Mechanisms of remodeling circuit connectivity after traumatic brain injury

脑外伤后回路连接重塑机制

• 批准号: 8885321
• 负责人: DAVID F MEANEY
• 金额: $ 34.45万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8885321
• 关键词: Algorithms; Animals; Brain; Brain Diseases; CREB1 gene; Calcineurin; Calcium; Cause of Death; Cessation of life; Cognitive deficits; Data; Dimensions; Disease; Equilibrium; Genetic Transcription; Goals; Human; Image; In Vitro; Individual; Injury; Lead; Life; Maintenance; Measures; Mechanics; Mediating; Mitochondria; Modeling; N-Methyl-D-Aspartate Receptors; Nerve Degeneration; Neurons; Outcome; Pathway interactions; Patients; Pattern; Pharmacy (field); Phosphorylation; Population; Pre-Clinical Model; Protocols documentation; Public Health; Receptor Activation; Recovery; Relative (related person); Role; Signal Pathway; Signal Transduction; Structure; Testing; Therapeutic; Time; Trauma; Traumatic Brain Injury; Traumatic Brain Injury recovery; Work; awake; brain circuitry; calmodulin-dependent protein kinase II; cognitive recovery; disability; improved; in vivo; injured; innovation; insight; mitochondrial permeability transition pore; nervous system disorder; neural circuit; neurobehavior; novel; pre-clinical; public health relevance; reconstruction; relating to nervous system; repaired; response

 DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) remains a major public health problem and is on pace to become the third leading cause of death and disability in the world population by 2020. Although we know that both neuronal degeneration and cognitive deficits are common features of human TBI, we are only beginning to appreciate an entirely new dimension of the disease: how brain networks change immediately after injury, and how cognitive recovery may depend critically on rebuilding these networks. The broad, long-term goal of our work identifies the fundamental mechanisms on how neural activity and intracellular signaling pathways together contribute to rebuilding a circuit after TBI. To our knowledge, our preliminary data is the first evidence showing how the structure of neural circuits changes after TBI, and the first observation on how combining circuit activation with pharmaceutics can together rebuild a network. We build on our preliminary data and propose the following aims: Specific Aim 1: To examine mechanisms of neuronal disconnection from a network after mechanical injury in vitro and in vivo. Specific Aim 2: To determine mechanisms for the activity-induced re-integration of neurons into an injured microcircuit over time, extending this into measuring circuit remodeling in awake, behaving animals subjected to TBI. Our general hypotheses are: (a) Connectivity directly influences neuronal disconnection from a network following injury, as well as network recovery (b) neuronal re-integration into the network is mediated by calcineurin activity and CREB-phosphorylation, (c) neuronal disconnection is mediated by mitochondrial signaling, and (d) prolonged circuit activation, in combination with pharmaceutics, can optimally control the reconstruction of networks. Impact: Knowing the mechanisms for remodeling neuronal connections in a circuit over time after TBI will give us insight into treatments protecting the network structure. Once the mechanisms for remodeling circuitry in the living brain after TBI are better understood, we envision testing therapies in preclinical TBI models within the next 5-10 years. Broadly, we believe this work will shift the therapeutic focus away from reducing neuronal death and towards approaches to rebuild functional circuits after TBI.