The Impact of Early Life Stress On Amygdala Circuitry And Chronic Excessive Aggression

早期生活压力对杏仁核回路和慢性过度攻击性的影响

• 批准号: 10729031
• 负责人: Jacob Nordman
• 金额: $ 44.55万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY CARBONDALE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-21 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10729031
• 关键词: Acute; Address; Adolescence; Adolescent; Adult; Aggressive behavior; American; Amygdaloid structure; Anger; Area; Behavior; Brain; Calcium; Cells; Chemosensitization; Childhood; Chronic; Complement; Data; Development; Electrophysiology (science); Fiber; Fright; Genetic; Goals; House mice; Hyperactivity; Image; Individual; Knowledge; Label; Life; Link; MK801; Measures; Medial; Mission; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; National Institute of Child Health and Human Development; Neurons; Pathologic; Pathway interactions; Post-Traumatic Stress Disorders; Predisposition; Public Health; Recurrence; Research; Research Personnel; Rewards; Role; Science; Shock; Signal Transduction; Social isolation; Societies; Stress; Synapses; System; Techniques; Testing; Therapeutic; Therapeutic Intervention; Violence; Viral; Work; antagonist; brain shape; career; cost; design; detection method; early adolescence; early life stress; experience; experimental study; foot; graduate student; improved; in vivo; innovation; insight; mouse model; neuromechanism; neuronal circuitry; neuronal excitability; new therapeutic target; novel diagnostics; novel therapeutic intervention; optogenetics; patch clamp; pediatric trauma; physical abuse; rearrest; social group; stressor; synaptogenesis; training opportunity; traumatic stress; undergraduate student; violent crime

Early life stress is a reliable predictor of aggression in the adult. For example, 38% of violent criminals are physically abused during childhood, and 28% will be rearrested for a violent crime later in life, costing the American taxpayers billions of dollars annually. Few treatment options exist, and those that do are largely ineffective and far from preventative. Given the immense danger of unchecked violence and aggression to society and its relationship to stress experienced during childhood, a more thorough examination of the underlying neural mechanisms will be essential in developing new and better therapies. Previously we showed that social isolation early in adolescence followed by acute traumatic stress late in adolescence, which we refer to as early life stress, promotes long-lasting aggression by inducing plasticity changes within medial amygdala (MeA) pathways. Weakening these pathways suppresses the aggression increase, while strengthening these pathways can simulate the effects of early life stress on aggression. Importantly, neither social isolation nor acute traumatic stress alone is sufficient to promote the long-lasting increase in excessive aggression, suggesting that these stressors drive the aggression increase through distinct but reinforcing plasticity mechanisms. The objective of this proposal will be to determine how social isolation and acute traumatic stress alter amygdala circuits to produce long-lasting attack behavior. The central hypothesis is that social isolation and acute traumatic stress during adolescence induce complementary intrinsic, synaptic, and structural plasticity changes in MeA circuits to drive excessive aggression in the adult. This will be tested in two specific aims: 1) assess the role of social isolation during adolescence on MeA circuit plasticity and long-lasting aggression after acute traumatic stress; 2) determine if early life stress promotes long-lasting increases in aggression through structural plasticity in MeA pathways. The proposed studies are conceptually and technically innovative because they use cutting-edge in vivo viral tracing, imaging, chemogenetic, and optogenetic techniques to address how social isolation and acute traumatic stress work in tandem to induce intrinsic, synaptic, and structural plasticity changes in amygdala circuits, leading to excessive aggression lasting into adulthood. The proposed research is significant because it will identify key neural mechanisms governing how early life stress shapes brain circuits to drive long-lasting excessive aggression. The long-term goal of the proposed studies is to 1) advance our understanding of how early life stress induces plasticity changes in aggression circuitry underlying long-lasting aggressive behavior, 2) improve methods for detecting changes in plasticity in mouse models of aggression, and 3) aid in the development of new drug targets for improved therapeutics for excessive and recurring aggression. The results will have an important positive impact because they will provide fundamental knowledge regarding the impact of childhood trauma on brain function, eventually leading to new diagnostic and therapeutic strategies for the management of pathological anger and aggression.

早期生活压力是成人侵略性的可靠预测指标。例如，38％的暴力罪犯是 童年时期对身体受虐待，在以后的生活中，将为暴力犯罪重新占领，使 美国纳税人每年数十亿美元。很少有治疗选择，而这样做的选择很少 无效，远非预防。考虑到不受限制的暴力和侵略的巨大危险 社会及其与儿童期间经历的压力的关系，对 潜在的神经机制对于开发新的和更好的疗法至关重要。以前我们显示了 在青春期的早期，这种社会隔离，然后是青春期后期的急性创伤压力，我们指的是 作为早期生活压力，通过诱导内侧杏仁核内的可塑性变化来促进持久的攻击 （MEA）途径。削弱这些途径会抑制攻击性的增加，同时加强这些途径 途径可以模拟早期生活压力对攻击的影响。重要的是，社会隔离也不是敏锐的 仅创伤性压力就足以促进过度侵略的持久增加，这表明 这些压力源通过不同但增强的可塑性机制提高了攻击性。这 该建议的目的是确定社会隔离和急性创伤压力如何改变杏仁核 产生持久攻击行为的电路。中心假设是社会隔离和敏锐的 青春期创伤应力引起的互补固有，突触和结构可塑性变化 在MEA电路中，以驱动成人过度侵略。这将以两个具体目的进行测试：1）评估 青春期社会隔离在MEA电路塑性上的作用和急性后的持久攻击 创伤应力； 2）确定早期生活压力是否促进了通过结构的侵略性增长 MEA途径中的可塑性。拟议的研究在概念和技术上都是创新的，因为它们 使用尖端的体内病毒追踪，成像，化学遗传学和光遗传学技术来解决社交方式 串联的隔离和急性创伤应力工作，诱导内在，突触和结构可塑性变化 在杏仁核电路中，导致过度侵略持续到成年。拟议的研究是 意义重大，因为它将确定有关早期压力如何塑造脑电路的关键神经机制 驱动持久的过度侵略。拟议研究的长期目标是1）提高我们的 了解早期压力如何引起长期侵略电路的可塑性变化 侵略性行为，2）改进检测小鼠攻击模型可塑性变化的方法， 3）有助于开发新药物靶标，以改善过度和反复侵略的治疗剂。 结果将产生重要的积极影响，因为它们将提供有关有关的基本知识 儿童创伤对脑功能的影响，最终导致了新的诊断和治疗策略 用于管理病理愤怒和侵略。