，整合大脑回路的机制，以及它们是如何被激活的。 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。 焦虑和抑郁等精神疾病以及如何更有效地治疗这些疾病。